Chapter 4: The Chromosome Theory of Inheritance

Chapter 4: The Chromosome Theory of Inheritance CHAPTER OUTLINE: 4.1 Chromosomes: The Carriers of Genes 4.2 Mitosis: Cell Division That Preserves Chromosome Number 4.3 Meiosis: Cell

Chapter 4: The Chromosome

Theory of Inheritance

CHAPTER OUTLINE:

4.1 Chromosomes: The Carriers of Genes

4.2 Mitosis: Cell Division That Preserves

Chromosome Number

4.3 Meiosis: Cell Divisions That Halve

Chromosome Number

4.4 Gametogenesis

4.5 Validation of the Chromosome Theory

Chapter 4 of the textbook: Genetics: From Genes

to Genomes, 4th edition (2011), Hartwell H et al

1

Down syndrome: One extra chromosome 21 has widespread phenotypic consequences

Trisomy 21, gives rise to an abnormal phenotype, including a

wide skull, an unusually large

tongue, learning disabilities, as well

as heart disorders, rapid aging, and

leukemia

How can one extra copy of

a chromosome that is itself of

normal size and shape cause such

wide-ranging phenotypic effects?

http://anthro.palomar.edu/abnor mal/images/Down_Syndrome_ Karyotype.jpg

4.1 Chromosomes: The Carriers of

Genes

3

Evidence that Genes Reside in the Nucleus

• 1667 – Anton van Leeuwenhoek

– Microscopist

– Semen contains spermatozoa (sperm animals)

– Hypothesized that sperm enter egg to achieve fertilization

• 1854-1874 – confirmation of fertilization through

union of eggs and sperm, main parts are their nuclei – Recorded frog and sea urchin fertilization using microscopy and time-lapse drawings and micrographs

Genes reside in chromosomes

• 1880s – innovations in microscopy and staining techniques

identified thread-like structures

• Provided a means to follow movement of chromosomes during cell division

• Mitosis - nuclear division that generates two daughter cells

containing the same number and type of chromosomes as

parent cell

• Meiosis - Nuclear division that generates gametes (egg and

sperm) containing half the number of chromosomes found in other cells

4

Fertilization: The union of haploid gametes to produce diploid zygotes

• Fertilized eggs carry matching sets of chromosomes, one set from maternal gamete and one set from paternal gamete

• Gametes are haploid (n) – carry only a single set of

Diploid versus haploid: 2n versus n

6

Most body cells are diploid (each

chromosome pair has one

maternal and one paternal copy)

In Drosophila, 2n = 8, n = 4

In humans , 2n = 46 and n = 23

Nomenclature for Drosophila genetics

• Homologous chromosomes contain the same set of genes, but can have different alleles for some genes

• Nonhomologous chromosomes carry completely unrelated sets of genes

7

Karyotype of a human male

• Karyotype – micrograph of stained chromosomes arranged in homologous pairs

– Sex chromosomes – unpaired X and Y chromosome

– Autosomes – all chromosomes except X and Y

• Each homologous pair arranged in order of decreasing size

8 Fig 4.4

Sex chromosomes: one chromosome pair determines sex in grasshoppers

• W S Sutton studied meiosis in great lubber grasshoppers

• Before meiosis, testes cells had 24 chromosomes

– 22 in matched pairs (autosomes) and 2 unmatched (large = X and smaller

= Y)

• After meiosis, two types of sperm were formed and

separated:

– 1/2 of sperm had 11 chromosomes and an X

– 1/2 of sperm had 11 chromosomes and a Y

• After meiosis, only one type of egg was produced

– All had 11 chromosomes plus an X

• Then Sutton did the fertilization as follow:

9

The great lubber grasshopper

• Sutton concluded that the X and Y chromosomes determine sex

10 Fig 4.5

The great lubber grasshoppers

(Brachystola magna)

In this mating pair, the smaller

male is astride the female

The X and Y chromosomes determine

sex in humans

11

• Children receive an X chromosome from their mother, but

either an X or Y chromosome from their father

• Results in 1:1 ratio of females-to-males

Species variations in sex determination

• In Drosophila, ratio of X chromosomes to autosomes

determines gender

• In humans, presence or absence of Y chromosome

determines gender

• Abnormal numbers of X or Y chromosomes have different

effects in humans and flies

12 Table 4.1

4.2 Mitosis: Cell Division That Preserves Chromosome Number

Some terminally differentiated cells

stop dividing and arrest in G0 stage

Chromosomes replicate to form

sister chromatids during S phase

Chromosomes replicate during S phase

• G1 phase – chromosomes

are not duplicating or

dividing Length of time

varies in different cell types

During interphase, cells grow and

replicate their chromosomes

Interphase – period of cell cycle between divisions During interphase, cells grow and replicate their chromosomes

• Within nucleus:

− G1, S, and G2 phase – cell growth, protein synthesis, chromosome replication

• Outside of nucleus: Formation of microtubules radiating out

into cytoplasm, crucial for interphase processes

− Centrosome – organizing center for microtubules located near nuclear envelope

− Centrioles – pair of small darkly stained bodies at center of centrosome in animals (not found in plants)

15

VNU-University of Science - DNThai

During mitosis, sister chromatids separate and two daughter nuclei form

The five stages of mitosis and their major events

• Prophase - (from the Greek pro- meaning “before”), chromosomes condense and become visible

• Prometaphase – (“before middle stage”), spindle forms and sister chromatids attach to microtubules from opposite centrosomes

• Metaphase – (“middle stage”), chromosome align at the cell's

equator

• Anaphase – (from the Greek ana- meaning “up” as in “up toward

the poles”), sister chromatids separate and move to opposite poles

• Telophase – (from the Greek telomeaning “end”), chromosomes

decondense and are enclosed in two nuclei

16

Prophase -Chromosomes condense

– Inside nucleus

• Chromosomes condense into structures suitable for replication

• Nucleoli begin to break down and disappear

– Outside nucleus

• Centrosomes which replicated during interphase move apart and migrate

to opposite ends of the nucleus

• Interphase microtubules disappear and are replaced by microtubules that rapidly grow from and contract back to centrosomal organizing centers

Fig 4.8a

Prometaphase: The spindle forms

18

Fig 4.8b

– Nuclear envelope breaks down

– Microtubules invade nucleus

– Chromosomes attach to microtubules through kinetochore – Mitotic spindle – composed of three types of microtubules

• Kinetochore microtubules – centrosome to kinetochore

• Polar microtubules – centrosome to middle of cell

• Astral microtubules – centrosome to cell’s periphery

Metaphase: Chromosomes align at the

cell’s equator

• Chromosomes align on the metaphase plate with sister chromatids facing opposite poles

• Forces pushing and pulling chromosomes to or from

each pole are in balanced equilibrium

19 Fig 4.8c

Anaphase: Sister chromatids move to

opposite spindle poles

• Centromeres of all chromosomes divide simultaneously

• Kinetochore microtubules shorten and pull separated

sister chromatids to opposite poles (characteristic V

shape)

20 Fig 4.8d

Telophase: Identical sets of chromosomes are enclosed in two nuclei

• Spindle fibers disperse

• Nuclear envelope forms around group of chromosomes

Cytokinesis is the final stage of cell

Cytokinesis – The cytoplasm divides,

producing two daughter cells

• Animals have contractile

ring that contracts to form

cleavage furrow

• Plants have cell plate that

forms near equator of cell

the next step of

the cycle can

begin

4.3 Meiosis: Cell Divisions That Halve

Chromosome Number

• Somatic cells make up vast majority of cells in the

mitosis

• Germ cells are precursors to gametes

– Set aside from somatic cells during embryogenesis – Become incorporated into reproductive organs

– Only cells that undergo meiosis produce haploid

gametes

25

An overview of meiosis

• The chromosomes

replicate once, while the

nuclei divide twice thus

halve chromosome

number

• During meiosis I,

homologs pair, exchange

parts, and then

Prophase I: Homologs condense and pair, and

crossing-over occurs with five substages

• Leptotene (from the Greek for “thin” and “delicate”)

• Zygotene (from the Greek for “conjugation”)

• Pachytene (from the Greek for “thick” or “fat”)

• Homologs pair and are held together by synaptonemal

complex; Crossing-over occurs during prophase I

27

The last two substages of prophase:

Diplotene and diakinesis

• Diplotene (from the Greek for “twofold” or “double”)

• Diakinesis (from the Greek for “double movement”)

• Synaptonemal complex dissolves and chromatids in each tetrad become visible

28

Metaphase I and Anaphase I

• Metaphase I: Paired homologs attach to spindle fibers from opposite poles; Anaphase I: Homologs move to opposite spindle poles

• Note that the centromeres do not divide and sister chromatids are not separated

29

Telophase I and Interkinesis

• Meiosis I is often called a reductional division, because

the number of chromosomes is reduced to one-half the normal diploid number

30

During meiosis II, sister chromatids separate to produce haploid gametes

31 Feature Fig 4.13

Meiosis II is an equational division

32 Feature Fig 4.13

Mistakes in meiosis produce defective

gametes

• Nondisjunction – mistakes in chromosome

segregation during meiosis I or II

– May result in inviable gametes or embryos

– Can also result in abnormal chromosome numbers in

viable individuals (e.g trisomy 21, Down syndrome; or XXY, Klinefelter syndrome)

• Many hybrids between species (i.e donkey x horse

 mule) are sterile because chromosomes cannot pair properly

33

Comparison of mitosis and meiosis

35 Table 4.3

Comparison of mitosis and meiosis

(continued)

36 Table 4.3

4.4 Gametogenesis – the formation of

gametes

• Germ line – specialized diploid cells set aside during embryogenesis

• Gametogenesis in sexually reproducing animals

– Involves meiosis as well as specialized events before and after meiosis

– Different types of animals have variations on general aspects of this process

– In humans, oogenesis produces one ovum from each primary

oocyte – In humans, spermatogenesis produces four sperm from each

primary spermatocyte

37

The chromosome theory correlates Mendel’s

laws with chromosome behavior during meiosis

Chromosome Behavior

 Each cell contains two copies of each

chromosome

 Chromosome complements appear

unchanged during transmission from parent

to offspring

 Homologous chromosomes pair and then

separate to different gametes

 Maternal and paternal copies of

chromosome pairs separate without regard

to the assortment of other homologous

chromosome pairs

 At fertilization an egg’s set of

chromosomes unite with randomly

encountered sperm’s chromosomes

 In all cells derived from a fertilized egg,

one half of chromosomes are of maternal

origin, and half are paternal

 In all cells derived from a fertilized gamete, one half of genes are of maternal origin, and half are paternal

4.5 Validation of the Chromosome

Theory

In 1903, Walter Sutton suggested that chromosomes

carry Mendel's units of heredity

A test of the chromosome theory: If genes are on specific chromosomes, then traits determined by the gene should be transmitted with the chromosomes

By doing the experiment in Drosophila, Thomas Hunt Morgan,

an American experimental biologist, demonstrated sex-linked

inheritance of a gene determining eye-color, the result confirmed definitely that the transmission of traits with chromosomes

39

Nomenclature for Drosophila genetics

40

Gene symbol identified by abnormal phenotype

Wild-type allele denoted with superscript +

Recessive mutant allele denoted with lowercase

 e.g gene symbol for white gene is w

 wild-type allele (w +) specifies brick-red eyes

 mutant allele (w) specifies white eyes

Dominant mutant allele denoted with upper case

 e.g gene symbol for bar eyes is Bar

 wild-type allele (Bar +) specifies normal eye

 mutant allele (Bar) specifies abnormal eyes

The Drosophila white gene is located on the

X chromosome, no gene in Y chromosome

• T H Morgan (1910) discovered a white-eyed Drosophila mutant

and did a series of crosses

• At a cross D – daughters inherit the phenotype of their fathers, sons inherit the phenotype of their mothers (crisscross inheritance)

Support for the chromosome theory from the analysis of nondisjunction

• C Bridges found 1/2000

male progeny of white

females have red eyes

• Hypothesized that red-eyed

males arise from mistakes in

Example of an X-linked trait in humans

(Top) View of the world to a person with

normal color vision

(Bottom) View of the world to a person with

red-green colorblindness

E B Wilson – 1911, assigned gene for this

trait to the X chromosome

An example of a pedigree for an X-linked recessive trait: Hemophilia

45 Fig 4.22a

An example of a pedigree for an X-linked

dominant trait: Hypophosphatemia

46 Fig 4.22b

division, the chromosomes again duplicate to form sister

chromatids

Essential Concepts

• During the first and second divisions of meiosis, homologous chromosomes in germ cells segregate from each other As a

result, each gamete receives one member of each matching pair,

as predicted by Mendel’s first law

• Also during the first meiotic division, the independent

alignment of each pair of homologous chromosomes at the

cellular midplane results in the independent assortment of genes carried on different chromosomes, as predicted by Mendel’s

second law

• Crossing-over and the independent alignment of homologs

during the first meiotic division generate diversity

rare mistakes in meiotic chromosome segregation

(nondisjunction) yielded more detailed proof that specific genes are carried on specific chromosomes

Chapter 5: Linkage, Recombination

and the Mapping of Genes on

Chromosomes

CHAPTER OUTLINE:

5.1 Gene Linkage and Recombination

5.2 The Chi-Square Test and Linkage Analysis

5.3 Recombination: A Result of Crossing-Over During

Meiosis

5.4 Mapping: Locating Genes Along a Chromosome

Chapter 5 of the textbook: Genetics: From Genes

to Genomes, 4th edition (2011), Hartwell H et al

50

Pedigrees indicate that colorblindness and

two forms of hemophilia are X-linked traits

(a) Transmission of

colorblindness and hemophilia A

The traits travel together through

the pedigree, indicating their

genetic linkage

(b) Transmission of

colorblindness and hemophilia B

Even though both genes are X

linked, the mutant alleles are

inherited together in only one of

four grandsons in generation III

These two pedigrees indicate that the gene for colorblindness is close

to the hemophilia A gene but far away from the hemophilia B gene

5.1 Gene linkage and recombination

• Genes linked together on the same chromosome usually assort together

• Linked genes may become separated by recombination

Two themes in this chapter:

• Further apart two genes are, the greater the probability of

recombination

• Recombination data can be used to generate maps of relative

locations of genes on chromosomes

Detecting linkage by analyzing the progeny

of dihybrid crosses: X-linked genes

Syntenic genes – genes located on the same chromosome

Two X-linked genes in Drosophila with recessive alleles

• w+ (red eyes) and w (white eyes)

• y+ (brown body) and y (yellow body)

Note that in this cross:

 F1 males get their only X

chromosome from their mothers

 F1 females are dihybrids