Human genetics, concepts and applications 5th ed lewis (mcgraw, 2003)

They include: • A breast cancer DNA “chip” that predicts which drugs will work on which women chapter 1 • Greatly expanded coverage of stem cells chapters 2 and 3 • Relationship between

Very few events in human history can besaid, in retrospect, to divide time September

11, 2001, is one such date

I was revising this edition on thatbright and clear Tuesday morning, lookingforward to penning an upbeat preface cele-brating the human genome annotation pro-ceeding in various laboratories It was not to

be Now as I write this, the largest such lab isinstead applying the high-throughput DNAsequencing that it used to sequence the hu-man genome to analyzing thousands of bits

of teeth and bones that arrive daily in dence bags Somber lab workers are extract-ing the mitochondrial DNA that persists af-ter the genetic material of softer tissues isobliterated by fire and crushing pressure

evi-Earlier, closer to that date that divided time,DNA fingerprinters at another biotechcompany probed softer samples shippedfrom the wreckage, along with cheekbrushsamples bearing DNA from relatives, andbits of skin and hair left clinging to tooth-brushes and hairbrushes and clothing on aday that everyone thought would be like anyother It was an astonishing and horrifyingcontrast to the depiction of DNA finger-printing in the first chapter of the fourthedition of this book—tracing the ancestry

of wine grapes

Times have changed

With DNA sequencing subverted to apurpose that no one could have predicted,revising a textbook didn’t, at first, seem veryimportant anymore But in the weeks thatfollowed September 11, as the belatedrecognition and response to bioterrorismexposed a frighteningly pervasive lack ofknowledge of basic biology among ourleaders, the importance of the average citi-zen’s understanding of what genes are andwhat they do emerged At the same time,new questions arose Should researchers

continue to publish new genome sequences?Suddenly, those wondrous reports of unex-pected gene discoveries mined from micro-bial genomes held the seeds of potentialweaponry

Times have changed

Before September 11, politicians hotlydebated stem cells, renegade scientiststouted their human cloning efforts, and en-vironmentalists donned butterfly suits anddestroyed crops to protest the perceivedthreat of corn genetically altered to escapethe jaws of caterpillars Gene therapy strug-gled to regain its footing in the wake of atragic death in 1999, while a spectacularlysuccessful new cancer drug, based on ge-netic research, hit the market With time, in-terest in these areas will return, and maybe

we will even begin to care again about the

ancestry of wine grapes Human Genetics: Concepts and Applications, fifth edition will

guide the reader in understanding geneticsand genomics and applying it to daily life.That has not changed

What’s New and Exciting About This Edition

Focus on Genomics—Of SNPs, Chips, and More

While Mendel’s laws, the DNA double lix, protein synthesis and population dy-namics will always form the foundation ofgenetics, the gradual shift to a genomicview opens many new research doors, andintroduces new ways of thinking aboutourselves Completion of the humangenome draft sequence has catapulted hu-man genetics from the one-gene-at-a-timeapproach of the last half of the last century

he-to a more multifache-torial view Genes andthe environment interact to mold who weare It is a little like jumping from listeningPreface

to individual instruments to experiencing a

symphony created by an entire orchestra

The fourth edition of Human Genetics:

Concepts and Applications introduced

geno-mics; in the fifth edition, the impact of this

new view of genes is so pervasive that it is

integrated into many chapters, rather than

saved for a final chapter Rather than

blud-geon the reader with details, acronyms and

jargon, the approach to genomics is in

con-text—association studies in chapter 7,

hu-man genome annotation in chapter 10,

fill-ing in chromosome details in chapter 12,

and glimpses into human evolution in

chapter 15 Immunity is presented in

chap-ter 16 from the point of view of the

pathogen, courtesy of genomes Because of

the integration of the genomic view

throughout the text, the final chapter is free

to tell the story of how this view came to

be—and where it will go

New Chapter on Behavior

The evolution of genetic thought, from a

Mendelian paradigm to a much broader

consideration of genes against a backdrop

of environmental influences, is perhaps

nowhere more evident than in the study of

human behavior With each edition,

cover-age of behavior has expanded until, like a

cell accumulating cytoplasm, a division was

in order The resulting binary fission of the

fourth edition’s chapter 7—Multifactorial

and Behavioral Traits—naturally yielded a

chapter on methods and basic concepts, and

another on specific interesting behaviors

Chapter 7 in this fifth edition,

Multi-factorial Traits, retains the classical

adoption/twin/empiric risk approaches,

and introduces association studies, which

are critical in analyzing the traits and

disor-ders described in depth in chapter 8, The

Genetics of Behavior

The topics for chapter 8 came from two

general sources—my curiosity, and

infor-mation from several human genome

con-ferences held since 2000 The chapter opens

with a focus on new types of evidence about

the role of genes in behavior, then applies

these new tools to dissect the genetic

Fabulous New Art

Long-time users of Human Genetics:

Concepts and Applications will note at a

glance that all of the art is new Vibrant newcolors and closer attention to clarity of con-cepts ease the learning experience and makestudying this complex subject less intimi-dating Some of the figures are also available

as Active Art, which enables the learner tomanipulate portions of the illustration toreview the steps to a process Entirely new il-lustrations include:

7.11 Association studies arecorrelations of SNP profiles8.6 How alcohol alters geneexpression in the brain10.18 One prion, multipleconformations10.19 Proteomics meets medicine10.20 Exon shuffling expands gene number10.21 Genome economy occurs inseveral ways

11.12 Myotonic dystrophies—novelmutation mechanism12.4 Subtelomeres15.8 A human HOX mutation causessynpolydactyly

15.11 Probing the molecules of extinctorganisms

16.19 M cells set up immunity in thedigestive tract

19.1,2,3 Three gene therapies20.9 The global GM foods picture22.4 Two routes to the human genomesequence

22.9 Genome sequencing, from start tofinish

22.10 Comparative genomicsSeveral new photos put faces on geneticdiseases

Tables Tell the Tale

A student reviewing for an impending examshould be able to get the gist of a chapter in

10 minutes by examining the tables—if thetables are appropriately chosen and pre-

sented, as they are in this book Table 8.5, forexample, reviews every behavioral trait ordisorder discussed in this new chapter, inthe order of the subsections

Most tables summarize and organizefacts, easing studying A few tables add in-formation (table 12.1 Five Autosomes, table14.1 Founder Populations; table 16.8Sequenced Genomes of Human Pathogens),and some provide perspective (table 1.1Effects of Genes on Health) Chapter 10,Gene Action and Expression, a top candi-date for “toughest chapter,” illustrates howthe tables tell the tale:

Table 10.1 How RNA and DNA DifferTable 10.2 Major Types of RNATable 10.3 Deciphering RNA Codons

and the Amino Acids TheySpecify

Table 10.4 The Genetic CodeTable 10.5 The Non-protein Encoding

Parts of the GenomeThe final table in chapter 10 is new, a sum-mary of answers to the question, certain to

be posed by students and instructors alike,

“If less than 2 percent of the genome codes protein, what does the rest of it do?”This is a table that will obviously evolvewith each edition as we learn more

en-New “In Their Own Words” and Bioethics Boxes

“In Their Own Words” essays are written by

individuals who experience inherited ease, as patients, family members, or re-searchers New essays in the fifth editionintroduce:

dis-• Patricia Wright, who only recentlydiscovered that she has had signs andsymptoms of alkaptonuria all her life.(chapter 5)

• Francis Barany, a microbiologist whonearly burned his leg off searching forheat-loving bacteria with usefulenzymes in a Yellowstone Park hotsprings (chapter 9)

• Toby Rodman, an immunologist andoctogenarian who discovered a newsource of antibodies that may protectagainst HIV infection (chapter 16)They join from past editions Don Miller, thefirst recipient of gene therapy for hemo-philia; Stefan Schwartz, who has Klinefelter

disease, and Kathy Naylor, whose little girl

died of cri-du-chat syndrome

Bioethics: Choices for the Future essays

continue their look at controversies that

arise from genetic technology These essays

explore population databases (chapter 1),

cloning and stem cell research (chapter 3),

sex reassignment (chapter 6),

xenotrans-plants (chapter 16), Canavan disease as a

test of fair use of genetic tests (chapter 19)

and GM foods (chapter 20) Bioethical

is-sues weave throughout the narrative as well

New section 21.4, for example, examines the

dilemma of what to do with in vitro

fertil-ized “spares.”

Significant Changes

in Content

The two obvious changes in content are the

addition of a chapter devoted to behavior,

and a substantial new section in chapter 10,

“The Human Genome Sequence Reveals

Unexpected Complexity.” This section is

es-sentially a summary of the mid-February

2001 issues of Science and Nature, which

cov-ered the annotation of the draft human

genome sequence, aka “the golden path.” The

rest of the chapter has been rewritten to

em-brace the new genome information as well

Favorite examples and stories have

been retained, and new ones added, many

gleaned from my articles in The Scientist.

They include:

• A breast cancer DNA “chip” that

predicts which drugs will work on

which women (chapter 1)

• Greatly expanded coverage of stem

cells (chapters 2 and 3)

• Relationship between Mendel’s second

law and DNA microarrays (chapter 4)

• Clearer coverage of mitochondrial

genes (chapter 5)

• Moved and expanded coverage of DNA

repair (chapter 11)

• Updates on chromosome structure

with new coverage of centromeres and

subtelomeres (chapter 12)

• Applications of DNA fingerprinting to

events of 9-11-01 (chapter 13)

• New coverage of genetic basis of

resistance to AIDS drugs (chapter 14)

• New section on genome distinctions

between humans and chimps

(chapter 15)

• Genome information applied toimmunity, with new sections on crowddiseases, bioweapons, and pathogengenomes (chapter 16)

• Genetic modification of pig excrement

to reduce pollution (chapter 18)

• Gene therapy for Canavan disease(chapter 19)

• Impact of genomics on agriculturalbiotechnology (chapter 20)

• History of the human genome project(chapter 22)

Supplements

As a full service publisher of quality cational products, McGraw-Hill doesmuch more than just sell textbooks toyour students We create and publish anextensive array of print, video, and digitalsupplements to support instruction onyour campus Orders of new (versus used)textbooks help us to defray the cost of de-veloping such supplements, which is sub-stantial Please consult your localMcGraw-Hill representative to learn aboutthe availability of the supplements that ac-

edu-company Human Genetics: Concepts and Applications.

For the Student

Online Learning Center Get online

at www.mhhe.com/lewisgenetics5Explore this dynamic site designed tohelp you get ahead and stay ahead in yourstudy of human genetics Some of the activ-ities you will find on the website include:

Self-quizzes to help you master material ineach chapter

Flash cards to ease learning of newvocabulary

Case Studies to practice application of yourknowledge of human genetics

Links to resource articles, popular presscoverage, and support groups

Genetics: From Genes to Genomes CD-ROM This easy-to-use CD covers themost challenging concepts in the course andmakes them more understandable throughpresentation of full-color animations andinteractive exercises Icons in the text indi-cate related topics on the CD

Case Workbook in Human Genetics,

third edition by Ricki Lewis, ISBN 246274-4 This workbook is specifically de-

0-07-signed to support the concepts presented in

Human Genetics through real cases adapted

from recent scientific and medical journals,with citations included With cases nowspecifically related to each chapter in the book,the workbook provides practice for construct-ing and interpreting pedigrees; applyingMendel’s laws; reviewing the relationships ofDNA, RNA, and proteins; analyzing the effects

of mutations; evaluating phenomena that tort Mendelian ratios; designing gene thera-pies; and applying new genomic approaches

dis-to understanding inherited disease An

Answer Key is available for the instructor.

For the Instructor

Online Learning Center Find plete teaching materials online atwww.mhhe.com/lewisgenetics5 including:

com-A complete Instructor’s Manual,

pre-pared by Cran Lucas of Louisiana StateUniversity, is available online Downloadthe complete document or use it as a chap-ter resource as you prepare lectures or ex-ams Features of the manual include:Chapter outlines and overviewsChapter-by-chapter resource guide to use

of visual supplementsAnswers to questions in the textAdditional questions and answers for eachchapter

Internet resources and activities

Downloadable Art is provided foreach chapter in jpeg format for use in classpresentations or handouts In this edition,every piece of art from the text is provided

as well as every table, and a number of tographs

pho-Instructors will also find a link to

Pageout: The Course Website Development Center to create your own course website.

Pageout’s powerful features help create acustomized, professionally designed website,yet it is incredibly easy to use There is noneed to know any coding Save time andvaluable resources by typing your course in-formation into the easy-to-follow templates

Test Item File Multiple choice tions and answers that may be used in test-

Many heartfelt thanks to Deborah Allen for

guiding yet another edition of this, my

fa-vorite book, and to Joyce Berendes and

Carol Kromminga and the superb artists at

Precision Graphics for making this book

possible Many thanks also to my wonderful

family, cats, guinea pigs, and Speedy the

re-located tortoise

Reviewers

Many improvements in this edition are a

di-rect result of the suggestions from reviewers

and diarists who provided feedback for this

edition and previous editions of Human

Genetics: Concepts and Applications To each

of them, a sincere thanks We also thank the

students in Ruth Sporer’s Human Genetics

class at the University of Pennsylvania for

their review of the fourth edition, Ivan E

Leigh of West Chester, Pennsylvania for his

careful review of the manuscript from the

perspective of a mature student, and Clifton

Poodry, Director of Minority Opportunities

in Research Division of NIH, for his advice

about handling issues of diversity and ference with sensitivity throughout thebook

dif-Reviewers for This Edition

Western Connecticut State University

Reviewers for Previous Editions

University of Arkansas at Little Rock

ing are provided for each chapter Prepared

by Cran Lucas of Louisiana State University,

this resource covers the important concepts

in each chapter and provides a variety of

levels of testing The file is available through

PageOut and is also available on a

cross-platform CD to adopters of the text

Overhead Transparencies A set of

100 full-color transparencies showing key

illustrations from the text is available for

adopters Additional images are available

for downloading from the text website

Digital Content Manager New to

this edition is an instructor’s CD containing

a powerful visual package for preparing

your lectures in human genetics On this

CD, you will find:

All Text Art in a format compatible with

presentation or word processing software

Powerpoint Presentations covering each

chapter of the text

New Active Art! Build images from simple

to complex to suit your lecture style

Mary Beth Curtis

Tulane University

Ann Marie DiLorenzo

Montclair State College

North Carolina State University

Mary Rengo Murnik

Ferris State University

Southern Illinois University at Carbondale

Michael James Patrick

Seton Hill College

Portland Community College

Georgia Floyd Smith

Arizona State University

1.1 A Look Ahead

Testing for inherited diseases and

susceptibilities will become standard

practice as health care becomes

increasingly individualized Tests that

detect specific variations in genetic

material will enable physicians to select

treatments that a person can tolerate

and that are the most likely to be

effective

1.2 From Genes to Genomes

DNA sequences that constitute genes

carry information that tells cells how to

manufacture specific proteins A gene’s

effects are evident at the cell, tissue,

organ, and organ system levels Traits

with large inherited components can be

traced and predicted in families

Genetic change at the population level

underlies evolution Comparing

genomes reveals that humans have

much in common with other species

1.3 Genes Do Not Usually Function Alone

In the twentieth century, genetics dealtalmost entirely with single-gene traitsand disorders Today it is becomingclear that multiple genes and theenvironment mold most traits

1.4 Geneticists Use Statistics

to Represent Risks

Risk is an estimate of the likelihood that

a particular individual will develop aparticular trait It may be absolute for anindividual, or relative based on

comparison to other people

1.5 Applications of Genetics

Genetics impacts our lives in diverseways Genetic tests can establishidentities and diagnose disease Geneticmanipulations can provide new

Genetics is the study of inherited variation

and traits Sometimes people confuse

genet-ics with genealogy, which considers

rela-tionships but not traits With the advent of

gene-based tests that can predict future

dis-ease symptoms, some have even compared

genetics to fortune telling! But genetics is

neither genealogy nor fortune telling—it is

a life science Although genetics is often

as-sociated with disease, our genes provide a

great variety of characteristics that create

much of our individuality, from our hair

and eye color, to the shapes of our body

parts, to our talents and personality traits

Genes are the units of heredity, the sets

of biochemical instructions that tell cells,

the basic units of life, how to manufacture

certain proteins These proteins ultimately

underlie specific traits; a missing protein

blood-clotting factor, for example, causes

the inherited disease hemophilia A gene is

composed of the molecule

deoxyribonu-cleic acid, more familiarly known as DNA.

Some traits are determined nearly entirely

by genes; most traits, however, have

consid-erable environmental components The

complete set of genetic information

charac-teristic of an organism, including

protein-encoding genes and other DNA sequences,

constitutes a genome.

Genetics is unlike other life sciences in

how directly and intimately it affects our

lives It obviously impacts our health,

be-cause we inherit certain diseases and disease

susceptibilities But principles of genetics

also touch history, politics, economics,

soci-ology, and psychsoci-ology, and they force us to

wrestle with concepts of benefit and risk,

even tapping our deepest feelings about

right and wrong A field of study called

bioethics was founded in the 1970s to

ad-dress many of the personal issues that arise

in applying medical technology Bioethicists

have more recently addressed concerns that

new genetic knowledge raises, issues such as

privacy, confidentiality, and discrimination

An even newer field is genomics, which

considers many genes at a time The

ge-nomic approach is broader than the

empha-sis on single-gene traits that pervaded

ge-netics in the twentieth century It also

enables us to compare ourselves to other

species—the similarities can be astonishing

and quite humbling!

New technology has made genomics

pos-sible Researchers began deciphering genomes

cause several of her relatives developed thiscondition as adults She knows that medica-tion can control the abnormal blood glu-cose level, but that dietary and exerciseplans are essential, too If she knows she is athigh risk of developing the condition, she’lladopt these habits right away However,Laurel refuses a test for inherited suscepti-bility to Alzheimer disease, even though agrandfather died of it She does not want toknow if this currently untreatable condition

is likely to lie in her future Because pastblood tests revealed elevated cholesterol,Laurel seeks information about her risk ofdeveloping traits associated with heart andblood vessel (cardiovascular) disease.Each student proceeds through thesteps outlined in figure 1.1 The first step is

to register a complete family history Next,each young woman swishes a cotton swab

on the inside of her cheek to obtain cells,which are then sent to a laboratory foranalysis There, DNA is extracted and cutinto pieces, then tagged with molecules thatfluoresce under certain types of light Thestudents’ genetic material is then applied to

“DNA chips,” which are small pieces of glass

or nylon to which particular sequences ofDNA have been attached Because the genes

on the chip are aligned in fixed positions,this device is also called a DNA microarray

A typical DNA microarray bears dreds or even thousands of DNA pieces One

hun-of Mackenzie’s DNA chips bears genes thatregulate her circadian (daily) rhythms andencode the receptor proteins on nerve cellsthat bind neurotransmitters If Mackenzieencounters addictive substances or activities

in the future, having certain variants of thesegenes may increase her risk of developingaddictive behaviors Another DNA chipscreens for gene variants that greatly in-crease risk for lung cancer, and a third DNAchip detects genes associated with colon can-cer Her fourth DNA chip is smaller, bearingthe genes that correspond to four types ofinherited Alzheimer disease

Laurel’s chips are personalized to suither family background and specific re-quests The microarray panel for CF isstraightforward—it holds 400 DNA se-quences corresponding to variants of the CFgene known to be associated with themilder symptoms that appear in Laurel’sfamily The microarray for diabetes bearsgene variants that reflect how Laurel’s body

in 1995, starting with a common bacterium

Some three dozen genome projects later, by

2000, a private company and an international

consortium of researchers added Homo sapiens

to the list, with completion of a “first draft”

sequence of the human genome The genomes

of more than 100 species have been sequenced

It will take much of the new century tounderstand our genetic selves Following is aglimpse of how two young people might en-counter genomics in the not-too-distant fu-ture All of the tests mentioned already exist

The year is 2005 Human genomics has notyet progressed to the point that newbornsundergo whole-genome screens—that isstill too expensive—but individuals can takeselected gene tests tailored to their healthhistories Such tests can detect gene variantsthat are associated with increased risk of de-veloping a particular condition Young peo-ple sometimes take such tests—if they wantto—when there are ways to prevent, delay,

or control symptoms Consider two year-old college roommates who choose toundergo this type of genetic testing

19-Mackenzie requests three panels oftests, based on what she knows about herfamily background An older brother andher father smoke cigarettes and are prone toalcoholism, and her father’s mother, also asmoker, died of lung cancer Two relatives

on her mother’s side had colon cancer

Mackenzie also has older relatives on bothsides who have Alzheimer disease She asksfor tests to detect genes that predispose her

to developing addictions, certain cancers,and inherited forms of Alzheimer disease

Laurel, Mackenzie’s roommate, quests a different set of tests, based on herfamily history She has always had frequentbouts of bronchitis that often progress topneumonia, so she requests a test for cysticfibrosis (CF) Usually a devastating illness,

re-CF has milder forms whose symptoms areincreased susceptibility to respiratory infec-tions These cases often go unrecognized as

CF, as Laurel knows from reading a journalarticle for a biology class last year Becauseher sister and mother also get bronchitis of-ten, she suspects mild CF in the family

Laurel requests tests for type II insulin-dependent) diabetes mellitus, be-

(non-handles glucose transport and uptake into

cells The DNA microarray for

cardiovascu-lar disease is the cardiovascu-largest and most diverse It

includes thousands of genes whose protein

products help to determine and control

blood pressure, blood clotting, and the

syn-thesis, transport, and metabolism of

choles-terol and other lipids

A few days later, the test results are in,

and a very important part of the process

occurs—meeting a genetic counselor, who

explains the findings Mackenzie learns that

she has inherited several gene variants that

predispose her to addictive behaviors and

to developing lung cancer—a dangerouscombination But she does not have genesthat increase her risk for inherited forms

of colon cancer or Alzheimer disease

Mackenzie is relieved She knows to avoidalcohol and especially smoking, but is reas-sured that her risks of inherited colon can-cer and Alzheimer disease are no greaterthan they are for the general population—

in fact, they are somewhat less

Laurel finds out that she indeed has amild form of cystic fibrosis The microarrayalso indicates which types of infections she ismost susceptible to, and which antibiotics

will most effectively treat her frequent sodes of bronchitis and pneumonia Shemight even be a candidate for gene therapy—periodically inhaling a preparation contain-ing the normal version of the CF-causinggene engineered into a “disabled” virus thatwould otherwise cause a respiratory infec-tion The diabetes test panel reveals a riskthat is lower than that for the general popula-tion Laurel also learns she has several genevariants that raise her blood cholesterol level

epi-By following a diet low in fat and high infiber, exercising regularly, and frequentlychecking her cholesterol levels, Laurel can

Step 1: Research and record family history

Step 2: Provide cell sample

Step 3: Sample DNA isolated and applied to personalized DNA chips

Step 4: Results calculated, communicated

Type II diabetes mellitus

Cystic fibrosis 100% diagnosis

Less than general population Cardiovascular

disease

Greater than general population

help keep her heart and blood vessels

healthy On the basis of the cardiovascular

disease microarray panel, her physician can

also tell which cholesterol-lowering drug she

will respond to best, should lifestyle changes

be insufficient to counter her inherited

ten-dency to accumulate cholesterol and other

lipids in the bloodstream

The DNA microarray tests that

Mac-kenzie and Laurel undergo will become part

of their medical records, and tests will be

added as their interests and health status

change For example, shortly before each

young woman tries to become pregnant, she

and her partner will take prenatal DNA

mi-croarray panels that detect whether or not

they are carriers for any of several hundred

illnesses, tailored to their family

back-grounds and ethnic groups Carriers can

pass an inherited illness to their offspring

even when they are not themselves affected

If Laurel, Mackenzie or their partners carry

inherited conditions, DNA microarray tests

can determine whether their offspring

in-herit the illness

Impending parenthood isn’t the only

reason Laurel and Mackenzie might seek

ge-netic testing again If either young woman

suspects she may have cancer, for example,

DNA microarrays called expression panels

can determine which genes are turned on or

off in affected cells compared to

nonaf-fected cells of the same type Such

informa-tion can identify cancer cells very early,

when treatment is more likely to work

These devices also provide information on

how quickly the disease will progress, and

how tumor cells and the individual’s

im-mune system are likely to respond to

partic-ular drugs A DNA microarray can reveal

that a particular drug will produce

intolera-ble side effects before the patient has to

ex-perience that toxicity

The first DNA microarray to analyze

cancer, the “lymphochip,” was developed

before completion of the human genome

project It identifies cancer-causing and

as-sociated genes in white blood cells A

differ-ent DNA microarray test, for breast cancer,

is used on samples of breast tissue to track

the course of disease and assess treatment

The “chip” was featured on a cover of

Nature magazine with the headline,

“por-trait of a breast cancer.” In one experiment,

DNA microarray tests were performed on

tumor cells of 20 women with advanced

breast cancer before and after a 3-monthregimen of chemotherapy The gene pat-tern returned to normal only in the threewomen who ultimately responded to thetreatment, demonstrating the test’s predic-tive power

Though Laurel and Mackenzie will gainmuch useful information from the genetictests, their health records will be kept confi-dential Laws prevent employers and insur-ers from discriminating against anyonebased on genetic information This is apractical matter—everyone has some genevariants that are associated with disease

With completion of the humangenome project, the medical world is ex-ploding with new information One com-pany has already invented a five-inch byfive-inch wafer that houses up to 400 DNAmicroarrays, each the size of a dime andcontaining up to 400,000 DNA pieces

New health care professionals are beingtrained in genetics and the new field of ge-nomics; older health care workers are alsolearning how to integrate new geneticknowledge into medical practice Anotherchange is in the breadth of genetics In thepast, physicians typically encountered ge-netics only as rare disorders caused by singlegenes, such as cystic fibrosis, sickle cell dis-ease, and muscular dystrophy, or chromo-some disorders, such as trisomy 21 Downsyndrome Today, medical science is begin-ning to recognize the role that genes play inmany types of conditions (table 1.1)

A study of the prevalence of geneticdisorders among 4,224 children admitted toRainbow Babies and Children’s Hospital inCleveland in 1996 revealed that genes con-

tribute much more to disease than manymedical professionals had thought Nearlythree-quarters of the children, admitted for

a variety of problems, had an underlying netic disorder or susceptibility Specifically,

ge-35 percent had clearly genetic conditions(the first two entries in table 1.1); 36.5 per-cent had an underlying condition with a ge-netic predisposition, such as asthma, cancer,

or type 1 diabetes mellitus; and the rest werehospitalized for an injury or had no under-lying disease

t a b l e 1.1

Effects of Genes on Health

Type of Disorder or Association Example Chapter

Complex (multifactorial) disorder Diabetes mellitus 3, 7, 8

Single nucleotide polymorphisms (SNPs) Associated with various 7, 8, 22

conditions in different populations

Genetics investigates inherited traits andtheir variations Genes, composed ofDNA, are the units of inheritance, andthey specify particular proteins Not allDNA encodes protein A genome is thecomplete genetic instructions for anorganism Human genome informationwill personalize medicine and predict future illness

of our trillions of cells contains two sets

of chromosomes, each set a copy of thegenome Cells interact and aggregate into

tissues, which in turn combine to form

organs and organ systems At the family

level, inherited disease may be evident

Finally, genetic changes in populations

un-derlie evolution

DNA

Genes consist of sequences of four types of

DNA building blocks—adenine, guanine,

cytosine, and thymine, abbreviated A, G, C,

and T Each base bonds to a sugar and a

phosphate group to form a unit called a

nucleotide DNA bases are also called

ni-trogenous (nitrogen-containing) bases In

genes, DNA bases provide an alphabet of

sorts Each three DNA bases in a row

speci-fies the code for a particular amino acid,

and amino acids are the building blocks of

proteins

An intermediate language also encoded

in nitrogenous bases is contained in

ribo-nucleic acid (RNA) One type of RNA

car-ries a copy of a DNA sequence and presents

it to other parts of the cell In this way, the

information encoded in DNA can be used

to produce RNA molecules, which are then

used to manufacture protein DNA remains

in the nucleus to be passed on when a cell

divides Only about 1.5 percent of the DNA

in the human genome encodes protein

Researchers have not yet discovered the

function of much of the rest, but they are

learning more as they analyze genome

in-formation Similarly, not all functions of

RNA are understood The definition of

“gene” has changed over the past half

cen-tury to embrace new knowledge It might be

most accurate, in light of all that remains to

be learned from human genome

informa-tion, to define a gene as a sequence of DNA

that has a known function

Gene

Individual genes come in variants that differ

from each other by small changes in the

DNA base sequence The variants of a gene

are called alleles, and these changes in DNA

sequence arise by a process called mutation.

Some mutations are harmful, causing

dis-ease; others provide variation, such as

freck-led skin; and some mutations may actually

be helpful In some people, for example, a

rare mutation renders their cells unable to

bind HIV, making them resistant to HIV

in-fection This genetic variant would probablyhave remained unknown had AIDS notarisen Many mutations have no visible ef-fect at all because they do not change theencoded protein in a way that affects itsfunction, just as a minor spelling error doesnot destroy the meaning of a sentence

Parts of the DNA sequence can varyamong individuals, yet not change externalappearance or health A variant in sequencethat is present in at least 1 percent of a pop-

ulation is called a polymorphism A

poly-morphism can occur in a part of the DNAthat encodes protein, or in a part that doesnot encode protein

“Polymorphism” is a general term thatliterally means “many forms.” It includesdisease-causing variants The terminologycan be somewhat confusing A mutation isactually a type of polymorphism A poly-morphism can be helpful, harmful, or, inmost instances, have no effect at all (that weknow of) The term polymorphism hasbeen part of the language of genetics fordecades, but has recently begun to attract agreat deal of attention from other fields,such as information technology and medi-cine This is because of the realization thatpolymorphisms can be used in DNA micro-array panels to predict risks of developingspecific medical conditions

Researchers have identified more than

3 million single nucleotide

polymor-phisms (SNPs, pronounced “snips”) SNPs

are single base sites that differ among viduals The human genome may include

indi-up to 20 million SNPs, or 1 in every 1,250 or

so DNA nucleotides, although they are notevenly distributed DNA microarrays in-clude both disease-causing mutations andSNPs that merely mark places where peoplediffer A technique called an associationstudy examines DNA variants in popula-tions and detects particular combinations

of SNPs that are found almost exclusivelyamong people with a particular disorder,but not otherwise

Chromosome

Genes are part of larger structures called

chromosomes, which also include proteins

that the DNA wraps around A human cellhas 23 pairs of chromosomes Twenty-two

pairs are autosomes, or chromosomes that

do not differ between the sexes The

auto-somes are numbered from 1 to 22, with 1being the largest The other two chromo-

somes, the X and the Y, are sex

chromo-somes The Y chromosome bears genes that

determine maleness In humans, lacking a Ymakes one a female

Missing even small portions of a mosome has a devastating effect on health,because many genes are deleted To detectchromosome abnormalities, geneticists use

chro-charts called karyotypes that order the

chromosome pairs from largest to smallest.The chromosomes are stained with dyes orfluorescent chemicals that create differentpatterns to highlight abnormalities (seefigure 1.2)

Genome

The 46 chromosomes in a human cell holdtwo complete sets of genetic information, ortwo copies of each chromosome type Thehuman genome probably contains from28,000 to 34,000 protein-encoding genes,scattered among three billion DNA basesamong each set of 23 chromosomes.(Higher estimates may count repeated genesmore than once.) Two entire genomes aretucked into each of a person’s many, manycells As noted geneticist Hermann J Mullerwrote in 1947, “In a sense we contain our-selves, wrapped up within ourselves, tril-lions of times repeated.”

Cells, Tissues, and Organs

A human body consists of trillions of cells.Most cells contain all of the genetic instruc-tions, but cells differ in appearance and func-tion by using only some of their genes, in a

process called differentiation Specialized

cells with related functions aggregate andinteract to form tissues, which in turn formthe organs and organ systems of the indi-vidual Organs also include less specialized

cells, called stem cells, that retain the ability

to differentiate further, should the needarise—perhaps when an injury requires thatcertain cells be replaced Some repositories

of these replenishing stem cells, includingthose in the brain, have only recently beendiscovered Others, such as the bone mar-row cells that continually replenish theblood, are better known A new field calledregenerative medicine uses stem cells to re-place degenerating cells that cause condi-

tions such as Parkinson disease and

Hunt-ington disease

Individual

Two terms distinguish between the alleles

that are present in an individual and the

al-leles that are expressed The genotype refers

to the underlying instructions (alleles

pres-ent), and the phenotype is the visible trait,

biochemical change, or effect on health

(al-leles expressed) Al(al-leles are further

distin-guished by how many copies it takes to

af-fect the phenotype A dominant allele

produces an effect when present in just one

copy (on one chromosome), whereas a

re-cessive allele must be present on both

chro-mosomes to be expressed (Alleles on the Y

chromosome are an exception; recessive

al-leles on the X chromosome in males are

ex-pressed because there is no second X

chro-mosome to block expression.)

Family

Individuals are genetically connected into

families Traditionally, the study of traits in

families has been called transmission genetics

or Mendelian genetics Molecular genetics,

which considers DNA, RNA, and proteins,

often begins with transmission genetics,

when an interesting trait or illness in a family

comes to a researcher’s attention Charts

called pedigrees are used to represent the

members of a family and to indicate which

individuals have particular inherited traits

Figure 1.2 shows a pedigree, but an unusual

one—a family with identical triplets

Population

Above the family level of genetic

organiza-tion is the populaorganiza-tion In a strict biological

sense, a population is a group of

interbreed-ing individuals In a genetic sense, a

popula-tion is a large collecpopula-tion of alleles,

distin-guished by the frequency of particular

alleles People from Sweden, for example,

would have a greater frequency of alleles

that specify light hair and skin than people

from a population in Ethiopia who tend to

have dark hair and skin The fact that

groups of people look different and may

suffer from different health problems

re-flects the frequencies of their distinctive sets

of alleles All the alleles in a population

con-stitute the gene pool (An individual does

not have a gene pool.)Population genetics is very important

in applications such as health care andforensics It is also the very basis of evolu-tion In fact, evolution is technically defined

as “changing allele frequencies in tions,” as the chapters in part 4 describe

popula-These small-scale genetic changes foster themore obvious species distinctions most of-ten associated with evolution

Evolution

Geneticists have known for decades thatcomparing DNA sequences for individualgenes, or the amino acid sequences of theproteins that the genes encode, can revealhow closely related different types of organ-isms are The underlying assumption is thatthe more similar the sequences are, themore recently two species diverged from ashared ancestor Figure 15.7 shows suchanalysis for cytochrome C, a protein essen-tial for extracting energy from nutrients

Genomewide studies are even morestartling than comparing single genes

Humans, for example, share more than 98percent of the DNA sequence with chim-panzees Our genomes differ more in the or-ganization of genes and in the number ofcopies of genes than in the overall sequence

Still, learning the functions of the specific genes may explain the anatomicaldifferences between us and them Our kin-ship with other species extends much far-ther back in time than to chimpanzees, whoare in a sense our evolutionary first cousins

human-Humans also share many DNA sequenceswith pufferfish, fruit flies, mice, and evenbacteria At the level of genetic instructionsfor building a body, we are not very differentfrom other organisms

Comparisons of person to person at thegenome level reveal more sameness—we areincredibly like one another DNA sequencesimilarity among humans exceeds 99.9 per-cent Studies of polymorphisms among dif-ferent modern ethnic groups reveal thatmodern humans arose and came out ofAfrica and haven’t changed very muchsince The gene pools of all groups are sub-sets of the modern African gene pool

Genome analyses also confirm what gists have maintained for many years—thatrace is a social concept, not a biological one

biolo-“Race” is actually defined by fewer than 0.01percent of our genes Put another way, twomembers of different races may in fact havemore genes in common than two members

of the same race Very few, if any, gene ants are unique to any one racial or ethnicgroup Imagine if we defined race by a dif-ferent small set of genes, such as the ability

vari-to taste bitter substances!

Table 1.2 defines some of the termsused in this section

Genetics can be considered at differentlevels: DNA, genes, chromosomes,genomes, individuals, families, andpopulations • A gene can exist in morethan one form, or allele • Comparinggenomes among species revealsevolutionary relatedness

Function Alone

For much of its short history, the field of netics dealt almost exclusively with the thou-sands of traits and illnesses that are clearly

ge-determined by single genes These

Men-delian traits are named for Gregor Mendel,

who derived the laws of gene transmission

by studying single-gene traits in peas (thetopic of chapter 4) A compendium called

“Mendelian Inheritance in Man” has, fordecades, listed and described all knownsingle-gene traits and disorders in humans.The computerized version, “Online Men-delian Inheritance in Man,” is today a terrificresource “OMIM” numbers are listed at theend of each chapter for disorders men-tioned in the narrative Sequencing the hu-man genome, however, has revealed redun-dant entries in lists of single-gene disorders,whose actual number may be as low as1,100 For some genes, OMIM lists differentallele combinations as distinct disorders,such as different types of anemia that resultfrom mutations in the same gene

Genetics is far more complicated than aone-gene-one-disease paradigm Most genes

do not function alone, but are influenced bythe actions of other genes, and sometimes byfactors in the environment as well Traits

with several determinants are called

multi-factorial, or complex, traits (The term

complex traits has different meanings in a

scientific and a popular sense, so this book

uses the more precise term multifactorial.)

Table 1.3 lists some Mendelian and factorial conditions, and figure 1.3 gives anexample of each Confusing matters evenfurther is the fact that some illnesses occur

multi-in different forms—some multi-inherited, some

not, some Mendelian, some multifactorial.Usually the inherited forms are rarer, as isthe case for Alzheimer disease, breast can-cer, and Parkinson disease

Researchers can develop treatmentsbased on the easier-to-study inherited form

of an illness, which can then be used to treatmore common, multifactorial forms Forexample, the statin drugs that millions ofpeople take to lower cholesterol were devel-oped from work on children with familialhypercholesterolemia, which affects one in amillion individuals (see figure 5.2).Knowing whether a trait or illness is in-herited in a Mendelian or multifactorialmanner is important for predicting recur-rence risk The probability that a Mendeliantrait will occur in another family member issimple to calculate using the laws thatMendel derived In contrast, predicting therecurrence of a multifactorial trait is diffi-cult because several contributing factors are

at play Inherited breast cancer illustrateshow the fact that genes rarely act alone cancomplicate calculation of risk

t a b l e 1.2

A Mini-Glossary of Genetic Terms

Allele An alternate form of a gene; a gene variant

Autosome A chromosome not normally involved in determining sex

Chromosome A structure, consisting of DNA and protein, that carries the genes

DNA Deoxyribonucleic acid; the molecule whose building block sequence encodes the information that a cell uses to

construct a particular protein

Dominant An allele that exerts a noticeable effect when present in just one copy

Gene A sequence of DNA that has a known function, such as encoding protein or controlling gene expression

Gene pool All of the genes in a population

Genome A complete set of genetic instructions in a cell, including DNA that encodes protein as well as other DNA

Genomics The new field of investigating how genes interact, and comparing genomes

Genotype The allele combination in an individual

Karyotype A size-order display of chromosomes

Mendelian trait A trait that is completely determined by a single gene

Multifactorial trait A trait that is determined by one or more genes and by the environment Also called a complex trait

Mutation A change in a gene that affects the individual’s health, appearance, or biochemistry

Pedigree A diagram used to follow inheritance of a trait in a family

Phenotype The observable expression of an allele combination

Polymorphism A site in a genome that varies in 1 percent or more of a population

Recessive An allele that exerts a noticeable effect only when present in two copies

RNA Ribonucleic acid; the chemical that enables a cell to synthesize proteins using the information in DNA sequences.Sex chromosome A chromosome that carries genes whose presence or absence determines sex

t a b l e 1.3

Mendelian or Multifactorial Genetic Disorders

Mendelian Disorders Multifactorial Disorders

Mutations in a gene called BRCA1 cause

fewer than 5 percent of all cases of breast

cancer But studies of the disease incidence

in different populations have yielded

con-fusing results In Jewish families of eastern

European descent (Ashkenazim) with many

affected members, inheriting the most

com-mon BRCA1 mutation means an 86 percent

chance of developing the disease over a

life-time But women from other ethnic groups

who inherit this allele may have only a 45

percent chance of developing breast cancer,

because they have different alleles of other

genes with which BRCA1 interacts than do

the eastern European families

Environmental factors may also affect

the gene’s expression For example, exposure

to pesticides that mimic the effects of

estro-gen may be an environmental contributor to

breast cancer It can be difficult to tease apart

genetic and environmental contributions to

disease BRCA1 breast cancer, for example, is

especially prevalent among women who live

in Long Island, New York This population

includes both many Ashkenazim, and

wide-spread exposure to pesticides

Increasingly, predictions of inherited

disease are considered in terms of

“modi-fied genetic risk,” which takes into account

single genes as well as environmental and

family background information A

modi-fied genetic risk is necessary to predict

BRCA1 breast cancer occurrence in a family

The fact that the environment modifies

the actions of genes counters the idea that

an inherited trait is unchangeable, which is

termed genetic determinism The idea that

“we are our genes” can be very dangerous

In terms of predictive testing for inheriteddisease, effects of the environment requirethat results be presented as risks rather thanforegone conclusions That is, a personmight be told that she has a 45 percentchance of developing BRCA1 breast cancer,not “you will get breast cancer.”

Genetic determinism as part of socialpolicy can be particularly harmful In thepast, for example, the assumption that oneethnic group is genetically less intelligentthan another led to lowered expectationsand fewer educational opportunities forthose perceived to be biologically inferior

Environment, in fact, has a huge impact onintellectual development The bioethics es-say in chapter 8 considers genetic determin-ism further

Statistics to Represent Risks

Predicting the inheritance of traits in viduals is not a precise science, largely be-cause of the many influences on gene func-tion and the uncertainties of analyzingseveral factors Genetic counselors calculaterisks for clients who want to know thechance that a family member will inherit aparticular disease—or has inherited it, butdoes not yet exhibit the symptoms

indi-In general, risk assessment estimatesthe degree to which a particular event or sit-uation represents a danger to a population

In genetics, that event is the likelihood of heriting a particular gene or gene combina-tion The genetic counselor can infer thatinformation from a detailed family history,

in-or from the results of tests that identify agene variant or a protein that is absent orabnormal

Risks can be expressed as absolute or

relative figures Absolute risk is the

proba-bility that an individual will develop a

par-ticular condition Relative risk is the

likeli-hood that an individual from a particularpopulation will develop a condition in com-parison to individuals in another group,which is usually the general population.Relative risk is a ratio of the probability inone group compared to another In genetics,relative risks might be calculated by evaluat-ing any situation that might elevate the risk

of developing a particular condition, such

as one’s ethnic group, age, or exposure to acertain danger The threatening situation is

called a risk factor For example,

chromo-some abnormalities are more common inthe offspring of older mothers Pregnantwomen who undergo testing for Down syn-drome caused by an extra chromosome 21are compared by age to the general popula-tion of pregnant women to derive the rela-tive risk that they are carrying a fetus thathas the syndrome The risk factor is age.Determining a relative risk may seemunnecessary, because an absolute risk applies

to an individual However, relative risks help

to identify patients who are most likely tohave the conditions for which absolute riskscan be calculated Health care providers userelative risk estimates to identify individualswho are most likely to benefit from particu-lar medical tests A problem that genetic

figure 1.3

Mendelian versus multifactorial

traits (a) Hair color is multifactorial,

controlled by at least three genes plusenvironmental factors, such as the bleaching

effects of sun exposure (b) Polydactyly—

extra fingers and/or toes—is a Mendeliantrait, determined by a single gene

counselors face in assessing risk, however, is

that statistics tend to lose their meaning in a

one-on-one situation To a couple learning

that their fetus has Down syndrome, the fact

that the relative risk was low based on

popu-lation statistics pertaining to their age group

is immaterial

Mathematically, absolute and relative

risk are represented in different ways Odds

and percentages are used to depict absolute

risk For example, Mackenzie’s absolute risk

of developing inherited Alzheimer disease

over her lifetime is 4 in 100 (the odds) or 4

percent Determining her relative risk

re-quires knowing the risk to the general

population If that risk is 10 in 100, then

Mackenzie’s relative risk is 4 percent divided

by 10 percent, or 0.4 A relative risk of less

than 1 indicates the chance of developing a

particular illness is less than that of the

gen-eral population; a value greater than 1

indi-cates risk above that of the general

popula-tion For example, Mackenzie’s 0.4 relative

risk means she has 40 percent as much risk of

inheriting Alzheimer disease as the average

person in the general population; a relative

risk of 8.4, by contrast, indicates a

greater-than-8-fold risk compared to an individual

in the general population Determining the

risks for Alzheimer disease is actually much

more complicated than is depicted in this

hy-pothetical case Several genes are involved,

the percentage of inherited cases isn’t known,

and prevalence is highly associated with age

Elevated risk is linked to having more than

one affected relative and an early age of

on-set But Alzheimer disease is a very common

illness—about 40 percent of people over age

85 have the condition

Environment probably plays a role in

causing Alzheimer disease too One study of

several hundred nuns is investigating

non-genetic contributing factors to Alzheimer

disease So far, the study has shown that

nuns who expressed complex thinking in

writings early in life had a lower risk of

de-veloping Alzheimer disease than nuns with

more simplistic literary styles However, the

meaning of such an association, if any, is

unclear

Risk estimates can change depending

upon how the groups under comparison

are defined For a couple who has a child

with an extra chromosome, such as a child

with Down syndrome, the risk of this

hap-pening again is 1 in 100, a figure derived

from looking at many families who have at

least one such child Therefore, the nexttime the couple has a child, two risk esti-mates are possible for Down syndrome—1

in 100, based on the fact that they alreadyhave an affected child, and the risk associ-ated with the woman’s age The geneticcounselor presents the highest risk, to pre-pare the family for a worst-case scenario

Consider a 23-year-old and a 42-year-oldwoman who have each had one child withthe extra chromosome of Down syndrome(figure 1.4) Each faces a recurrence risk of

1 in 100 based on medical history, but thetwo women have different age-associatedrisks—the 23-year-old’s is 1 in 500, but the42-year-old’s is 1 in 63 The counselor pro-vides the 1 in 100 figure to the youngerwoman, but the age-associated 1 in 63 fig-ure to the older woman

Geneticists derive risk figures in several

ways Empiric risk comes from

population-level observations, such as the 1 in 100 risk

of having a second child with an extra mosome Another type of risk estimate de-rives from Mendel’s laws A child whoseparents are both carriers of the Mendeliandisorder sickle cell disease, for example,faces a 1 in 4, or 25 percent, chance of inher-iting the disease This child also has a 1 in 2,

chro-or 50 percent, chance of being a carrier, likethe parents The risk is the same for eachoffspring It is a common error to concludethat if two carrier parents have a child with

an inherited disorder, the next three dren are guaranteed to be healthy This isn’t

chil-so, because each conception is an dent event

indepen-Patient 1: Rebecca

Age:

Age-dependent risk for Down syndrome:

Risk based on previous child with Down syndrome:

23

1 in 500

Patient 2: Diane

Age:

Age-dependent risk for Down syndrome:

Risk based on previous child with Down syndrome:

to another population group

of Genetics

Barely a day goes by without some mention

of genetics in the news This wasn’t true just

a few years ago Genetics is impacting a

variety of areas in our everyday lives

Fol-lowing are looks at some of the topics that

are discussed more fully in subsequent

chapters

Establishing Identity—From

Forensics to Rewriting History

Comparing DNA sequences among

indi-viduals can establish, or rule out, that the

DNA came from the same person, from

blood relatives, or from unrelated people

Such DNA typing or fingerprinting has

many applications

Until September, 2001, the media

re-ported on DNA fingerprinting sporadically,

and usually in the context of plane crashes

or high profile crimes The same technology

became critical in identifying those killed at

the World Trade Center At two

biotechnol-ogy companies, researchers compared DNA

sequences in bone and teeth collected from

the scene to hair and skin samples from

hairbrushes, toothbrushes, and clothing of

missing people, as well as to DNA from

relatives

In more conventional forensic

applica-tions, a DNA match for rare sequences

be-tween a tissue sample left at a crime scene

and a sample from a suspect is strong

evi-dence that the accused person was at the

crime scene (or that someone cleverly

planted evidence of that person’s presence)

It has become almost routine for DNA

typ-ing to exonerate prisoners, some who had

been awaiting execution DNA typing can

add objectivity to a case skewed by human

subjectivity, when combined with other

types of evidence Consider what happened

to Ronald Jones

In 1985, at age 34, Jones confessed

un-der police pressure to raping and stabbing

to death a young Illinois mother of three

The woman, he claimed, was a prostitute

Jones soon recanted the confession, but he

was prosecuted and convicted, possibly

be-cause he fit a stereotype of someone capable

of committing this crime—he has an IQ of

80, and at the time he was homeless, he was

an alcoholic, and he begged on the streets

Results of a DNA test performed in 1989,

when the technique was not well developed,

were “inconclusive.” Jones continued to

proclaim his innocence A team of lawyers

believed him, and in 1995, after DNA typing

had overturned several dozen convictions,

they requested that another DNA test be

performed on sperm samples saved fromthe victim The DNA test revealed that theman who raped and murdered the young

woman was not Ronald Jones.

Illinois has been a trendsetter in DNAtyping In 1996, DNA tests exonerated theFord Heights Four, men convicted of a gangrape and double murder who had spenteighteen years in prison, two of them ondeath row In 1999, the men received com-pensation of $36 million A journalismclass at Northwestern University initiatedthe investigation that gained the men free-dom The case led to new laws grantingdeath row inmates new DNA tests if theirconvictions could have arisen from mis-taken identity

DNA evidence can shed light on ical mysteries, too Consider the offspring ofThomas Jefferson’s slave, Sally Hemings In

histor-1802, Jefferson had been accused of ing her eldest son, but DNA analysis eventu-ally ruled that out In 1998, DNA testingcompared DNA sequences on the Y chro-mosomes of descendants of several malesimportant to the case Y chromosomes wereanalyzed because they are passed only fromfather to son

father-The results were clear Jefferson’s maledescendants had very distinctive Y chromo-some DNA sequences, as did the descen-dants of Hemings’ youngest son Technic-ally, DNA results can disprove paternity, butnot prove it—they just provide evidence of

an extremely high probability that a mancould have fathered a particular child Abrother of Thomas Jefferson would havehad such similar DNA that he could nothave been excluded as a possible father ofSally Hemings’ youngest son

DNA analysis of bone cells from a childburied in a Roman cemetery in the year 450

A.D revealed sequences known to come fromthe parasite that causes malaria The geneticevidence is consistent with other signs ofmalaria, such as unusually porous bones andliterary references to an epidemic contribut-ing to the fall of the Roman Empire

History taken even farther back laps with Biblical times, and DNA typing canclarify these ancient relationships, too Forexample, comparing Y chromosomes revealsthat a small group of Jewish people, the co-hanim, share distinctive DNA sequences

over-The cohanim are known as priests and have

a special status in the religion By ing the number of DNA differences between

consider-cohanim and other Jewish people, how long

it takes DNA to mutate, and the average man generation time (25 years), researchersextrapolated that the cohanim can tracetheir Y chromosomes to an origin about2,100 to 3,250 years ago This is consistentwith the time of Moses According to reli-gious documents, Moses’ brother Aaron wasthe first priest Interestingly, the Jewishpriest DNA signature also appears amongthe Lemba, a population of South Africanswith black skin Researchers thought to look

hu-at them for the telltale gene variants becausetheir customs suggest a Jewish origin—they

do not eat pork (or hippopotamus), they cumcise their newborn sons, and they cele-brate a weekly day of rest This story there-fore involves genetics, religion, history, andanthropology

cir-DNA fingerprinting is also used in culture Researchers from France and theUnited States collected leaves and DNA fin-gerprints for 300 varieties of wine grapes.The goal was to identify the two parentaltypes that gave rise to the sixteen majortypes of wine The researchers already knewthat one parent was the bluish-purple Pinotgrape, but the DNA analysis revealed thatthe second parent was a variety of whitegrape called Gouais blanc (figure 1.5) Thissurprised wine authorities, because Gouaisblanc grapes are so unpopular that theyhaven’t been grown in France or the UnitedStates for many years and were actuallybanned during the Middle Ages Identifyingthis second parent provided very valuableinformation for vintners—if they maintainboth parental stocks, they can preserve thegene pool from which the sixteen majorwines derive The finding also confirmed along-held belief that Pinot and Chardonnaywine grapes are related

agri-Health Care

Inherited illnesses caused by a single genediffer from other illnesses in several ways(table 1.4) First, the recurrence risk of suchdisorders can be predicted by the laws of in-heritance, discussed in chapter 4 In contrast,

an infectious disease requires that a pathogen

be passed from one person to another—a farless predictable circumstance

A second key difference between ited illnesses and most other types of med-ical conditions is that in some situations, aninherited illness can be predicted before

inher-symptoms appear This is because the genes

causing the problem are present in every

cell from conception, even though they are

not expressed in every cell Cystic fibrosis,

for example, affects the respiratory system

and the pancreas, but cells taken from the

inside of the cheek or from blood can reveal

a mutation Such genetic information can

be considered along with symptoms in

re-fining a diagnosis Bioethicists debate the

value of predicting an untreatable inherited

condition years before symptoms arise

Huntington disease, for example, causes

personality changes and worsening

uncon-trollable physical movements, usually

be-ginning at around age 40 Most physiciansadvise against presymptomatic testing ofpeople under 18 years of age But olderyoung adults might seek such testing in or-der to help make decisions about whether

to have children and risk passing on thedisease-causing gene The fact that an in-herited illness can be passed by a healthyindividual raises questions about reproduc-tive choices

A third aspect of genetic disease is that,because of the structure of human popula-tions, certain inherited disorders are muchmore common in some populations thanothers For economic reasons, it is sensible

to offer costly genetic screening tests only topopulations in which the detectable genevariant is fairly common Jewish people ofeastern European descent, for example, de-velop about a dozen genetic diseases atmuch higher frequencies than other popu-lations, and some companies offer tests thatscreen for all of these diseases at once

“Jewish disease screens” and other tests geted to specific population groups are notmeant to discriminate, but simply to recog-nize a biological fact

tar-Genetic disease also differs from others

in that it can sometimes be treated by gene

therapy Gene therapy replaces a

malfunc-tioning gene in the affected parts of the

body, in effect correcting the gene’s faultyinstructions “In Their Own Words” onpage 13 is the first of a recurring feature inwhich people describe their experienceswith an inherited illness In this entry, DonMiller, the first recipient of gene therapy totreat hemophilia, describes his life with thisdisorder that impairs the ability of theblood to clot Sadly, not all gene therapy at-tempts are as successful as Don Miller’s is

so far In September 1999, an 18-year-olddied from gene therapy His story is told inchapter 19

Some people who know they can mit an inherited illness elect not to havechildren, or to use donated sperm or ova toavoid passing the condition to their off-spring A technique called preimplantationgenetic diagnosis screens eight-celled em-bryos in a laboratory dish, which allowscouples to choose those free of the mutation

trans-to complete development in the uterus.Another alternative is to have a fetus tested

to determine whether the mutant allele hasbeen inherited In cases of devastating ill-nesses, this information may prompt theparents to terminate the pregnancy Or, thesame information may enable parents toprepare for the birth of a disabled or illchild

Agriculture

The field of genetics arose from agriculture.Traditional agriculture is the controlledbreeding of plants and animals to select newcombinations of inherited traits in livestock,fruits, and vegetables that are useful to us.Yet traditional agriculture is imprecise, inthat it shuffles many genes—and thereforetraits—at a time The application of DNA-based techniques—biotechnology—enablesresearchers to manipulate one gene at atime, adding control and precision to agri-culture Biotechnology also enables re-searchers to create organisms that harborgenes that they would not naturally have.Foods and other products altered bythe introduction of genes from other types

of organisms, or whose own gene sion is enhanced or suppressed, are termed

expres-“genetically modified,” or GM More ically, an organism with genes from another

specif-species is termed transgenic A GM

trans-genic “golden” rice, for example, tures beta-carotene (a precursor of vitamin

manufac-figure 1.5

Surprising wine origins (a) Gouais blanc and (b) Pinot (noir) grapes gave rise to

nineteen modern popular wines, including Chardonnay

t a b l e 1.4

How Genetic Diseases Differ

from Other Diseases

1 Can predict recurrence risk in other

family members

2 Presymptomatic testing is possible

3 Different populations may have

dif-ferent characteristic frequencies

4 Correction of the underlying genetic

abnormality may be possible

A) and stores twice as much iron as

unal-tered rice Once these traits are bred into a

commercial strain of rice, the new crop may

help prevent vitamin A and iron deficiencies

in malnourished people living in

develop-ing nations (figure 1.6a) The new rice

vari-ant’s valuable traits result from the

intro-duction of genes from petunia and bacteria,

as well as boosted expression of one of the

plant’s own genes

Another GM crop is “bt corn.” A gene

from the bacterium Bacillus thuringiensis

(hence, bt) encodes a protein that kills certain

insect larvae, including the European cornborer, which devastates corn crops Organicfarmers have applied the bacterium’s natural

protein as a pesticide for decades, but bt corn

can make its own The GM crop provides creased yield and lessens reliance on syn-thetic chemical pesticides

in-GM animals are used to produce maceuticals, usually by receiving genes fromother species that they express in their milk

phar-For example, when sheep are given the

hu-man gene that encodes the factor VIII ting factor absent in people with hemo-philia, they secrete the protein in their milk.This provides a much purer and saferpreparation than the pooled blood extractsthat once transmitted infections

clot-Many people object to genetic lation, particularly in Europe, where morethan 75 percent of the population opposesexperimenting with, growing, and market-ing GM foods Protesters have destroyed

manipu-GM crops, and sometimes unaltered plants,

In Their Own Words

Living with Hemophilia

until it was necessary Of course there was

no AIDS then, but there were problems withtransmitting hepatitis through blood trans-fusions, and other blood-borne diseases Allthat whole blood can kill you from kidneyfailure When I was nine or ten I went to thehospital for intestinal polyps I was operated

on and they told me I’d have a 10 percentchance of pulling through I met other kidsthere with hemophilia who died from kid-ney failure due to the amount of fluid fromall the transfusions Once a year I went tothe hospital for blood tests Some years Iwent more often than that Most of the time

I would just lay there and bleed My jointsdon’t work from all the bleeding

By the time I got married at age 20,treatment had progressed to gamma globu-lin from plasma By then I was receivinggamma globulin from donated plasma andsmall volumes of cryoprecipitate, which isthe factor VIII clotting protein that my bodycannot produce pooled from many donors

We decided not to have children becausethat would end the hemophilia in the family

I’m one of the oldest patients at thePittsburgh Hemophilia Center I was HIVnegative, and over age 25, which is whatthey want By that age a lot of people withhemophilia are HIV positive, because theylived through the time period when we had

no choice but to use pooled cryoprecipitate

I took so little cryoprecipitate that I wasn’texposed to very much And, I had the time.The gene therapy protocol involves showing

up three times a week

The treatment is three infusions, one aday for three days, on an outpatient basis Sofar there have been no side effects Once thegene therapy is perfected, it will be a three-day treatment A dosage study will followthis one, which is just for safety Animalstudies showed it’s best given over threedays I go in once a week to be sure there is

no adverse reaction They hope it will be aone-time treatment The virus will lodge inthe liver and keep replicating

In the eight weeks before the infusion, Iused eight doses of factor In the 14 weekssince then, I’ve used three Incidents thatused to require treatment no longer do Aslong as I don’t let myself feel stressed, I don’thave spontaneous bleeding I’ve had twonosebleeds that stopped within minuteswithout treatment, with only a trace ofblood on the handkerchief, as opposed tohours of dripping

I’m somewhat more active, but fiftyyears of wear and tear won’t be healed bythis gene therapy Two of the treatments Irequired started from overdoing activity, sonow I’m trying to find the middle ground

on Miller was born in 1949 and

is semiretired from running the

math library at the University of

Pittsburgh Today he has a sheep

farm On June 1, 1999, he was

the first hemophilia patient to receive a

dis-abled virus that delivered a functional gene

for clotting factor VIII to his bloodstream

Within weeks he began to experience

re-sults Miller is one of the first of a new breed

of patients—people helped by gene therapy

Here he describes his life with hemophilia

The hemophilia was discovered when I was

circumcised, and I almost bled to death, but

the doctors weren’t really sure until I was

about eighteen months old No one where I

was born was familiar with it

When I was three, I fell out of my crib

and I was black and blue from my waist to

the top of my head The only treatment then

was whole blood replacement So I learned

not to play sports A minor sprain would

take a week or two to heal One time I fell at

my grandmother’s house and had a

1-inch-long cut on the back of my leg It took five

weeks to stop bleeding, just leaking real

slowly I didn’t need whole blood

replace-ment, but if I moved a little the wrong way,

it would open and bleed again

I had transfusions as seldom as I could

The doctors always tried not to infuse me

D

too, because the plants look normal In

Seattle, members of a radical environmental

activist group mistakenly destroyed 100

very rare trees growing in a laboratory—

only 300 exist in the wild The laboratory

trees were not genetically modified

Reasons cited to boycott GM foods

vary Some are practical—such as the

possi-bility of having an allergic reaction to one

plant-based food because it produces a

pro-tein normally found in another type of

plant Without food labeling, a consumer

would not know that one plant has a

pro-tein that it normally would not produce

Another concern is that field tests may notadequately predict the effects of altered

plants on ecosystems For example, bt corn

has been found growing in places where itwas not planted

Some of the changes made possiblethrough genetic modification are pro-found For example, a single gene exchangecan create a salmon that grows to twice itsnormal size, or enable a fish that normallylives in temperate waters to survive in coldwater thanks to an antifreeze gene from an-other type of fish What effects will theseanimals have on ecosystems?

Some objections to the genetic cation of plants and animals, however, arisefrom lack of knowledge about genetics (fig-

modifi-ure 1.6b) A public opinion poll in the

United Kingdom discovered that a majorreason citizens claim they wish to avoid

GM foods is that they do not want to eatDNA! One British geneticist wryly ob-served that the average meal provides some150,000 kilometers (about 93,000 miles)

of DNA

Ironically, the British public had beeneating GM foods for years before the cur-rent concern arose A very popular “vege-tarian cheese” was manufactured using anenzyme made in GM yeast; the enzymewas once extracted from calf stomachs.Researchers inserted the cow gene into theyeast genome, which greatly eased produc-tion and collection of the needed enzyme.Similarly, a tomato paste made fromtomatoes with a gene added to delayripening vastly outsold regular tomatoes

in England—because it was cheaper!Similarly, a poll of U.S citizens found that

a large majority would not knowingly eat

GM foods Most of the participants wereshocked when the interviewer informedthem that they had been eating these foodsfor years

A Word on Genetic Equity

DNA microarray tests, gene therapy, newdrugs based on genetic information—allare or will be expensive and not widelyavailable for years In a poor African na-tion where 2 out of 5 children have AIDSand many others die from other infectiousdiseases, these biotechnologies are likely toremain in the realm of science fiction forquite some time It was ironic that scien-tific journals announced the sequencing

of the human genome the same week thatthe cover of a news magazine featured the AIDS crisis in Africa It was starklyobvious that while people in economicallyand politically stable nations may contem-plate the coming of genome-based indi-vidualized health care, others in less-for-tunate situations just try to survive fromday to day

Human genetic information can, ever, ultimately benefit everyone Considerdrug development Today, there are fewerthan 500 types of drugs Genome informa-

how-figure 1.6

Genetic modification Modern techniques hold enormous promise, though they engender

fear in some (a) Beta-carotene, a precursor of vitamin A, turns this rice yellow The genetically

modified grain also has twice as much iron as nonmodified plants (b) This killer tomato

cartoon illustrates the fears some people have of genetic manipulation

Seymore Chwast, The Pushpin Group, Inc.

a.

b.

tion from humans and also from the

vari-ous pathogens and parasites that cause

ill-ness will reveal new drug targets Medical

organizations all over the world are

dis-cussing how nations can share new

diag-nostic tests and therapeutics that arise

from genome information Over the past

few years, genetics has evolved from a basic

life science and an obscure medical

spe-cialty, to a multifaceted discipline that will

impact us all

Genetics has applications in diverse areas Matching DNA sequences can clarify ships, which is useful in forensics, establishing paternity, and understanding certain histori-cal events • Inherited disease differs from other disorders in its predictability; the possibil-ity of presymptomatic detection; characteristic frequencies in different populations; and thepotential of gene therapy to correct underlying abnormalities.• Agriculture, bothtraditional and biotechnological, applies genetic principles • Information from the humangenome project has tremendous potential but must be carefully managed

relation-Bioethics: Choices for the Future

National Genetic Databases—Is GATTACA Coming?

sumed That is, citizens have to file a specialform to “opt out” of the project, and this isnot as simple as just mailing a letter Many ge-neticists from nations where consent must beboth voluntary and informed objected to thispractice A large part of the population is par-ticipating in the project, because it is adminis-tratively difficult not to

The story is different in Estonia, wheremore than 90 percent of the 1.4 millionpopulation favors a gene pool project TheEstonian Genebank Foundation runs theprogram, with a for-profit and a nonprofitorganization sharing control The peoplemust volunteer The project has access topatient registries for cancer, Parkinson dis-ease, diabetes mellitus, and osteoporosis

When patients show up for appointments,they learn about the project and are giventhe option to fill out a lengthy question-naire on their health history and donate ablood sample for DNA analysis The plan is

to search for single nucleotide phism (SNP) patterns that are associatedwith these and other multifactorial disor-ders, then develop new diagnostic tests andpossibly treatments based on the informa-tion Because these diseases are common inmany western nations, what is learned fromthe Estonians may apply to many others Apilot project consisting of 10,000 individu-als is under way to learn if the approachworks

polymor-Many population-based studies of genevariants are in the planning stages Bio-ethicists have suggested several strategies toensure that individuals can only benefitfrom such projects Some suggestions to as-sure fair use of genetic information include:

• Preserving choice in seeking genetictests

• Protecting the privacy of individuals

by legally restricting access to genomeinformation

• Tailoring tests to those genes that aremost relevant to an individual

• Refusing to screen for trivial traits inoffspring, such as eye or hair color, ortraits that have a large and controllableenvironmental component, such as intelligence

• Educating the public to make informeddecisions concerning genetic informa-tion, including evaluating the risks andbenefits of medical tests, judging theaccuracy of forensic data, or eating ge-netically modified foods

If these goals are met, human genomeinformation will reveal the workings of thehuman body at the molecular level, and add

an unprecedented precision and ization to health care

personal-n several parts of the world, projects

are underway to record genetic and

other types of health information on

citizens The plans vary in how people

participate, but raise similar

underly-ing questions and concerns: How will the

in-formation be used? Who will have access to

it? How can people benefit from the project?

Brave New World is a novel published in

1932 that depicts a society where the

gov-ernment controls reproduction When the

idea for population genetic databases was

initially discussed in the mid 1990s in

sev-eral nations, reaction was largely negative,

with people citing this novel as being

prophetic Then in 1998 came the film

GAT-TACA, in which a government of a very

re-pressive society records the genome

se-quence of every citizen A cell from a stray

eyelash gives away the main character’s true

identity

The first attempt to establish a

popula-tion genetic database occurred in Iceland,

where a company, deCODE Genetics,

re-ceived government permission in 1998 to

col-lect existing health and genealogy records, to

be supplemented with DNA sequence data

Some Icelandic families trace back more than

1,000 years, and have family trees etched in

blood on old leather The government has

promised the people health benefits if the

col-lected information leads to new treatments

Participation in the Icelandic database is

pre-I

1.1 A Look Ahead

1 Genes are the instructions to manufacture

proteins, which determine inherited traits

2 A genome is a complete set of genetic

information A cell contains two genomes

of DNA

3 Before whole genome screens become

available, people will choose specific gene

tests, based on family history, to detect or

even predict preventable or treatable

conditions DNA microarrays detect many

genes at once

4 Genes contribute to rare as well as

common disorders

1.2 From Genes to Genomes

5 Genes are sequences of DNA that encode

both the amino acid sequences of proteins

and the RNA molecules that carry out

protein synthesis RNA carries the gene

sequence information so that it can be

utilized, while the DNA is transmitted

when the cell divides Much of the genome

does not encode protein

6 Variants of a gene arise by mutation.

Variants of the same gene are alleles They

may differ slightly from one another, but

they encode the same product A

polymorphism is a general term for a

particular site or sequence of DNA that

varies in 1 percent or more of a population

The phenotype is the gene’s expression An

allele combination constitutes the genotype.

Alleles may be dominant (exerting an effect

in a single copy) or recessive (requiring two

copies for expression)

7 Chromosomes consist of DNA and

protein The 22 types of autosomes do not

include genes that specify sex The X and Y

sex chromosomes bear genes that

determine sex

8 The human genome is about 3 billion DNA

bases Cells differentiate by expressing subsets of genes Stem cells retain the

ability to divide without differentiating

9 Pedigrees are diagrams that are used to

study traits in families

10 Genetic populations are defined by their

collections of alleles, termed the gene pool.

11 Genome comparisons among species reveal

evolutionary relationships

1.3 Genes Do Not Usually Function Alone

12 Single genes determine Mendelian traits.

13 Multifactorial traits reflect the influence of

one or more genes and the environment

Recurrence of a Mendelian trait is based onMendel’s laws; predicting recurrence of amultifactorial trait is more difficult

14 Genetic determinism is the idea that

expression of an inherited trait cannot

be changed

1.4 Geneticists Use Statistics to Represent Risks

15 Risk assessment estimates the probability of

inheriting a particular gene Absolute risk,

expressed as odds or a percentage, is theprobability that an individual will develop

a particular trait or illness over his or her lifetime

16 Relative risk is a ratio that estimates how

likely a person is to develop a particularphenotype compared to another group,usually the general population

17 Risk estimates are empiric, based on

Mendel’s laws, or modified to account forenvironmental influences

1.5 Applications of Genetics

18 DNA typing can exclude an individual

from being biologically related to someoneelse or from having committed a crime

19 Inherited diseases are distinctive in that

recurrence risks are predictable, and acausative mutation may be detected beforesymptoms arise Some inherited disordersare more common among certain

population groups Gene therapy attempts

to correct certain genetic disorders

20 A transgenic organism harbors a gene or

genes from a different species

S u m m a r y

R e v i e w Q u e s t i o n s

1 Place the following terms in size order,

from largest to smallest, based on the

structures or concepts that they represent:

2 How is genomics changing the emphasis of

the field of human genetics?

3 Distinguish between:

a an autosome and a sex chromosome

b genotype and phenotype

c DNA and RNA

d recessive and dominant traits

e absolute and relative risks

f pedigrees and karyotypes

4 List three ways that inherited disease differs

from other types of illnesses

5 Cystic fibrosis is a Mendelian trait; height is

a multifactorial trait How do the causes ofthese characteristics differ?

6 How does an empiric risk estimate differ

from a risk estimate for a Mendeliandisorder?

7 Why is it inaccurate to assume that all

mutations are harmful?

A p p l i e d Q u e s t i o n s

1 Breast cancer caused by the BRCA1 gene

affects 1 in 800 women in the general U.S

population Among Jewish people of

eastern European descent, it affects 2 in

100 What is the relative risk for this form

of breast cancer among eastern European

Jewish women in the United States?

2 In the general U.S population, 12 in 10,000

people inherit a form of amyloidosis, in

which protein deposits destroy organs

Among a group of 1,000 individuals of an

isolated religious sect living in

Pennsylvania, 56 have the disorder What is

the relative risk that a person in this

Pennsylvania community will develop

the condition?

3 A man undergoes a DNA chip test for

several genes that predispose to developing

prostate cancer He learns that overall, his

relative risk is 1.5, compared to the risk in

the general population He is overjoyed,

and tells his wife that his risk of developing

prostate cancer is only 1.5 percent She says

that he is incorrect, that his risk is 50

percent greater than that of the average

individual in the general population Who

is correct?

4 Crohn disease is an inflammation of the

small intestine that causes painful cramps

About 15 percent of the half million people

in the United States who have the condition

have inherited a mutation that increases

their susceptibility A person who inherits

the mutation has about a 25 percent chance

of developing Crohn disease Cite tworeasons why the risk of developing Crohndisease for a person who inherits themutation is not 100 percent

5 Benjamin undergoes a genetic screening

test and receives the following relative risks:

– addictive behaviors 0.6– coronary artery disease 2.3

6 The Larsons have a child who has inherited

cystic fibrosis Their physician tells themthat if they have other children, each faces a

1 in 4 chance of also inheriting the illness

The Larsons tell their friends, the Espositos,

of their visit with the doctor Mr and Mrs

Esposito are expecting a child, so they asktheir physician to predict whether he or shewill one day develop multiple sclerosis—

Mr Esposito is just beginning to showsymptoms They are surprised to learn that,unlike the situation for cystic fibrosis,recurrence risk for multiple sclerosiscannot be easily predicted Why not?

7 A woman picked up scabies (genital crab

lice) during a rape The mites puncturehuman skin and drink blood Describe how

a forensic entomologist (an insect expert)might use DNA fingerprinting on materialfrom mites collected from the victim andthree suspects to identify the rapist (This is

a real case.)

8 What precautions should be taken to

ensure that GM foods are safe?

9 Burlington Northern Santa Fe Railroad

asked its workers for a blood sample, andthen supposedly tested for a gene variantthat predisposes a person for carpal tunnelsyndrome, a disorder of the wrists that iscaused by repetitive motions The companythreatened to fire a worker who refused to

be tested; the worker sued the company.The Equal Employment OpportunityCommission ruled in the worker’s favor,agreeing that the company’s action violatedthe Americans with Disabilities Act

a Do you agree with the company or theworker? What additional informationwould be helpful in taking sides?

b How is the company’s genetic testingnot based on sound science?

c How can tests such as those describedfor the two students at the beginning ofthis chapter be instituted in a way thatdoes not violate a person’s right toprivacy, as the worker in the railroadcase contended?

S u g g e s t e d R e a d i n g s

Cohen, Sharon August 15, 1999 Science and

investigations free death row inmates The

Associated Press A fascinating account of

cases where DNA testing made a difference

Emery, John, and Susan Hayflick April 28, 2001

The challenge of integrating genetic

medicine into primary care British Medical

Journal 322:1027–30 Genetic information

is entering medical practice

Foster, Eugene A., et al November 5, 1998

Jefferson fathered slave’s last child Nature

396:27–28 DNA testing can rewrite history

Holon, Tom February 19, 2001 Gene pool

expeditions The Scientist 15(4):1 A look at

population genetic database projects in

Estonia and the island of Tonga

Lewis, Ricki February 12, 2002 Race and theclinic: good science or political correctness?

The Scientist 16(4):14 Race may not be a

biological concept, but differences in genefrequencies among people of different skincolors may be clinically significant

Lewis, Ricki September 3, 2001 Where the bugs

are: forensic entomology The Scientist

15(17):10 DNA fingerprinting of insectsprovides helpful clues to solving crimes

Lewis, Ricki July 24, 2000 Keeping up: Genetics

to genomics in four editions The Scientist

14:46 A look at the evolution of thistextbook

Lewis, Ricki July 19, 1999 Iceland’s public

supports database, but scientists object The

Scientist 13:1 Geneticists attempted to

prevent genetic technology from interferingwith individual freedom and the right toprivacy

Lewis, Ricki October 13, 1997 Genetic testingfor cancer presents complex challenge

The Scientist 11:1 Testing for BRCA1 is a

genetic counseling nightmare

Lewis, Ricki, and Barry A Palevitz October 11,

1999 Science vs PR: GM crops face heat of

debate The Scientist 13:1 Consumers have

objections to GM crops that are not alwaysbased on scientific facts

Check out the resources on our website at

www.mhhe.com/lewisgenetics5

On the web for this chapter you will find

additional study questions, vocabulary

re-view, useful links to case studies, tutorials,

popular press coverage, and much more To

investigate specific topics mentioned in this

chapter, also try the links below:

Alliance of Genetic Support Groups

www.geneticalliance.org/

Alzheimer’s Association www.alz.org

American Cancer Society www.cancer.org

Cystic Fibrosis Foundation www.cff.org

Genetic Interest Group www.gig.org.uk

Glossary of Genetic Terms

BRCA1 breast cancer 113705cystic fibrosis 219700familial hypercholesterolemia 143890hemophilia A 306700

sickle cell disease 603903

National Coalition for Health ProfessionalEducation in Genetics www.nchpeg.org

National Hemophilia Foundation

The Scientist www.the-scientist.com

(to read articles by the author)

Paabo, Svante February 16, 2001 The human

genome and our view of ourselves Science

291:1219 Knowing the sequence of the

human genome provides new ways of

looking at ourselves

Singer, Peter A and Abdallah S Daar

October 5, 2001 Harnessing genomics and

biotechnology to improve global health

equity Science 294:87–89 The New African

Initiative is an effort to ensure that all

cultures have access to biotechnology

Skorecki, Karl, et al January 2, 1997

Y chromosomes of Jewish priests Nature

385:32 Tracing Y chromosomes confirmshistory

Verhovek, Sam Howe, and Carol Kaesuk Yoon

May 23, 2001 Foes of genetic engineering

are suspects in northwest fires The New

York Times, p F1 Radical opponents of GM

organisms sometimes target the wrongexperiments

Wade, Nicholas May 9, 1999 Group in Africa

has Jewish roots, DNA indicates The New

York Times, p F1 DNA and customs reveal

that the Lemba are Jewish

Wilford, John Noble February 20, 2001 DNAshows malaria helped topple Rome

The New York Times, p F1 DNA clues in

the bones of a three-year-old from 1,500years ago suggest that an epidemic ofmalaria may have contributed to the fall ofthe Roman Empire

Ye, Xudong, et al January 14, 2000 Engineeringthe provitamin A (beta carotene)biosynthetic pathway into (carotenoid-

free) rice endosperm Science 287:303–5.

“Golden rice” may prevent humanmalnutrition

O n t h e W e b

2.1 The Components of Cells

Inherited characteristics can ultimately

be explained at the cellular level The

genetic headquarters, the nucleus,

oversees the coordinated functions of

specialized organelles, the cell

membrane, and the cytoskeleton

2.2 Cell Division and Death

As a human grows, develops, and

heals, cells form and die Both cell

division and cell death are highly

regulated, stepwise events under

genetic control

2.3 Cell-Cell Interactions

Cells must communicate with each other

They do so by receiving and responding

to signals, and by physically contacting

one another Signal transduction and

cellular adhesion are genetically

2.5 Viruses and Prions—

Not Cells, But Infectious

All living organisms consist of cells

Viruses and prions are not cells, but theycan cause infections A virus is a nucleicacid in a protein coat A prion is aninfectious protein

C H A P T E R

2

Cells

The activities and abnormalities of cells

un-derlie inherited traits, quirks, and illnesses

The muscles of a boy with muscular

dystro-phy weaken because they lack a protein that

normally supports the cells’ shape during

forceful contractions A child with cystic

fi-brosis chokes on sticky mucus because the

cells lining her respiratory tract produce a

malfunctional protein that in its normal

form would prevent too much water from

leaving the secretions The red blood cells of

a person with sickle cell disease contain an

abnormal form of hemoglobin that

aggre-gates into a gel-like mass when the oxygen

level is low The mass bends the red cells

into sickle shapes, and they wedge within

the tiniest vessels, cutting off the blood

sup-ply to vital organs (figure 2.1)

Understanding what goes wrong in

cer-tain cells when a disease occurs suggests

ways to treat the condition—we learn what

must be repaired or replaced Understanding

cell function also reveals how a healthy body

works, and how it develops from one cell to

that fills red blood cells The more than 260specialized or differentiated cell types in ahuman body arise because the cells expressdifferent genes

Figure 2.1 illustrates three cell types inhumans, and figure 2.22 shows some others.The human body’s cells fall into four broadcategories: epithelium (lining cells), muscle,nerve, and connective tissues (blood, bone,cartilage, adipose, and others)

Other multicellular organisms, ing other animals, fungi, and plants, alsohave differentiated cells Some single-celledorganisms, such as the familiar parameciumand ameba, have very distinctive cells thatare as complex as our own Most of theplanet, however, is occupied by simpler single-celled organisms that are nonetheless suc-cessful life forms, because they occupiedearth long before we did, and are still abun-dant today

includ-Biologists recognize three broad eties of cells that define three major “do-mains” of life: the Archaea, the Bacteria, and

vari-trillions Our bodies include many tions on the cellular theme, with such spe-cialized cell types as bone and blood, nerveand muscle, and even variations of those

varia-Cells interact They send, receive, and spond to information Some aggregate withothers of like function, forming tissues,which in turn interact to form organs andorgan systems Other cells move about thebody Cell numbers are important, too—

re-they are critical to development, growth, andhealing These processes reflect a precise bal-ance between cell division and cell death

of Cells

All cells share certain features that enablethem to perform the basic life functions ofreproduction, growth, response to stimuli,and energy use Body cells also have special-ized features, such as the contractile pro-teins in a muscle cell, and the hemoglobin

a.

Normal muscle cells

Diseased muscle cells

Normal membrane protein

Normal red blood cell

Sickled red blood cell Abnormal

membrane protein

Carbohydrate molecule

Cell membrane

figure 2.1

Genetic disease at the whole-person and cellular levels (a) This young man has Duchenne muscular dystrophy The condition has

not yet severely limited his activities, but he shows an early sign of the illness—overdeveloped calf muscles that result from his inability to rise

from a sitting position the usual way Lack of the protein dystrophin causes his skeletal muscle cells to collapse when they contract (b) A parent

gives this child “postural drainage” therapy twice a day to shake free the sticky mucus that clogs her lungs due to cystic fibrosis The cells lining

her respiratory passages lack a cell membrane protein that controls the entry and exit of salts (c) Seye Arise was born with sickle cell disease,

enduring the pain of blocked circulation and several strokes At age four, he received a bone marrow transplant from his brother Moyo Today

he is fine! The new bone marrow produced red blood cells with a healthy doughnut shape—not the sickle shape his genes dictated

the Eukarya A domain is a designation that

is broader than the familiar kingdom

The Archaea and Bacteria are both

single-celled, but they differ in the sequences

of many of their genetic molecules and in

the types of molecules in their membranes

Because these differences are much less

ob-vious to us than those between, for example,

a tree and a bird, biologists only recently

rec-ognized the Archaea and Bacteria as separate

domains In the past, they were lumped

to-gether as prokaryotes, in recognition of the

fact that they both lack a nucleus, the

struc-ture that contains the genetic material in the

cells of other types of organisms Instead of

being contained in a nucleus, the DNA of

Archaea and Bacteria is complexed with

pro-tein in an area called the nucleoid Many

bi-ologists still distinguish organisms by

ab-sence of a nucleus (prokaryotes) or preab-sence

of a nucleus (eukaryotes)

The third domain of life, the Eukarya

or eukaryotes, includes single-celled

organ-isms that have nuclei, as well as all

multicel-lular organisms The cells of all three

do-mains contain globular structures of RNA

and protein called ribosomes Ribosomes

provide structural and enzymatic support

for protein synthesis

Chemical Constituents of Cells

Cells are composed of molecules The

chemicals of life (biochemicals) tend to

form large macromolecules The

macro-molecules that make up and fuel cells

in-clude carbohydrates (sugars and starches),

lipids (fats and oils), proteins, and nucleic

acids Cells require vitamins and minerals

in much smaller amounts, but they are also

essential to health

Carbohydrates provide energy and

contribute to cell structure Lipids form the

basis of several types of hormones, provide

insulation, and store energy Proteins have

many diverse functions in the human body

They participate in blood clotting, nerve

transmission, and muscle contraction and

form the bulk of the body’s connective

tis-sue Enzymes are proteins that are

espe-cially important because they speed, or

cat-alyze, biochemical reactions so that they

occur swiftly enough to sustain life

Most important to the study of genetics

are the nucleic acids deoxyribonucleic acid

(DNA) and ribonucleic acid (RNA) DNAand RNA form a living language that trans-lates information from past generationsinto specific collections of proteins that give

a cell its individual characteristics The set

of proteins that a cell can manufacture is

called its proteome.

Macromolecules often combine toform larger structures within cells For ex-ample, the membranes that surround cellsand compartmentalize their interiors con-sist of double layers (bilayers) of lipids em-bedded with carbohydrates and proteins

Life is based on the chemical principlesthat govern all matter Genetics is based on ahighly organized subset of the chemical re-actions of life Reading 2.1 describes somedrastic effects that result from abnormali-ties in the major classes of biochemicals

Organelles

A eukaryotic cell holds a thousand times thevolume of a bacterial or archaeal cell (figure2.2) In order to carry out the activities of life

Macrophages (eukaryotic)

Bacteria (prokaryotic)

figure 2.2

Eukaryotic and prokaryotic cells A human cell is eukaryotic and much more complex

than a bacterial cell, while an archaean cell looks much like a bacterial cell Here, humanmacrophages capture bacteria Note how much larger the human cells are than the bacterialcells

in such a large cell, structures called

or-ganelles divide the labor, partitioning off

cer-tain areas or serving a specific function.Saclike organelles sequester biochemicals thatmight harm other cellular constituents Someorganelles consist of membranes studded withenzymes arranged in a particular physical or-der that parallels their sequential participation

in the chemical reactions that produce a ticular molecule In general, organelles keeprelated biochemicals and structures closeenough to one another to interact efficiently.This eliminates the need to maintain a highconcentration of a particular biochemicalthroughout the cell Organelles enable a cell toretain as well as use its genetic instructions; ac-quire energy; secrete substances; and disman-tle debris The coordinated functioning of theorganelles in a eukaryotic cell is much like theorganization of departments in a departmentstore (figure 2.3)

par-The most prominent organelle, the cleus, is enclosed in a layer called the nuclear envelope Portals called nuclearpores are rings of proteins that allow certainbiochemicals to exit or enter the nucleus

Lysosome

Peroxisome Centrioles

Nuclear pore

Microfilament

Mitochondrion

Rough endoplasmic reticulum

Nucleus

Nuclear envelope Nucleolus

Cell membrane

Smooth endoplasmic reticulum

Golgi apparatus

Microtubule Ribosome

0.3 µm 0.5 µm

3 µm

figure 2.3

Generalized animal cell Organelles provide specialized functions for the cell.

Reading 2.1

Inherited Illness at the Molecular Level

like maple syrup Tim slept most of thetime, and he vomited so often that he hardlygrew A blood test revealed that Tim had in-

herited maple syrup urine disease He could

not digest three types of amino acids tein building blocks), so these amino acidsaccumulated in his bloodstream A diet verylow in these amino acids has helped Tim,but this treatment is new and his future uncertain

(pro-Nucleic Acids

From birth, Michael’s wet diapers containedorange, sandlike particles, but otherwise heseemed healthy By six months of age,though, urination was obviously painful Aphysician also noted that Michael’s writhingmovements were involuntary rather thannormal attempts to crawl

When the doctor inspected the orangeparticles in Michael’s diaper, she suspected

Lesch-Nyhan syndrome, a disorder caused

by extremely low levels of an enzyme calledHGPRT A blood test confirmed the diagno-sis The near absence of the enzyme blockedMichael’s body from recycling two of thefour types of DNA building blocks, insteadconverting them into uric acid, which formscrystals in urine

Other symptoms that lay in Michael’sfuture were not as easy to understand—

severe mental retardation and seizures

Most inexplicable would be the aggressiveand self-destructive behavior that is a hall-mark of Lesch-Nyhan syndrome By agethree or so, Michael would respond to stress

by uncontrollably biting his fingers, lips,and shoulders He would probably die before the age of 30 of kidney failure or infection

Vitamins

Vitamins enable the body to use the hydrates, lipids, and proteins we eat Julie in-

carbo-herited biotinidase deficiency, which greatly

slows the rate at which her body can use thevitamin biotin

If Julie hadn’t been diagnosed in a sponsored newborn screening program andstarted on biotin supplements shortly afterbirth, her future would have been grave Byearly childhood, she would have shown a va-riety of biotin-deficiency symptoms, includ-ing mental retardation, seizures, skin rash,and loss of hearing, vision, and hair Herslow growth, caused by her body’s inability

state-to extract energy from nutrients, would haveeventually proved lethal

Minerals

Ingrid is in her thirties, but she lives in thegeriatric ward of a state mental hospital, un-able to talk or walk Although her grin anddrooling make her appear mentally defi-cient, Ingrid is alert and communicates us-ing a computer In 1980, she was a vivacious,normal high-school senior Then symptoms

of Wilson disease began to appear, as her

weakened liver could no longer control theexcess copper her digestive tract absorbedfrom food

The initial symptoms of Ingrid’s ited copper poisoning were stomachaches,headaches, and an inflamed liver (hepati-tis) By 1983, very odd changes began—slurred speech; loss of balance; a gravelly,low-pitched voice; and altered handwriting.Ingrid received many false diagnoses, in-cluding schizophrenia, multiple sclerosis,and Parkinson disease, before a psychiatristnoted the greenish rings around her irises(caused by copper buildup) and diagnosedWilson disease Only then did Ingrid receivehelpful treatment A drug, penicillamine,enabled her to excrete the excess copper inher urine, which turned the color of brightnew pennies Although Ingrid’s symptomsdid not improve, the treatment halted thecourse of the illness Without the drug, shewould have soon died

inher-nzymes are proteins that catalyze

(speed) chemical reactions

There-fore, enzymes control a cell’s

pro-duction of all types of

macromole-cules When the gene that encodes

an enzyme mutates, the result can be too

much or too little of the product of the

spe-cific biochemical reaction that the enzyme

catalyzes Following are examples of

inher-ited diseases that reflect imbalance or

ab-normality of particular molecules

Carbohydrate

The new parents grew frustrated as they

tried to feed their baby, who yowled and

pulled up her chubby legs in pain a few

hours after each formula feeding Finally, a

doctor identified the problem—the baby

lacked the enzyme lactase, which enables the

digestive system to break down milk sugar,

which is the carbohydrate lactose Bacteria

multiplied in the undigested lactose in the

child’s intestines, producing gas, cramps,

and bloating Switching to a soybean-based,

lactose-free infant formula helped She had

inherited lactose intolerance.

Lipid

A sudden sharp pain began in the man’s arm

and spread to his chest—the first sign of a

heart attack At age 36, he was younger than

most people who suffer heart attacks, but he

had inherited a gene that halved the number

of protein receptors for cholesterol on his

liver cells Because cholesterol could not

en-ter the liver cells efficiently, it built up in his

arteries, constricting blood flow in his heart

and eventually causing a mild heart attack A

fatty diet had accelerated his familial

hyper-cholesterolemia, an inherited form of heart

disease

Protein

The first sign that the newborn was ill was

also the most innocuous—his urine smelled

E

(figure 2.4) Within the nucleus, an area that

appears darkened under a microscope, the

nucleolus (“little nucleus”), is the site of

ri-bosome production The nucleus is filled

with DNA that is complexed with many

proteins to form chromosomes Other

pro-teins form fibers that give the nucleus a

roughly spherical shape RNA is abundant

too, as are the enzymes and protein factors

required to synthesize RNA from DNA The

material in the nucleus, minus these

con-tents, is called nucleoplasm

The remainder of the cell—that is,

everything but the nucleus, organelles, and

cell membrane—is the cytoplasm Other

cellular components include stored proteins,

carbohydrates, and lipids; pigment

mole-cules; and various other small chemicals

Secretion—The Eukaryotic

Production Line

Organelles interact to coordinate basic life

functions and sculpt the characteristics of

specialized cell types The activities of several

types of organelles may be coordinated to

provide a complex function such as secretion

Secretion begins when the body sends a

biochemical message to a cell to begin

pro-ducing a particular substance For example,

an infant suckling a mother’s breast causes

the release of hormones from her brain that

signal cells in her breast to begin producing

milk (figure 2.5) In response, information

in certain genes is copied into molecules of

messenger RNA (mRNA), which then exit

the nucleus (see step 2 in figure 2.5) In the

cytoplasm, the messenger RNAs, with the

help of ribosomes and another type of RNA

called transfer RNA, direct the

manufac-ture of milk proteins

Most protein synthesis occurs on a maze

of interconnected membranous tubules and

sacs that winds from the nuclear envelope to

the cell membrane This membrane

laby-rinth is the endoplasmic reticulum (ER).

The portion of the ER nearest the nucleus,

which is flattened and studded with

ribo-somes, is called the rough ER because it

ap-pears fuzzy when viewed under an electron

microscope Messenger RNA attaches to the

ribosomes on the rough ER Amino acids

from the cytoplasm are then linked,

follow-ing the instructions in the mRNA’s sequence,

to form particular proteins that will either

exit the cell or become part of membranes

Nuclear pore Cytoplasm

Inside nucleus

Nuclear envelope

1 1

2 2

3 3

5 5

6 6

7

4 4

Final processing of proteins

in Golgi and packaging for export out of cell.

Milk proteins and lipids are packaged into vesicles from both rough and smooth ER for transport to Golgi.

Proteins and lipids released from cell by fusion of vesicles with cell membrane.

mRNA forms complex with ribosomes and moves

to surface of rough ER where protein is made

To milk ducts

figure 2.4

The nucleus (a) The largest structure within a typical eukaryotic cell, the nucleus is

surrounded by two membrane layers, which make up the nuclear envelope (b) Pores through

the envelope allow specific molecules to move in and out of the nucleus

figure 2.5

Secretion Milk production and secretion illustrate organelle functions and interactions in a

cell from a mammary gland: (1) through (7) indicate the order in which organelles participate

in this process

(step 3, figure 2.5) Proteins are also

synthe-sized on ribosomes not associated with the

ER These proteins remain in the cytoplasm

(Recent experiments on mammalian cells

growing in culture suggest that some

pro-teins may be synthesized in the nucleus.)

The ER acts as a quality control center

for the cell Its chemical environment enables

the protein that the cell is manufacturing

to start folding into the three-dimensional

shape necessary for its specific function

Misfolded proteins are pulled out of the ER

and degraded, much as an obviously

defec-tive toy might be pulled from an assembly

line at a toy factory and discarded

As the rough ER winds out toward the

cell membrane, the ribosomes become fewer,

and the diameters of the tubules widen,

forming a section called the smooth ER

Here, lipids are made and added to the

pro-teins arriving from the rough ER (step 4,

fig-ure 2.5) The lipids and proteins travel until

the tubules of the smooth ER eventually

nar-row and end Then they exit in

membrane-bound, saclike organelles called vesicles that

pinch off from the tubular endings of the

membrane (step 5, figure 2.5)

A loaded vesicle takes its contents to the

next stop in the secretory production line,

the Golgi apparatus This processing center

is a stack of flat, membrane-enclosed sacs

Here, sugars are synthesized and linked to

form starches or attach to proteins to form

glycoproteins or to lipids to form

glyco-lipids Proteins finish folding in the Golgi

apparatus (step 6) The components of

complex secretions, such as milk, are

tem-porarily stored here Droplets then bud off

the Golgi apparatus in vesicles that move

outward to the cell membrane, fleetingly

becoming part of the membrane until they

are released (secreted) to the cell’s exterior

(step 7, figure 2.5) Some substances, such as

lipids, retain a layer of surrounding

mem-brane when they leave the cell

Cellular Digestion—Lysosomes

and Peroxisomes

Eukaryotic cells break down molecules and

other structures as well as produce them

Organelles called lysosomes are

membrane-bounded sacs that contain enzymes that

dis-mantle captured bacterial remnants,

worn-out organelles, and other debris (figure 2.6)

Lysosomal enzymes also break down some

digested nutrients into forms that the cellcan use Lysosomes fuse with vesicles carry-ing debris from the outside or from withinthe cell, and the lysosomal enzymes then degrade the contents A lysosome loadedwith such “garbage” moves toward the cellmembrane and fuses with it, dumping its

contents to the outside The word lysosome means “body that lyses;” lyse means “to cut.”

Lysosomal enzymes originate on the

ER These enzymes require a very acidic vironment, and the organelle maintains thisenvironment without harming other cellu-lar constituents

en-Cells differ in the number of lysosomesthey contain Certain white blood cells andmacrophages (see figure 2.2) are the body’sscavengers, moving about and engulfing

bacteria They are loaded with lysosomes.Liver cells require many lysosomes to breakdown cholesterol and toxins

All lysosomes contain more than 40types of digestive enzymes, which must be

in correct balance to maintain health.Absence or malfunction of just one type of

enzyme causes a lysosomal storage disease.

In these inherited disorders, the moleculethat the missing or abnormal enzyme nor-mally degrades accumulates The lysosomeswells, crowding organelles and interferingwith the cell’s functions In Tay-Sachs dis-ease, for example, deficiency of an enzymethat normally breaks down lipid in the cellsthat surround nerve cells buries the nervoussystem in lipid An affected infant begins tolose skills at about six months of age, then

Intracellular debris; damaged mitochondria

Budding vesicles with lysosomal enzymes: lysosomes

Digestion

Peroxisome fragment

Lysosome membrane

Mitochondrion fragment

Lysosomal enzymes

Golgi apparatus Cell

membrane

Extracellular debris

0.7 µm

figure 2.6

Lysosomes Lysosomes fuse with vesicles or damaged organelles, activating the enzymes

within to recycle the molecules for use by the cell Lysosomal enzymes also dismantle bacterialremnants These enzymes require a very acidic environment to function

gradually loses sight, hearing, and the

abil-ity to move, typically dying within three

years Even before birth, the lysosomes of

af-fected cells swell

Peroxisomes are sacs with outer

mem-branes that are studded with several types

of enzymes These enzymes perform a

vari-ety of functions, including breaking down

certain lipids and rare biochemicals,

syn-thesizing bile acids used in fat digestion,

and detoxifying compounds that result

from exposure to toxic oxygen-free

radi-cals Peroxisomes are large and abundant in

liver and kidney cells (figure 2.7) (The

Suggested Readings in chapter 12 lists a

re-cent article about a peroxisomal disease,

Zellweger syndrome.)

Absence or malfunction of a single

en-zyme in a lysosome or peroxisome results in

a general type of disorder called an inborn

error of metabolism The nature of the

ac-cumulating or missing substance

deter-mines specific symptoms

The 1992 film Lorenzo’s Oil recounted

the true story of a child with an inborn

er-ror of metabolism caused by an absent

per-oxisomal enzyme Six-year-old Lorenzo

Odone had adrenoleukodystrophy (ALD)

His peroxisomes lacked a normally dant protein that transports an enzyme intothe peroxisome, where it catalyzes a reac-tion that helps break down a certain type oflipid called a very-long-chain fatty acid

abun-Without the enzyme transporter protein,the cells of the brain and spinal cord accu-mulate the fatty acid Early symptoms in-clude low blood sugar, skin darkening,muscle weakness, and heartbeat irregulari-ties The patient eventually loses controlover the limbs and usually dies within a fewyears Ingesting a type of lipid in rapeseed(canola) oil—the oil in the film title—slowsbuildup of the very-long-chain fatty acidsfor a few years, but eventually impairsblood clotting and other vital functions

Ultimately, the illness progresses

The disappointment over the failure of

“Lorenzo’s oil” may be lessened by the newuse of a drug to activate a different gene

This gene’s protein product can replace themissing or abnormal one in ALD In micethat have the human ALD gene, and in cellstaken from children with ALD, the replace-ment gene stopped the buildup of very-long-chain fatty acids, and also increasedthe number of peroxisomes

Energy Production—Mitochondria

The activities of secretion, as well as themany chemical reactions taking place in thecytoplasm, require enormous and continual

energy Organelles called mitochondria

provide energy by breaking down the ucts of digestion (nutrients)

prod-A mitochondrion has an outer brane similar to those in the ER and Golgiapparatus and an inner membrane that isfolded into structures called cristae (figure2.8) These folds hold enzymes that catalyzethe biochemical reactions that release en-ergy from the chemical bonds of nutrientmolecules The bonds that hold together amolecule called adenosine triphosphate(ATP) capture this energy ATP is, therefore,

mem-a cellulmem-ar energy currency

The number of mitochondria in a cellvaries from a few hundred to tens of thou-sands, depending upon the cell’s activitylevel A typical liver cell, for example, hasabout 1,700 mitochondria, but a musclecell, with its very high energy requirements,has many more

Mitochondria are especially interesting

to geneticists because, like the nucleus, theycontain DNA, although a very small amount.Another unusual characteristic of mitochon-dria is that they are almost always inheritedfrom the mother only, because mitochondriaare in the middle regions of sperm cells butusually not in the head regions that entereggs Mitochondria that do enter with asperm are usually destroyed in the very earlyembryo A class of inherited diseases whosesymptoms result from abnormal mitochon-dria are always passed from mother to off-spring These illnesses usually produce ex-treme muscle weakness, because muscleactivity requires many mitochondria Chap-ter 5 discusses mitochondrial inheritance.Evolutionary biologists study mitochondrialgenes to trace the beginnings of humankind,discussed in chapter 15

Table 2.1 summarizes the structuresand functions of organelles

The Cell Membrane

Just as the character of a community ismolded by the people who enter and leave

it, the special characteristics of different celltypes are shaped in part by the substances

that enter and leave The cell membrane

Peroxisomes

Glycogen granules

Smooth endoplasmic reticulum

Protein crystal

0.5 µm

figure 2.7

Peroxisomes The high concentration of enzymes within peroxisomes results in

crystallization of the proteins, giving peroxisomes a characteristic appearance Peroxisomes

are abundant in liver cells, where they assist in detoxification processes

controls this process It forms a selectivebarrier that completely surrounds the celland monitors the movements of molecules

in and out of the cell The chemicals thatcomprise the cell membrane and how theyassociate with each other determine whichsubstances can enter or leave Similar mem-branes form the outer boundaries of severalorganelles, and some organelles consist en-tirely of membranes

A biological membrane is built of adouble layer (bilayer) of molecules called

phospholipids (figure 2.9) A phospholipid

is a lipid (fat) molecule with attached phate groups (PO4, a phosphorus atombonded to four oxygen atoms) The ability ofphospholipid molecules to organize them-selves into sheetlike structures makes mem-brane formation possible Phospholipids dothis because their ends have opposite reac-tions to water The phosphate end of a phos-pholipid is attracted to water, and thus is hy-drophilic (water-loving); the other end,which consists of two chains of fatty acids,moves away from water, and is therefore

phos-Cristae

Inner membrane

Outer membrane

0.5 µm

figure 2.8

A mitochondrion Cristae, infoldings of the inner membrane,

increase the available surface area containing enzymes for energy

reactions in this mitochondrion

t a b l e 2 1

Structures and Functions of Organelles

Endoplasmic Membrane network; rough Site of protein synthesis and

reticulum ER has ribosomes, smooth folding; lipid synthesis

ER does notGolgi apparatus Stacks of membrane- Site where sugars are made and

enclosed sacs linked into starches, or joined to

lipids or proteins; proteins finishfolding; secretions storedLysosome Sac containing digestive Degrades debris, recycles cell

Mitochondrion Two membranes; inner Releases energy from nutrients

membrane enzyme-studdedNucleus Porous sac containing DNA Separates DNA from rest of cell

Peroxisome Sac containing enzymes Catalyzes several reactions

Ribosome Two associated globular Scaffold and catalyst for protein

subunits of RNA and protein synthesisVesicle Membrane-bounded sac Temporarily stores or transports

substances

Cytoplasm

Microfilament (cytoskeleton) Cholesterol

Phospholipid bilayer

Outside cell

Proteins

Carbohydrate molecules

Glycoprotein

figure 2.9

Anatomy of a cell membrane In a cell membrane,

mobile proteins are embedded throughout a phospholipidbilayer, producing a somewhat fluid structure An underlyingmesh of protein fibers supports the cell membrane Jutting fromthe membrane’s outer face are carbohydrate molecules linked

to proteins (glycoproteins) and lipids (glycolipids)

hydrophobic (water-fearing) Because of

these water preferences, phospholipid

mole-cules in water spontaneously arrange into

bilayers, with the hydrophilic surfaces

ex-posed to the watery exterior and interior of

the cell, and the hydrophobic surfaces facing

each other on the inside of the bilayer, away

from the water

The phospholipid bilayer forms the

structural backbone of a biological

mem-brane Embedded in the bilayer are proteins,

some traversing the entire bilayer, others

poking out from either or both faces Other

molecules can attach to these membrane

proteins, forming glycoproteins and

glyco-lipids The proteins, glycoproteins, and

gly-colipids that jut from a cell membrane create

the surface topographies that are so

impor-tant in a cell’s interactions with other cells

Many molecules that extend from the

cell membrane serve as receptors These are

structures that have indentations or other

shapes that fit and hold molecules outside

the cell The molecule that binds to the

re-ceptor, called the ligand, sets into motion a

cascade of chemical reactions that carries

out a particular cellular activity This

process of communication from outside to

inside the cell is termed signal

transduc-tion Other membrane proteins enable a

cell to stick to other cells in a process called

cellular adhesion Signal transduction and

cellular adhesion are discussed in greater

detail in section 2.3 The surfaces of your

own cells indicate that they are part of your

body, and also that they have differentiated

in a particular way

The phospholipid bilayer is oily and

many of the proteins move within it like

ships on a sea The inner hydrophobic

re-gion of the phospholipid bilayer blocks

en-try and exit to most substances that dissolve

in water However, certain molecules can

cross the membrane through proteins that

form passageways, or when they are

es-corted by a “carrier” protein Some

mem-brane proteins form channels for ions,

which are atoms or molecules that bear an

electrical charge Reading 2.2 describes how

faulty ion channels can cause disease

The Cytoskeleton

The cytoskeleton is a meshwork of tiny

pro-tein rods and tubules that molds the

distinc-tive structures of cells, positioning

or-ganelles and providing three-dimensional

shapes The proteins of the cytoskeleton arebroken down and built up as a cell performsspecific activities Some cytoskeletal ele-ments function as rails, forming conduitsthat transport cellular contents; other parts

of the cytoskeleton, called motor molecules,power the movement of organelles alongthese rails by converting chemical energy tomechanical energy

The cytoskeleton includes three major

types of elements—microtubules,

micro-filaments, and intermediate filaments

(fig-ure 2.10) They are distinguished by proteintype, diameter, and how they aggregate intolarger structures Other proteins connectthese components to each other, creatingthe meshwork that provides the cell’sstrength and ability to resist forces, whichmaintains shape

Long, hollow microtubules providemany cellular movements A microtubule iscomposed of pairs (dimers) of a protein,called tubulin, assembled into a hollow tube.The cell can change the length of the tubule

by adding or removing tubulin molecules.Cells contain both formed micro-tubules and individual tubulin molecules.When the call requires microtubules tocarry out a specific function—dividing, forexample—the free tubulin dimers self-assemble into more tubules After the celldivides, some of the microtubules fall apartinto individual tubulin dimers This replen-ishes the cell’s supply of building blocks.Cells are in a perpetual state of flux, build-ing up and breaking down microtubules.Some drugs used to treat cancer affect themicrotubules that pull a cell’s duplicated

Protein dimer

Tubulin dimer

10 µm

figure 2.10

The cytoskeleton is made of protein rods and tubules The three major

components of the cytoskeleton are microtubules, intermediate filaments, and microfilaments.Through special staining, the cytoskeleton in this cell glows yellow under the microscope (nmstands for nanometer, which is a billionth of a meter.)

chromosomes apart, either by preventing

tubulin from assembling into microtubules,

or by preventing microtubules from

break-ing down into free tubulin dimers In each

case, cell division stops

Microtubules also form structures

called cilia that move or enable cells to

move Cilia are hairlike structures that

move in a coordinated fashion, producing a

wavelike motion An individual cilium is

constructed of nine microtubule pairs that

surround a central, separated pair A type of

motor protein called dynein connects the

outer microtubule pairs and also links

them to the central pair Dynein supplies

the energy to slide adjacent microtubules

against each other This movement bendsthe cilium Coordinated movement of thesecellular extensions sets up a wave thatmoves the cell or propels substances alongits surface Cilia beat particles up and out ofrespiratory tubules, and move egg cells inthe female reproductive tract Reading 2.3describes a condition caused by abnormaldynein that alters the positions of certainorgans in the body

Another component of the ton is the microfilament, which is a long,thin rod composed of the protein actin Incontrast to microtubules, microfilamentsare not hollow and are narrower Micro-filaments provide strength for cells to sur-

cytoskele-vive stretching and compressive forces.They also help to anchor one cell to anotherand provide many other functions withinthe cell through proteins that interact withactin When any of these proteins is absent

or abnormal, a genetic disease results.Intermediate filaments are so namedbecause their diameters are intermediatebetween those of the other cytoskeletal ele-ments Unlike microtubules and microfila-ments, which consist of a single protein, in-termediate filaments are made of differentproteins in different specialized cell types.However, all intermediate filaments share acommon overall organization of dimers en-twined into nested coiled rods Intermediate

Reading 2.2

Inherited Diseases Caused by Faulty Ion Channels

HPP results from abnormal sodiumchannels in the cell membranes of musclecells But the trigger for the temporaryparalysis is another ion: potassium A risingblood potassium level, which may follow in-tense exercise, slightly alters a muscle cellmembrane’s electrical charge Normally,this slight change would have no effect, but

in horses with HPP, sodium channels opentoo widely, allowing too much sodium intothe cell The muscle cell cannot respond tonervous stimulation for awhile, and theracehorse falls

People can inherit HPP, too In one ily, several members collapsed suddenly aftereating bananas! These fruits are very high inpotassium, which caused the symptoms

fam-Long-QT Syndrome and Potassium Channels

Four children in a Norwegian family wereborn deaf, and three of them died at agesfour, five, and nine All of the children hadinherited from unaffected carrier parents

long-QT syndrome associated with deafness.

(“QT” refers to part of a normal heartrhythm on an EKG.) They had abnormalpotassium channels in the heart muscle and

in the inner ear In the heart, the tioning channels disrupted electrical activ-

malfunc-ity, causing a fatal disturbance to the heartrhythm In the inner ear, the abnormalchannels caused an increase in the extracel-lular concentration of potassium ions, im-pairing hearing

Cystic Fibrosis and Chloride Channels

A 17th century English saying, “A child that

is salty to taste will die shortly after birth,”described the consequence of abnormalchloride channels in CF The chloride chan-nel is called CFTR, for cystic fibrosis trans-ductance regulator In most cases of CF,CFTR protein remains in the cytoplasm,unable to reach the cell membrane, where it

would function (see figure 2.1b) CF is

in-herited from carrier parents The majorsymptoms of difficulty breathing, frequentsevere respiratory infections, and a cloggedpancreas that disrupts digestion all resultfrom buildup of extremely thick mucoussecretions

Abnormal chloride channels in cells ing the lung passageways and ducts of thepancreas cause the symptoms of CF The pri-mary defect in the chloride channels alsocauses sodium channels to malfunction Theresult: salt trapped inside cells draws mois-ture in and thickens surrounding mucus

lin-hat do collapsing horses,

irreg-ular heartbeats in teenagers, and

cystic fibrosis have in common?

All result from abnormal ion

channels in cell membranes

Ion channels are protein-lined tunnels in

the phospholipid bilayer of a biological

membrane These passageways permit

elec-trical signals to pass in and out of membranes

in the form of ions (charged particles)

Ion channels are specific for calcium

(Ca+2), sodium (Na+), potassium (K+), or

chloride (Cl–) A cell membrane may have a

few thousand ion channels specific for each

of these ions Ten million ions can pass

through an ion channel in one second! The

following disorders result from abnormal

ion channels

Hyperkalemic Periodic

Paralysis and Sodium

Channels

The quarter horse was originally bred in the

1600s to run the quarter mile, but one of

the four very fast stallions used to establish

much of today’s population of 3 million

animals inherited hyperkalemic periodic

paralysis (HPP) The horse, otherwise a

champion, collapsed from sudden attacks

of weakness and paralysis

W

Reading 2.3

A Heart in the Wrong Place

die in childhood from heart abnormalities

Kartagener syndrome was first described in

1936 by a Swiss internist caring for a familywith several members who had strangesymptoms—chronic cough, sinus pain, poorsense of smell, male infertility, and mis-placed organs—usually a heart on the right

Many years later, researchers identifiedanother anomaly in patients with Kartagenersyndrome, which explained how the heartwinds up on the wrong side of the chest Allaffected individuals lack dynein, the proteinthat enables microtubules to slide past oneanother and generate motion Withoutdynein, cilia cannot wave In the upper respi-ratory tract, immobile cilia allow debris andmucus to accumulate, causing the cough,clogged sinuses, and poor sense of smell

Lack of dynein also paralyzes sperm tails,producing male infertility But how coulddynein deficiency explain a heart that devel-ops on the right instead of the left?

One hypothesis is based on the fact thatdynein helps establish the spindle, the struc-ture that determines the orientation of di-viding cells in the embryo with respect toeach other The dynein defect may, early on,set cells on a developmental pathway that

diverts normal migration of the heart fromthe embryo’s midline to the left

Another explanation for how organsend up in the wrong locations comes frommice genetically altered to lack a gene whoseprotein product is required for assemblingcilia About 50 percent of the mice have re-versed organs All of the animals either lackcilia that are normally present on cells of theearly embryo, called node cells, or the ciliacannot move Node cells are the sites wherethe first differences between right and leftarise, and they set the pattern for organplacement Normally, the cilia rotate coun-terclockwise, which moves fluids to the left.This movement creates a gradient (changingconcentration across an area) of molecules,called morphogens, that control develop-ment The differing concentrations of spe-cific morphogens in different parts of thebody may send signals that guide the devel-opment of organs Without cilia that canmove, organs wind up on the left or the right

at random This is why only 50 percent ofthe genetically altered mice, and presumablynot all people who inherit Kartagener syn-drome, have organs in the wrong place Just

by chance, some of them develop normally

Right lung

Left lung

Heart

b.

Heart Lobes of left lung Liver

a.

Lobes of

right lung

Spleen Stomach

n the original Star Trek television

se-ries, Dr McCoy often complained

when examining Mr Spock that

Vul-can organs weren’t where they were

supposed to be, based on human

anat-omy The good doctor would have had a

hard time examining humans with a

condi-tion called situs inversus, in which certain

normally asymmetrically located organs

de-velop on the wrong side of the body

In a normal human body, certain

or-gans lie either on the right or the left of the

body’s midline The heart, stomach, and

spleen are on the left, and the liver is on the

right The right lung has three sections, or

lobes; the left lung has two Other organs

twist and turn in either a right or left

direc-tion All these organs originate in the center

of an initially symmetrical embryo, and

then the embryo turns, and the organs

mi-grate to their final locations

Misplaced body parts are a symptom of

Kartagener syndrome, in which the heart,

spleen, or stomach may be on the right, both

lungs may have the same number of lobes,

the small intestine may twist the wrong way,

or the liver may span the center of the body

(figure 1) Many people with this syndrome

I

figure 1

Situs inversus The drawing on the left (a) shows the normal position of the heart, lungs, liver, spleen, and stomach In situs inversus, certain

organs form on the wrong side of the body (b) Note the location of the heart.

Minor mechanical stress

a.

b.

Blister

filaments are scarce in many cell types, but

are very abundant in skin

Intermediate filaments in actively

di-viding skin cells in the bottommost layer of

the epidermis form a strong inner

frame-work which firmly attaches the cells to each

other and to the underlying tissue These

cellular attachments are crucial to the skin’s

barrier function In a group of inherited

conditions called epidermolysis bullosa,

in-termediate filaments are abnormal, which

causes the skin to blister easily as tissue

lay-ers separate (figure 2.11)

Disruption in the structures of

cy-toskeletal proteins, or in how they interact,

figure 2.11

Intermediate filaments in skin Keratin intermediate filaments internally support cells in

the basal (bottom) layer of the epidermis (a) Abnormal intermediate filaments in the skin cause

epidermolysis bullosa, a disease characterized by the ease with which skin blisters (b).

Cytoplasm

Ankyrin Interior

face of cell

Phospholipid bilayer

Extracellular matrix (outside of cell)

Carbohydrate molecules

Glycoprotein

a.

b.

figure 2.12

The red blood cell

membrane (a) The

cytoskeleton that supports the cellmembrane of a red blood cellenables it to withstand the greatturbulent force of circulation

(b) In the cell membrane, proteins

called ankyrins bind molecules ofspectrin from the cytoskeleton tothe interior face On its other end,ankyrin binds proteins that helpferry molecules across the cellmembrane In hereditaryspherocytosis, abnormal ankyrincauses the cell membrane tocollapse—a problem for a cellwhose function depends upon its shape

can be devastating Consider hereditaryspherocytosis, which disturbs the interfacebetween the cell membrane and the cy-toskeleton in red blood cells

The doughnut shape of normal redblood cells enables them to squeezethrough the narrowest blood vessels Rods

of a protein called spectrin form a work beneath the cell membrane, strength-ening the cell, and proteins called ankyrinsattach the spectrin rods to the cell mem-brane (figure 2.12) Spectrin also attaches

mesh-to the microfilaments and microtubules ofthe cytoskeleton Spectrin molecules arelike steel girders, and ankyrins are like nuts

and bolts If either ankyrins or spectrin is

absent, the cell collapses

In hereditary spherocytosis, the

ankyr-ins are abnormal, parts of the red blood cell

membrane disintegrate, and the cell

bal-loons out The bloated cells obstruct narrow

blood vessels—especially in the spleen, the

organ that normally disposes of aged red

blood cells Anemia develops as the spleen

destroys red blood cells more rapidly than

the bone marrow can replace them,

produc-ing great fatigue and weakness Removproduc-ing

the spleen can treat the condition

Cell cycle rate varies in different tissues

at different times A cell lining the small testine’s inner wall may divide throughoutlife; a cell in the brain may never divide; acell in the deepest skin layer of a 90-year-old may divide more if the person lives longenough Frequent mitosis enables the em-bryo and fetus to grow rapidly By birth, themitotic rate slows dramatically Later, mito-sis must maintain the numbers and posi-tions of specialized cells in tissues and or-gans

in-The cell cycle is a continual process,but we divide it into stages based on what

we see The two major stages are interphase

(not dividing) and mitosis (dividing) ure 2.14) In mitosis, a cell’s replicatedchromosomes are distributed into twodaughter cells This maintains the set of 23chromosome pairs characteristic of a hu-man somatic cell Another form of cell divi-sion, meiosis, produces sperm or eggs

(fig-These cells contain half the usual amount

of genetic material, or 23 single somes Chapter 3 discusses meiosis

chromo-Interphase—A Time of Great Activity

Interphase is a very active time The cellcontinues the basic biochemical functions

of life and also replicates its DNA and othersubcellular structures for distribution todaughter cells

Interphase is divided into two gap (G)

phases and one synthesis (S) phase A cell

can exit the cell cycle at G1to enter G0, a escent phase A cell in G0can maintain itsspecialized characteristics, but it does notreplicate its DNA or divide It is a cellular

qui-“time out.” During the first gap phase (G1),the cell resumes synthesis of proteins, lipids,and carbohydrates following mitosis These

Cells are the units of life They consist

mostly of carbohydrates, lipids, proteins,

and nucleic acids • Organelles

subdi-vide specific cell functions They include

the nucleus, the endoplasmic reticulum

(ER), Golgi apparatus, mitochondria,

lysosomes, and peroxisomes • The cell

membrane is a flexible, selective

phos-pholipid bilayer with embedded proteins

• The cytoskeleton is an inner structural

framework made of protein rods, tubules,

connectors, and motor molecules

and Death

The cell numbers in a human body must be in

balance to develop normally and maintain

health The process of mitotic cell division, or

mitosis, provides new cells by forming two

cells from one Mitosis occurs in somatic cells

(all cells but the sperm and eggs) Although it

seems counterintuitive, some cells must die as

a body forms, just as a sculptor must take away

some clay to shape the desired object A foot,

for example, might start out as a webbed

trian-gle of tissue, with digits carved from it as

cer-tain cells die This type of cell death, which is a

normal part of development, is called

apopto-sis It is a precise, genetically programmed

se-quence of events, as is mitosis (figure 2.13)

The Cell Cycle

Many cell divisions transform a single

fertil-ized egg into a many-trillion-celled person A

series of events called the cell cycle describes

when a cell is dividing or not dividing

Cell division Cell death

figure 2.13

Mitosis and apoptosis mold a body.

Biological structures in animal bodiesenlarge, allowing organisms to grow, asopposing processes regulate cell number

Cell numbers increase from mitosis anddecrease from apoptosis

In

rph

M ito sis

Remain specialized

Cell death

Proceed to division

Telophase Cytokinesis

figure 2.14

The cell cycle The cell cycle is divided

into interphase, when cellular componentsare replicated to prepare for division, andmitosis, when the cell splits in two,distributing its contents into two daughtercells Interphase is divided into two gapphases (G1and G2), when the cellduplicates specific molecules and structures,and a synthesis phase (S), when it replicatesthe genetic material Mitosis is divided intofour stages, plus cytokinesis, which is whenthe cells physically separate Another stage,

G0, is a “time-out” when a cell “decides”which course of action to follow

molecules will surround the two new cells

that form from the original one G1is the

period of the cell cycle that varies the most

in duration among different cell types

Slowly dividing cells, such as those in the

liver, may exit at G1and enter G0, where they

remain for years In contrast, the rapidly

di-viding cells in bone marrow speed through

G1in 16 to 24 hours Early cells of the

em-bryo may skip G1entirely

During the next period of interphase, S

phase, the cell replicates its entire genome, so

that each chromosome consists of two

copies joined at an area called the

cen-tromere In most human cells, S phase takes

8 to 10 hours Many proteins are also

synthe-sized during this phase, including those that

form the mitotic spindle structure that will

pull the chromosomes apart Microtubules

form structures called centrioles near the

nucleus Centriole microtubules are

ori-ented at right angles to each other, forming

paired oblong structures that organize other

microtubules into the spindle

The second gap phase, G2, occurs after

the DNA has been replicated but before

mi-tosis begins A cell in this phase synthesizes

more proteins Membranes are assembled

from molecules made during G1and stored

as small, empty vesicles beneath the cell

membrane These vesicles will be used to

enclose the two daughter cells

Mitosis—The Cell Divides

As mitosis begins, the chromosomes are

replicated and condensed enough to be

visi-ble, when stained, under a microscope The

two long strands of identical chromosomal

material of a replicated chromosome are

called chromatids (figure 2.15) They are

joined at their centromeres At a certain

point during mitosis, a replicated

chromo-some’s two centromeres part, allowing each

chromatid pair to separate into two

individ-ual chromosomes

During prophase, the first stage of

mi-tosis, DNA coils tightly, shortening and

thickening the chromosomes, which

en-ables them to more easily separate (figure

2.16) Microtubules assemble to form the

spindle from tubulin building blocks in the

cytoplasm Toward the end of prophase, the

nuclear membrane breaks down The

nucle-olus is no longer visible

Metaphase follows prophase

Chromo-somes attach to the spindle at their

cen-tromeres and align along the center of thecell, which is called the equator When thecentromeres part, each daughter cell re-ceives one chromatid from each replicatedchromosome Metaphase chromosomes areunder great tension, but they appear mo-tionless because they are pulled with equalforce on both sides, like a tug-of-war ropepulled taut

Next, during anaphase, the cell

mem-brane indents at the center, where themetaphase chromosomes line up A band ofmicrofilaments forms on the inside face ofthe cell membrane, and it constricts the celldown the middle Then the centromerespart, which relieves the tension and releasesone chromatid from each pair to move toopposite ends of the cell—like a tug-of-warrope breaking in the middle and the partici-pants falling into two groups Microtubulemovements stretch the dividing cell During

the very brief anaphase stage, a cell porarily contains twice the normal number

tem-of chromosomes because each chromatidbecomes an independently moving chro-mosome, but the cell has not yet physicallydivided

In telophase, the final stage of mitosis,

the cell looks like a dumbbell with a set ofchromosomes at each end The spindle fallsapart, and nucleoli and the membranesaround the nuclei re-form at each end of theelongated cell Division of the genetic mate-rial is now complete Next, during a process

called cytokinesis, organelles and

macro-molecules are distributed between the twodaughter cells Finally, the microfilamentband contracts like a drawstring, separatingthe newly formed cells

Control of the Cell Cycle

When and where a somatic cell divides iscrucial to health, and regulation of mitosis

is a daunting task Quadrillions of mitosesoccur in a lifetime, and these cell divisions

do not occur at random Too little mitosis,and an injury may go unrepaired; too much,and an abnormal growth forms

Groups of interacting proteins

func-tion at times called checkpoints to ensure

that chromosomes are faithfully replicatedand apportioned into daughter cells (fig-ure 2.17) A “DNA damage checkpoint,”for example, temporarily pauses the cellcycle while special proteins repair dam-aged DNA The cell thus gains time to re-cover from an injury An “apoptosis check-point” turns on as mitosis begins Duringthis checkpoint, proteins called survivinsoverride signals telling the cell to die,keeping it in mitosis rather than apopto-sis Later during mitosis, the “spindle as-sembly checkpoint” oversees construction

of the spindle and the binding of somes to it

chromo-Cells obey an internal “clock” thattells them how many times to divide.Mammalian cells grown (cultured) in adish divide about 40 to 60 times A con-nective tissue cell from a fetus, for exam-ple, divides on average about 50 times But

a similar cell from an adult divides only 14

to 29 times The number of divisions leftdeclines with age

How can a cell “know” how many sions it has undergone and how many re-main? The answer lies in the chromosome

divi-Unreplicated chromosome

Replicated chromosome

Furrow Chromatids

Centromere

Sister chromatids

DNA synthesis and condensation

of a replicated chromosome join at the

centromere (a) In the photograph (b), a

human chromosome is in the midst offorming two chromatids A longitudinalfurrow extends from the chromosome tips inward

tips, called telomeres (figure 2.18)

Telo-meres function like a cellular fuse that burnsdown as pieces are lost from the very ends.Telomeres have hundreds to thousands ofrepeats of a specific six-nucleotide DNA se-quence At each mitosis, the telomeres lose

50 to 200 of these nucleotides, graduallyshortening the chromosome like a fuse.After about 50 divisions, a critical amount

of telomere DNA is lost, which signals sis to stop The cell may remain alive but notdivide again, or it may die An enzymecalled telomerase keeps chromosome tipslong in eggs and sperm, in cancer cells, and

mito-in a few types of normal cells (such as bonemarrow cells) that must supply many newcells However, most cells do not producetelomerase, and their chromosomes gradu-ally shrink Telomerase includes a six-baseRNA sequence that functions as a model, ortemplate, used to add DNA nucleotides totelomeres Figure 17.1 depicts the action attelomeres

Outside factors also affect a cell’s totic clock Crowding can slow or halt mito-

mi-Chromatid pairs Nuclear membrane Spindle fibers

Mitosis in a human cell During

interphase (a), chromosomes are not yet

condensed, and hence not usually visible

(b) In prophase, chromosomes are

condensed and visible when stained The

spindle assembles, centrioles appear at

opposite poles of the cell, and the nuclear

membrane breaks down (c) During

metaphase, chromosomes align along the

spindle (d) In anaphase, the centromeres

part and the chromatids separate (e) In

telophase, the spindle disassembles and the

nuclear membrane re-forms In a separate

process, cytokinesis, the cytoplasm and

other cellular structures distribute and pinch

off into two daughter cells

Are chromosomes aligned down the equator?

Apoptosis checkpoint

Spindle assembly checkpoint

Telophase Cytokinesis

DNA damage

checkpoint

If survivin accumulates, mitosis ensues

figure 2.17

Cell cycle checkpoints Checkpoints ensure that events occur in the correct sequence.

Many types of cancer result from deranged checkpoints

sis Normal cells growing in culture stop viding when they form a one-cell-thicklayer lining the container If the layer tears,the cells that border the tear grow and di-vide to fill in the gap, but stop dividing once

di-it is filled Perhaps a similar mechanism inthe body limits mitosis

Chemical signals control the cell cyclefrom outside as well as from inside the cell

Hormones and growth factors are icals from outside the cell that influence mi-totic rate A hormone is a substance synthe-sized in a gland and transported in thebloodstream to another part of the body,where it exerts a specific effect Hormonessecreted in the brain, for example, signal thecells lining a woman’s uterus to build upeach month by mitosis in preparation forpossible pregnancy Growth factors actmore locally Epidermal growth factor, forexample, stimulates cell division beneath ascab

biochem-Two types of proteins, cyclins and nases, interact inside cells to activate thegenes whose products carry out mitosis

ki-The two types of proteins form pairs Levels

of cyclins fluctuate regularly throughout thecell cycle, while kinase levels stay the same

A certain number of cyclin-kinase pairsturn on the genes that trigger mitosis Then,

as mitosis begins, enzymes degrade cyclin.The cycle starts again as cyclin begins tobuild up during the next interphase

Apoptosis

Apoptosis rapidly and neatly dismantles acell into neat, membrane-bounded piecesthat a phagocyte (a cell that engulfs and de-stroys another) can mop up It is a little liketaking the contents of a messy room andpackaging them into garbage bags—thendisposing of it all

Like mitosis, apoptosis is a continuousprocess that occurs in a series of steps It be-gins when a “death receptor” on the doomedcell’s membrane receives a signal to die With-

in seconds, enzymes called caspases are vated inside the cell, stimulating each otherand snipping apart various cell components

figure 2.18

Telomeres Fluorescent tags mark the

telomeres in this human cell