Evolutionary genetics, concepts and case studies c fox, j wolf (oxford, 2006) 1

Chippindale Department of Biology Queen's University Kingston, Ontario K7L 3N6, Canada Aviv Bergman Department of Pathology and Molecular Genetics Albert Einstein College of Medicine

EVOLUTIONARY GENETICS Concepts and Case Studies

Concepts and Case Studies

AG = G(Y-PP) G + 2M

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Charles W Fox Jason B Wolf

Copyrighted mate ■

EVOLUTIONARY GENETICS

Copyrighted material

1 *

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Evolutionary genets»; concepts and case srudhcVrdited by Oiaries V Pox, Jason B Wolf

| I ) N I M : L Genetic*, Population 2- F.volufson 3, Gcitotypt* 4T M o M s Genetic* 5 Variation (Genetics)

Q H 4SfF.92S 2005) 1 Fox, Charles W I I Wolf, Jason K

Preface

Ev o l u t i o n a r y genetics is 1 broad field that has T h e signature o f this r e v o l u t i o n is clearly seen 111 seen p a r t i c u l a r l y r a p i d g r o w t h a n d expansion this v o l u m e , in w h i c h t h e m a j o r i t y o f chapters

in recent years T h i s diverse field is u n i f i e d hy a sec discuss patterns o r processes t h a i occur at t h e

o f m i r r o r -image goals: (1) t o understand the impact molecular level o r have been influenced by t h e

t h a t e v o l u t i o n a r y processes have o n the patterns o f a v a i l a b i l i t y of m o l e c u l a r d a t a

genetic v a r i a t i o n w i t h i n a n d a m o n g p o p u l a t i o n s o r A l t h o u g h w e m a y define e v o l u t i o n a r y genetics species a n d (2) t o understand the consequences o f as a single integrated f i e l d , there is a c o n t i n u u m in these patterns o f genetic v a r i a t i o n l o r various e v o l u * t h e degree t o w h i c h research is e v o l u t i o n a r y versus

l i o n a r y processes Research i n evolutionary genetic* genetic At one extreme» e v o l u t i o n a r y genetics stretches across a c o n t i n u u m o f scale, f r o m studies informs molecular geneticists, whose primary interest

o f D N A sequence e v o l u t i o n (e.g Chapters 7 a n d 9i may he f i n d i n g a n d characterizing genes affecting

t o studies o f m u l t i v a r i a t e phenorypic e v o l u t i o n (e.g., t r a i t s , of the consequences t h a t p o p u l a t i o n suhdivi*

C h a p t e r 2 0 ) , a n d across a c o n t i n u u m o f r i m e , f r o m siou a n d linkage d i s e q u i l i b r i u m have o n their inter ancient events that lead t o c u r r e n t species diversity p r e t a t i o n o f associations between loci a n d trait (e.g., Chapter 281 t o r a p i d e v o l u t i o n seen over rela- expression (e.g., Tcmpleton et aL 2005) At t h e o t h e r tively short t i m e scales in e x p e r i m e n t a l e v o l u t i o n extreme, evolutionary biologists may use t h e results studies (Chapter 3 1 ) o f these *gene discovery" studies t o identify genes

A m a j o r cause o f the recent g r o w t h a n d e x p a n - that underlie e v o l u t i o n a r y i m p o r t a n t genetic varia­

t i o n o f e v o l u t i o n a r y genetics has been the m o d e r n l i o n (e.g.* Beldade et a l 2 0 0 2 ) However, differ»

r e v o l u t i o n in molecular biology, w h i c h has fueled e n t i t l i n g research i n t o t h e extremes o f these the g r o w t h o f areas o f evolutionary genetic* focused categories is b e c o m i n g increasingly d i f f i c u l t as

o n the analysis o f sequence d a t a , the g e n o t y p e - e v o l u t i o n a r y approaches permeate genetics just as phenotype r e l a t i o n s h i p , a n d genome e v o l u t i o n molecular biology permeates e v o l u t i o n a r y biology

A l t h o u g h many o f t h e questions at the forefront T h e development o f this b o o k was i n i t i a t e d

o f the field have been a r o u n d stnee the early days late in 2 0 0 2 I t was conceived as a c o m p a n i o n t o

o f e v o l u t i o n a r y genetics (e.g., since the M o d e r n Evolutionary Ecology: Concepts arul CMS*' Studies

Synthesis), the a v a i l a b i l i t y o f relatively inexpensive (edited by Fox et a l 2 0 0 1 ) , also published by

h i g h - t h r o u g h p u t genetic technology a n d t h e result- O x f o r d University Press O u r p r i m a r y objective i n

i n g large databases o f molecular genetic data has led this b o o k , as in its c o m p a n i o n v o l u m e , is t o

t o the emergence o f m a n y n e w areas o f study provide a c o l l e c t i o n of readings that w i l l i n t r o d u c e

a n d a sort o f r e v o l u t i o n in e v o l u t i o n a r y genetics, students t o concepts a n d c o n t e m p o r a r y research

p r o g r a m s in e v o l u t i o n a r y genetics O u r hope w h e n

conceiving this v o l u m e was that it m i g h t be a d o p t e d

ai« a t e x t f o r graduate courses a n d seminars* as ha*

been the case for Evolutionary Fxology We thus

targeted the level o f this b o o k so that it can be used

by advanced undergraduates, graduate students,

a n d established researchers in genetics or e v o l u t i o n

l o o k i n g for a concise i n t r o d u c t i o n t o e v o l u t i o n a r y

genetics A u t h o r s were asked t o target this audience

w h i l e w r i t i n g , a n d reviewers a n d t h e editors focused

on n u k i n g the v o l u m e accessible t o this audience

w h i l e r e v i e w i n g each chapter

Chapter a u t h o r s are a l l leading researchers in

t h e i r fields a n d were chosen t o p r o v i d e their partic­

ular perspectives on a topic Chapters thus represent

the current stage o f evolutionary genetics better than

a n y single-authored t e x t b o o k c o u l d , a n d the diver­

sity o f authors introduces readers t o the divcrsiry o f

ideas, approaches, a n d o p i n i o n s t h a t are the nature

o f science However, a m u l t i - a u t h o r e d t e x t b o o k

presents special challenges A u t h o r s vary in the level

at w h i c h they present material a n d in the a m o u n t

o f b a c k g r o u n d that they expect readers t o have

A u t h o r s also vary in t h e i r w r i t i n g styles, t h e w a y

that they organize their chapters a n d , o f course, each

has a u n i q u e perspective o n the o v e r a l l field We

have a t t e m p t e d t o m i n i m i z e this v a r i a t i o n t h r o u g h

a u t h o r guidelines a n d by aggressively e d i t i n g a n d

revising chapters H o w e v e r , s o m e v a r i a t i o n a m o n g

chapters is unavoidable a n d reflects the v a r i a t i o n in

styles a n d approaches c o m m o n t h r o u g h o u t science

A s w i t h any b o o k , especially an edited v o l u m e ,

this b o o k is n o t comprehensive T o keep the length

of the b o o k p r a c t i c a l , a n d the price a f f o r d a b l e , w c

h a d t o impose restrictions o n chapter length a n d the

n u m b e r o f references T h i s a l l o w e d us t o increase

the diversity o f subjects covered b u t at the expense

o f depth o f coverage M o s t topics could fill an entire

b o o k ( a n d m a n y are indeed the subject o f entire

books) Chapters are i n t e n d e d t o serve as introduc­

t i o n s t o t h e i r t o p i c , focusing o n basic concepts

rather than becoming comprehensive reviews (the

reference l i m i t was intended t o m i n i m i z e t h e latter)

Such a f o r m a t imposed unavoidable l i m i t a t i o n s o n

authors a n d , as e d i t o r s , w e take responsibility for

the necessary omission o f missing topics a n d the

lack o f many a d d i t i o n a l references that are perhaps

equally a p p r o p r i a t e as examples o r case studies

Chapters include a "Suggestions for Further Reading"

section t o guide readers o n where t o go next for

a d d i t i o n a l coverage o f t h e topic We hope that read­

ers w i l l be inspired t o delve m o r e fully i n t o at least

some o f the research areas a n d thus discover t h e vast literature t h a t w c have been unable t o include here,

T h e volume is structured i n t o six parts A l t h o u g h

this might suggest that there are six clearly defined sets o f t o p i c s , such s t r u c t u r i n g is s o m e w h a t a r t i f i ­

c i a l E v o l u t i o n a r y genetics is a highly integrated field w i t h n o clear lines d i v i d i n g research topics

T h e structure o f t h e b o o k is simply a convenient

w a y o f collecting m o r e related topics together We start w i t h a collection o f chapters presenting many

o f the principles o f e v o l u t i o n a r y genetics that serve

as the f o u n d a t i o n for the rest o f the subject (Part I) For this p a r t readers need have o n l y a decent back­

g r o u n d in genetics, t h o u g h a b a c k g r o u n d in e v o l u ­

t i o n a r y biology w i l l certainly be helpful Later parts

o f the b o o k assume an understanding o f b o t h general concepts o f genetics a n d the concepts presented in earlier p a n s Parts I W V are ordered hierarchically

s t a r t i n g at the basic level o f biological c o m p l e x i t y ,

t h e D N A sequence (Part I I ) , b u i l d i n g t h r o u g h devel­

o p m e n t (Part I I I ) t o studies o f complex phenotypes (quantitative genetics; P a n I V ) a n d on t o the inter­actions between i n d i v i d u a l s and their e n v i r o n m e n t (sexual a n d social selection; also Part I V ) These parts are f o l l o w e d by one on the genetics o f species differences a n d speciation (Part V ) that integrates across the hierarchy o f complexity t o investigate wrhat

is o f t e n considered the m o s t f u n d a m e n t a l p r o b l e m

in evolutionary1 b i o l o g y : the o r i g i n o f species, l a s t l y

w c include a p a r t i l l u s t r a t i n g h o w the theoretical,

c o n c e p t u a l , a n d e m p i r i c a l approaches developed in previous chapters are applied t o specific p r o b l e m s

in b i o l o g y (Part V I ) T h e p o t e n t i a l choice o f topics here is e n o r m o u s b u t w e could choose o n l y a couple

o f representative examples that w e find p a r t i c u l a r l y

e x c i t i n g , Because w c enforced l e n g t h restrictions on chapters, many i m p o r t a n t a n d e x c i t i n g topics were necessarily left o u t O t h e r topics were outside the expertise o f t h e a u t h o r s o r w e r e i m p o r t a n t topics that d i d n o t fit well into the structure o f the chapters

W c thus include a large n u m b e r o f boxes focusing

on specific topics presented largely independently

o f the m a i n b o d y of the text w i t h w h i c h they arc associated W i t h the exception o f Box 24.1 { w h i c h

w c use t o introduce Part V, Genetics o f Speciation),

a l l boxes appear w i t h i n the pages o f t h e chapters t o

w h i c h they a r c m o s t relevant M a n y wrcrc w r i t t e n

by the same a u t h o r as the chapter that they comple­

m e n t ; these largely e x p a n d o n topics m e n t i o n e d in the main b o d y o f t h e chapter o r they present a

topic that did not fit well in the main body of the

chapter Other boxes were written by scientists

who did not write full chapters; these boxes read

more like mini-chapters Most could indeed have

been full chapters but, alas, the realities of publish­

ing prevented us from including every chapter

we would want* We also included three boxes on

model organisms in biology* (in Pan V!) since so

much of what we know about evolutionary genet*

ics, and biology i n general, comes from studies

of model organisms The choice of box topics reflects

the views of the editors, the reviewers, and the many

chapter authors who suggested topics for boxes

Lastly, we have compiled a glossary of terms»

Initially wc asked authors to include footnotes or

tables defining the terminology of their Held but the

large number of submissions made this impractical,

so we converted these (at the suggestion of multiple

authors) to a glossary at the end of the text* It is by

no means a comprehensive glossary of genetics or

even evolutionary genetics terms* it is intended to

aid the reader by providing definitions for terms

that might be considered jargon special to some

areas of research, or terms that you know you once

learned but may have since forgoncn; that is, the

terminology not necessarily standard in a working

scientist's vocabulary* The glossary entries are

largely written by the chapter authors, heavily

supplemented (and editcd> by the editors; we have

thus given the appropriate author credit after each

entry In a few cases we have included multiple

entries for a single term because multiple entries

were submitted by authors and the difference

between those entries was itself informative

Each chapter and box was reviewed by at least

one other contributor to the book and, in most

cases, one or more external reviewers Wc are truly indebted t o all these reviewers for generously donating their time and providing thorough and constructive reviews Without their help it would nor have been possible t o produce such a volume given the vast diversity of topics covered and the limits of the editors* expertise We thus thank the external reviewers, including Hiroshi Akashi, Cerise Allen, Bill Atchlcy, Score Carrol), James Crow, Mary* Kllen Cze^ak, Tony Frankino, Oscar Ciagginrti,

C William K i r k p a t r i c k , Larry Leamy, Susan Lindquist, Curt 1 ivcly, Manyuan )~ong, Bryant McAllister, Tami Mcndclson, Dchra Murray, Joshua Mutic, John Obrycki, Susan Perkins, Massimo Pigliucci, Richard Preziosi, Will Provine, David Queller, Glenn-Peter Sactre» Laura Salter, Douglas Schemske, l l a m i s h Spencer, Marc Tatar, Kric

(Rick) Taylor, L i n d i Wahi, Cunrcr Wagner,

John Wakeley, Bruce Walsh, Joe Williams, and a few others w h o asked to remain anonymous Wc also thank Lisa Hitchcock, Denise Johnson, and Oriaku N j o k u for help proofreading chapter* and references*

Finally, and most importantly, we thank the authors for their willingness 10 invest the subsian* rial amount of time needed t o write excellent chap* ters and boxes* The success of the volume ultimately depends on the quality of the contributions by authors Wc are fortunate to have recruited an out­ standing group o f scientists who dedicated tremen­ dous time and effort to making this project a success Thank you for being such a wonderful group of people with which t o w o r k !

Charles W Fox Jason B* Wolf

Copyrighted materi

J,

Contents

C o n r r i h n r n r * ^ l l l

Part I - Principles of Evolutionary Genetics

1 From Mendel to Molecules: A Brict History of Evolutionary Genetics i

Mich.wt K Motrirf,

2 Genetic Variation H

Marta L Wayne and Michael M» Miyamoto

Box 2.1 Maternal Ff frets 19

Box 5,1 The Probability of Extinction of an Allclc 68

Box 5.2 Mutational Landscape Model 7Q

6 Genetics a n d Evolution in Structured Populations 8 0

Charles / Goodnight

Box 6.1 Fpistasis and rhc Conversion ot Generic Variance S7

Jason B Wolf

x Contents

Part II - Molecular Evolution

7 Detecting Selection at the Molecular Level 103

Michael ffi Narhman

fl Rflrr* pf Molecular Bmliitiop LL9

Francisco RodrigueZ'Trelles, Rosa Tarrio and Francisco f Ayala

Box 8.1, Timing Evolutionary Events with a Molecular Clock 122

Box 8.2 Tjgtjng the Hypothesis of the Molecular Clock 125

9 Weak Selection on Noncoding Gene Features 133

Ying Chen and Wolfgang Stepban

10 Evolution of Eukaryotic Genome Structure 144

Dmitri A Petrov and Jonathan R Wendel

11 New Genes» New Functions: Gene Family Evolution and Phylogenetics 157

foe Thornton

12 Gene Genealogies 173

Noah A Rosenberg

Part III - From Genotype to Phenotype

Mark L* Siegal and Aviv Bergman

Box 16.1 Computational Modeling of the Evolution of Gene Regulatory Networks 243

17 Evolutionary Epigcnctics 252

Eva fablonka and Marion h Lamb

Part IV - Quantitative Genetics and Selection

18 Evolutionary Quantitative Genetics 267

Derek A Roff

ftr»* t f l l Individual T-irnres SllrfilCa - ' " ^ Mnlrivariaf^ SckctlQD 263

lasan B Wolf

Contents

19 Genetic Architecture of Quantitative Variation 2X8

fames At Chevcrud

Box 19.1 Genotvpic Values: Additivitv, Dominance, and Epkrasis 289

ttox 1 <*.? <\mw Valiireand O n r n r Variance 2211

Box 19.3 How to Perform a QTL Analysis 291

Box 19.4 Evolutionary Morphonictrics 294

Christian Peter KlingenberR

Box 19.5 Modularity 304

lason G Mezev

2 0 Fvnhirion of Genetic Variance-Covariance Structure UH

Box 20.1 What U i Co-variance? 311

Box 20-2 Plciotropic Effects 313

Box 20.3 Evolution of the G Matrix 316

2 1 G e n o t y p e - E n v i r o n m e n t Interactions and Evolution 326

Samuel At Srhriner

2 2 GenCtka of Sexual Selection 119

Allen / Moore j«rf Patricia / M o o r e

Stwpn A Frank

Box 2 3 X Coefficients of Relatedness 352

Part V - Genetics of Speciation

Box, Species Concepts 367

lames Mallrt

24 T h e Evolution of Reproductive Isolating Barriers 3 7 4

Norman A Johnson

2 5 Genetics of Reproductive Isolation a n d Species Differences in Model O r g a n i s m s 3 8 7

Pawel Michalak and Mohamed A F Nnor

Box 25.1 The Dohzhanskv-Mullcr Model 392

2 6 N a t u r a l Hybridization 399

Michael I Arnold and John At Burke

Box 26 1 Porential Outcomes of Natural Hybridization 400

2 7 Population Bottlenecks and F o u n d e r Effects 4 1 4

Lisa Marie Meffert

Box 27 L Models of the Shifts in Selection Pressures Experienced by Bottlcnecked

Populations 415

2 8 T h e o r y of Phylogcnetic Estimation 4 2 6

Box 28 1 Philosophical ;uui Methodological Diffcrcnccs in Phylofienetics 434

XH Contents

Part VI - Evolutionary Genetics in Action

29 Evolutionary Genetics of Host-Parasite Interactions 447

Box 29,1, The C<revolutionary Consequences of Tolerance vcrtus Resistance 448

Box 29,2, Arahtdopsis as a Model Organism in Evolutionary Genetics 453

Kcntaro K Shimizu ami Michael D Puni^anan

Box 29,3 Evolution of Virulence 456

30 T h e Evolutionary Genetics of Senescence 464

Daniel £ / Vromishw and Anne M Rronikowski

Box 30*1 Demography of an Age-Structured Population 466

St Louis, Missouri 6.1110, USA Adam K Chippindale

Department of Biology Queen's University Kingston, Ontario K7L 3N6, Canada

Aviv Bergman

Department of Pathology and

Molecular Genetics

Albert Einstein College of Medicine

New York, New York 10461, USA

Keith A Crandall Department of Microbiology and Molecular Biology

Brigham Young University Prove, Utah 84602, USA

Anne M Bronikowski

Department of Ecology

Evolution and Organtsmal Biology

Iowa State University

Ames, Iowa 50011, USA

Hanover, New Hampshire 03755, USA Ashley N Egan

Department of Microbiology and Molecular Biology

Brigham Young University Provo, Utah 84602, USA'

Daphne J Fairbairn Department of Biology University of California Riverside, California 92521, USA

Department of Biological Science

Florida State University

Tallahassee, Florida 32306, USA

Eva Jablonka

The Cohn Institute for the History and

Philosophy of Science and Ideas

Tel Aviv University

Tel Aviv 69789, Israel

Amherst, Massachusetts 01003, USA

Christian Peter Klingcnberg

Faculty of Life Sciences

National Institutes of Health

Bethesda, Maryland 20894, USA

Paula X Kover Faculty of Life Sciences University of Manchester Manchester M13 9PT, United Kingdom Marion J Lamb

Senior Lecturer (retired!

Birkbeck College University of London, United Kingdom Richard E Lcnski

Department of Microbiology and Molecular Genetics

Michigan State University East Lansing, Michigan 48824, USA

Simon C Lovcll Faculty of Life Sciences University of Manchester Manchester M I 3 9PT, United Kingdom

James Mallet Department of Biology University College London London NW1 2HE, United Kingdom

Katrina L McGuigan Center for Ecology and Evolutionary Biology University of Oregon

Eugene, Oregon 97405, USA

Lisa M Meffert Department of Ecology and Evolutionary Biology

Rice University Houston, Texas 77251, USA

Jason G Mezey Department of Biological Statistics and Computational Biology

Cornell University7

Ithaca, New York 14853, USA

Pawcl Michalak Department of Biology University of Texas Arlington, Texas 76019-0498, USA

Copyrighted mater:

Centre for Ecology and Conservation

University of Exeter in Cornwall

Tremough, Pcnryn TRIO 9EZ,

United Kingdom

Patricia J Moore

Centre for Ecology and Conservation

University of Exeter in Cornwall

Tremough, Pcnryn TRIO 9EZ»

United Kingdom

Timothy A Mousscau

Department of Biological Sciences

University of South Carolina

Columbia, South Carolina 29208, USA

Biological Research Center

Hungarian Academy of Sciences

Yale University New Haven, Connecticut 06520, USA

Daniel E L PromUlow Department of Genetics The University of Georgia Athens, Georgia 30602» USA Stephen Proulx

Department of Ecology, Evolution and Organismal Biology

University of Iowa Ames, Iowa 50011, USA

Michael D Purugganan Department of Genetics North Carolina State University Raleigh, North Carolina 27695, USA

Francisco Rodrigucz-Trellcs Fundacion Puhlica dc Medieina Genomica Hospital Clinico Universirario

Universidad de Santiago de Composrela

15706 Santiago Spain

Derek A, Roff Department of Biology University of California Riverside, California 92521» USA

Noah A Rosenberg Department of Human Genetics and Bioinformatics Program

University of Michigan Ann Arbor, Michigan 48109-2218, USA Samuel M Scheiner

Division of Environmental Biology National Science Foundation Arlington, Virginia 22230, USA

Kcntaro K Shimizu Department of Genetics Box 7614

North Carolina State University Raleigh» North Carolina 27695, USA

xvi Contributors

Mark L, Sjggaj

New York University

New York New York 10003, USA

Fundacion Publica de Medicina Genomica

Hospital Clinico Universitario

Universidad dc Santiago de Compostcla

Bloomington Indiana 47405, USA

Marta L Wayne

Department of Zoology University of Florida Gainesville Florida 32611, USA

Jonathan F Wendd Department of Botany Iowa State University Ames, Iowa 5 0 0 1 USA

Jason B Wolf Faculty of Life Sciences University of Manchester Manchester, M l 3 9PT, United Kingdom

PRINCIPLES OF EVOLUTIONARY GENETICS

I

Copyrighted material

1

From Mendel to Molecules: A Brief History

of Evolutionary Genetics

MICHAEL R DIETRICH

Biologists have been g r a p p l i n g w i t h selection ever

since D a r w i n Historians also face a p r o b l e m o f

selection—not n a t u r a l selection» b u t the selection

of w h i c h events t o include i n their narratives* N o

historical narrative c a n be complete i n the sense o f

i n c l u d i n g every event, actor, a n d idea H i s t o r i a n s

must choose w h i c h events they w i l l include a n d

w h i c h they w i l l n o t W r i t i n g a survey o f the history

of evolutionary genetics in such a short space makes

this p r o b l e m o f selection especially acute

A n u m b e r o f different approaches have been

taken t o the history o f evolutionary genetics* W i l l

Provine has suggested that the history o f evolutionary

biology is one o f persistent controversy* (Provine

1989; see also L e w o n t i n 1974) C e r t a i n l y one c o u l d

w r i t e a h i s t o r y o f e v o l u t i o n a r y genetics in terms o f

(he disputes b e t w e e n , for instance, the M c n d e h a n s

a n d B i o m c t r i c i a n s , Sewall W r i g h t a n d R A Fisher,

saltationists a n d gradualists, the classical a n d balance

approaches, a n d neutralists a n d selectionists (Provine

1 9 8 6 , 1 9 9 0 ; Beany 1 9 8 7 b ; D i e t r i c h 1 9 9 4 , 199S,

1 9 9 8 ; Smocovitis 1 9 9 6 ; Skipper 2 0 0 2 ) Such a n

antagonistic view o f evolutionary genetics comple­

ments histories emphasizing the great collaborations

that h a w also characterized the history o f the subject,

such as those between Theodosius D o b z h a n s k y

a n d Sewall W r i g h t , E- B F o r d a n d R A Fisher, o r

indeed those w i t h i n a n y o f the m a n y l a b o r a t o r y

groups w o r k i n g in the t w e n t i e t h century (Provine

19861, M o r e i n s t i t u t i o n a l l y m i n d e d historians have

emphasized the rise o f societies, j o u r n a l s , a n d f u n d ­

ing sources (Smocovitis 1996; C a i n 1993)* A t the

same time, others have documented the development

of theoretical a m i experimental tools a n d techniques,

such as the use o f c h r o m o s o m a l inversions,

elec-r elec-r o p h o elec-r e s i s , sequence data» p o p u l a t i o n cages,

c o m p u t e r s i m u l a t i o n s , a n d t h e vast array o f e v o l u ­

t i o n a r y models and concepts ( L e w o n t i n 1 9 8 1 , 1 9 9 1 ;

K o h l c r 1 9 9 1 ; Powell 1 9 9 4 ; G a y o n & Veuille 2 0 0 1 )

In this brief history; I w i l l focus o n the m a j o r controversies that have m a r k e d the historv o f c v o l u -tionary genetics in the t w e n t i e t h century w i t h special emphasis o n the nature of genetic variability a n d the evolutionary processes acting u p o n this variability* This a p p r o a c h captures key developments in e v o l u ­

t i o n a r y genetics such as the resolution of the c o n f l i c t between M e n d e l i s m a n d D a r w i n i s m a n d t h e c o n t i n *

u i n g i m p a c t of molecular biology a n d molecular techniques*

M E N D E U A N S D A R W I N I A N S

A N D T H E O R I G I N S O F

E V O L U T I O N A R Y G E N E T I C S

T h e study of e v o l u t i o n and heredity have been inter­

t w i n e d since at least Grcgor Mendel's a n d Charles

D a r w i n ' s separate efforts t o m a k e sense o f the origins

o f varieties a n d the s t a b i l i t y of species* Mendel's experiments w i t h m a n y different species sought l o explore t h e idea t h a t n e w stable varieties could

be created t h r o u g h h y b r i d i z a t i o n ( O l b y 1979) H i s

f a m o u s series o f experiments w i t h the garden pea

q u a n t i f i e d the instability o f his h y b r i d crosses as ir documented their hereditary patterns Darwin's much less q u a n t i t a t i v e a p p r o a c h t o hereditary s t a b i l i t y

o r c o n t i n u i t y across generations p u t m u c h greater emphasis o n processes <>r e v o l u t i o n a r y change and

4 Principles of Evolutionary Genetics

the problem of the origin of heritable variation

The differences between Mendel and Darwin were

exaggerated after the rediscovery of Mendel's work

in 1900 hy Carl Corrcns, Hugo Dc Vrics, and Erich

von Tsehcrmak At this nmc, Darwinian evolution

was criticized as insufficient for the production

of new species (Bowler 1983) Evolution was widely

acknowledged, but the processes of evolution

remained in dispute Hugo De Vrics, for instance,

articulated his Mutation Theory as a saltarionist

alternative to Darwinism during this period Even

Darwin's early defenders expressed concern about

Darwin's account of the power of natural selection

(Provine 1971)

Darwin acknowledged t w o forms of variation:

continuous or blending variations and "sports* or

monstrosities Although he admincd that his knowl­

edge of variation was insufficient, Darwin thought

that continuous variations were the source of heri­

table variation for natural selection "Sports'* were

larger* structural deviations, which Darwin thought

were too rare and too harmful t o be of evolution­

ary significance Fleming Jenkins criticisms of his

views in the Origin of Species caused Darwin to

take the idea of "sports* or discontinuous varia­

tion more seriously Although "Darwin's bulldog,"

T, H , Huxley, advocated discontinuous variation,

advocacy of this view is often associated w i t h

the early Mendelians, Hugo Dc Vrics and William

Bateson (Provine 1971; Kim 1994)

Darwin developed his own theory of blending

inheritance as a physiological theory called

"pangc-ncsis," Like other material theories of heredity that

would follow Darwin's in the late nineteenth century,

Darwin postulated hereditary particles, pangenes,

which corresponded t o different body parts and

were collected and transmitted via the gametes*

While Darwin's cousin, Francis Galton, helped to

refute this theory, he supported blending inheritance

by developing statistical tools for precisely describ­

ing the similarities between characters Using corre­

lation and regression, Galton reconsidered heredity

from a statistical point of view Because he under*

stood characters t o he continuous, Galton believed

that their distribution was best described hy a normal

distribution The effects o f selection were reconsid­

ered in terms of effects on population means and

variances Selection could shift the mean of a popu­

lation over a number of generations to create a new

characteristic population mean The relationship

between parent and offspring was presented in terms

of a law* of ancestral heredity where a particular

character of an offspring CM he determined from

the diminishing contribution of its ancestors I Provine

1971; Kim 1994) Galton's Natural Inheritance

(1889) inspired Karl Pearson and \V K R Weldon

to develop a statistical approach to biology and evolution that they called biometrics Within the biomctrical tradition, weldon and others applied statistical methods to support gradual Darwinian evolution by natural selection Weldon himself collected statistical evidence from crab carapaces, which he thought demonstrated the effect of selec­ tion in reducing population variability as well as the size of the carapace front These and other efforts convinced the Biometricians that statistical methods were essential for understanding evolution and heredity

William Bateson had also been impressed with Gallon's work, hut was not convinced that statistical methods were the best tools or that either evolution o r heredity should be understood as continuous or blending In 1894, Bateson argued in

his book Materials for the Study of Variation tvith

Special Regard to Discontinuity in the Origin of Species, that discontinuous variations were common

and saltational evolution of new species was prob­ ably the norm The dispute between Bateson and the Biometricians began with Weldon's hostile review of his book It was transformed into the Mendelian- Biometrician controversy when Bateson read Mendel's paper in 1900 Bateson translated Mendel's paper into English and immediately began champi­ oning it as the key to heredity and evolution» As a result» Weldon and Pearson would debate the significance of Mendel's paper vociferously over the next 10 years*

The dispute between the Mendelians and Biometricians was at once about genetic variation (continuous vs discontinuous) and evolutionary change (gradual vs saltational) as well as the appro­ priateness of statistical methods, and was overlaid with a struggle for authority and position within English biology During the course of this dispute, the Biometricians and Mendelians drew on extended networks of biologists, and historian Kyung-Man Kim argues that the controversy was resolved by members of this extended network, not by the prin­ cipal antagonists who remained strongly polarized 4Kim 1994) A D Darbishirc, for instance, set out to refute Mendelism with a set of experiments on albino and waltzing mice Following Galton, Darbishirc

From Mendel t o Molecules S

reasoned that as the p r o p o r t i o n o f a l b i n o mice

f o r m i n g the parental a n d g r a n d p a r c n r a l genera­

t i o n s increased s o s h o u l d t h e percentage o f a l b i n o

o f f s p r i n g i D a r b i s h i r e 1904) Darbishire's evidence

in 1904 seemed t o support exactly this interpretation

until both W i l l i a m Castle a n d W i l l i a m Bateson w r o t e

devastating c r i t i q u e s r e i n t e r p r e t i n g Darbishirc's

results in M c n d c i i a n terms (Castle 190.5; K i m 1994)

l>arbjshirc himself was convinced w h e n he tested

his h y b r i d s a n d realized that some of the mice that

produced o n l y a l b i n o o f f s p r i n g d i d so because they

were d o m i n a n t In this case, statistical analysis o f

external appearance was n o t a reliable guide t o

genetic constitution* Darbishire's defection infuriated

Pearson* b u t this was one o f several conversions

I K i m 1994)

M o r e biologists joined the Mendelians after

W i l h e l m J o h a n n s c n i n t r o d u c e d his p u r e l i n e

approach Beginning in 1 9 0 1 , Johannsen sought t o

rest whether selection c o u l d change the mean o f a

population's character d i s t r i b u t i o n Using a c o n t i n u ­

ous d i s t r i b u t i o n o f bean size a n d w e i g h t , Johannsen

selected f o r large, medium» a n d small beans H e

discovered that after many generations o f selection

he could isolate a number o f p u r e lines f r o m the

original d i s t r i b u t i o n , Pure lines h a d stable characters

and selection n o longer had an effect on their i n d i ­

vidual means Selection had made a difference in the

original p o p u l a t i o n because it was selecting a m o n g

different p u r e lines, n o t because it was selecting

w i t h i n a p u r e line Johannsen's d i s t i n c t i o n between

the d i s t r i b u t i o n o f a character ( p h c n o t y p e l a n d the

u n d e r l y i n g p u r e line (genotype) was essential for

resolving the M e n d e l i a n - B i o m e t r i c i a n controversy*

As early as 1 9 0 4 , English m a t h e m a t i c i a n G U d n y

Yute r c c o g n i w d this as a way t o reconcile the

hiomcr-rical description of phenorypes w i t h M e n d e h a n

descriptions o f genotypes This r o u t e t o reconcilia­

t i o n was reinforced w i t h evidence f o r m u l t i p l e

f a c t o r s , w h i c h a l l o w e d Mendelians t o e x p l a i n a

c o n t i n u o u s character d i s t r i b u t i o n as the result o f

the interaction o f m a n y genes, each o f small effect*

By 1 9 1 0 , these developments h a d begun t o signifi­

cantly depolarize this controversy as many biologist

recognized the c o m p a t i b i l i t y o f the M c n d e l i a n a n d

b i o m c i r i c a l approaches ( K i m 1994),1

^Hitlufv^il niterprciatHint of thitiriiiiiftti'rrti h-nr ihcmtrkc*

Iven the 4uhvrxf ■>* o»nirmtm ttKicrrning the rebmc ro*c> ot

etkJrnU' and *uCiM i*nnr* in «he emirte «>f thr ditpint Src Kim

T H E D E V E L O P M E N T O F

P O P U L A T I O N C E N E T I C S

Regardless o f the outcome o f the M e n d e l i a n Biometrician controversy, the use ot statistical meth­ods f o r m a l i z e d a p o p u l a t i o n a p p r o a c h t o e v o l u t i o n

-in i h c early Twentieth century A t a t i m e w h e n even ihe basic language o f gencocs had yet t o be standard­ized it is n o t surprising that different approaches

t o the m a t h e m a t i c a l description o f e v o l u t i o n w o u l d also arise T h e rise of m a t h e m a t i c a l p o p u l a t i o n genetics is usually associated w i t h the w o r k o f three founders: Sewall W r i g h t , R A Fisher, a n d J B S Haldane T h e i r w o r k set the foundations for popula­tion genetics, as each attempted t o formally reconcile

he had developed his m e t h o d o f path coefficients

t o describe the effects o f inbreeding, assortativc

m a t i n g , a n d selection W h e n he joined the f a c u l t y

o f the University of C Chicago in 1923, W r i g h t shifted hts t h o u g h t s f r o m guinea p i g colonies a n d cattle herds t o e v o l v i n g n a t u r a l p o p u l a t i o n s By 1 9 3 1 *

he had articulated his s h i f t i n g balance t h e o r y of

e v o l u t i o n in his n o w classic paper " E v o l u t i o n in

M e n d e l i a n P o p u l a t i o n s ' ' ( W r i g h t 1 9 3 1 ; Provine 1986)

R A Fisher was an Fnglish biologist t r a i n e d

at C a m b r i d g e in m a t h e m a t i c s I n t r o d u c e d t o

M e n d e l i s m a n d Biometry at C a m b r i d g e , Fisher sought l o reconcile the t w o by u n d e r s t a n d i n g the

b i o m c i r i c a l properties of M e n d e l i a n p o p u l a t i o n s

T h i s a p p r o a c h led h i m t o characterize similarities

w i t h i n Mendelian populations in terms of their vari­ance a n d the contributions t o variance f r o m genetic sources, environmental sources, dominance, a n d gene interactions Fisher\ approach emphasized natural selection acting in very large n a t u r a l p o p u l a t i o n s

H e set o u t his general t h e o r y i n his 1930 b o o k The

GcnctWixl Theory of Natural Selection I Provine

1 9 7 1 I 9 S 6 L

J B S Haldane was also an raiglish biologist

w i t h b r o a d interests H e studied mathematics at

O x f o r d before s w i t c h i n g t o classics a n d philosophy

B e g i n n i n g in 1922, Haldane sought t o analyze the

m a t h e m a t i c a l consequences o t n a t u r a l selection, Starting f r o m simple M e n d e h a n models using t w o

6 Principles o f Evolutionary Genetics

allelesat a single locus* Haldane went on t o consider

selection w i t h s e l f - f e r t i l i z a t i o n , i n b r e e d i n g , over­

lapping generations* i n c o m p l e t e d o m i n a n c e , isola­

t i o n , m i g r a t i o n , a n d f l u c t u a t i n g selection intensities

(Provinc 1971) H a l d a n c ' s scries o f n i n e papers o n

selection c u l m i n a t e d in his 1932 b o o k * The Causes

of Evolution In the appendix t o this b o o k , Haldane

compares his views t o those o f Fisher a n d W r i g h t ,

While he agrees w i t h elements o f b o t h o f their views,

Haldane differed f r o m Fisher by p l a c i n g greater

emphasis o n s t r o n g selection o f single genes, m i g r a ­

t i o n , a n d cpisrasis H e sided w i t h Fisher, however,

mathematical perspectives, their disagreements were

not about mathematics, b u t a b o u t e v o l u t i o n a r y

processes a n d concepts a n d their representation in

different m a t h e m a t i c a l models A c c o r d i n g t o W i l l

Provine, Fisher a n d W r i g h t were engaged in a series

o f disputes f r o m 1929 u n t i l 1962 when Fisher died

(Provine 1 9 8 6 , 1992)- W h i l e they debated many

things, the core o f their difference lay in their general

theories o f e v o l u t i o n : W r i g h t ' s s h i f t i n g balance

rhcory a n d Fisher's large p o p u l a t i o n theory, Wright's

approach i n c o r p o r a t e d an array o f e v o l u t i o n a r y

processes a n d emphasized p o p u l a t i o n subdivision

( G o o d n i g h t , C h 6 o f this v o l u m e ) Fisher argued

that n a t u r a l selection was the d o m i n a n t process

a n d that large populations were the o p t i m u m These

differences were m o s t apparent a r o u n d the issue o f

the relative i m p o r t a n c e o f r a n d o m genetic d r i f t

A l t h o u g h W r i g h t c o n t i n u e d t o elaborate his view's,

his early w o r k on the s h i f t i n g balance r h c o r y gave

r a n d o m d r i f t a considerable r o l e in e v o l u t i o n ,

T o counter W r i g h t ' s v i e w , Fisher a n d his colleague

E, B Ford studied yearly fluctuations in the gene

(allelc) frequencies o f the m o t h Panaxia dommula

f r o m 1941 t o 1946 They f o u n d that the fluctua­

t i o n s they observed were t o o great t o be accounted

f o r by t h e a c t i o n o f r a n d o m genetic d r i f t Instead,

they proposed t h a t the fluctuations w e r e the result

o f r a n d o m fluctuations i n the strength o f n a t u r a l

selection As this dispute intensified a n d extended

i n t h e 1950s t o results o n b a n d i n g patterns i n t h e

snail Cepaea rtemorali$ t W r i g h t began t o m o d i f y

hts views, l i m i t i n g the action of r a n d o m d r i f t t o large,

but subdivided populations where it could serve as a

means f o r generating novel genotypic c o m b i n a t i o n s

(Provine 1986, 1992), T h e W r i g h t - F i s h e r debate

has resurfaced in recent years w i t h n e w p r o t a g o ­nists (Skipper 2 0 0 2 ) , b u t t h e o r i g i n a l debate was especially i n f l u e n t i a l because it occurred just as

N e o - D a r w i n i s m was being articulated in the evolu­

t i o n a r y synthesis (Provine 1992)*

T H E E V O L U T I O N A R Y

S Y N T H E S I S

The evolutionary synthesis is identified by historians

w i t h both the emerging discipline o f evolutionary biology a n d the integration of previously divergent fields such as paleontology, zoology, botany, systcm-atics, a n d genetics A c c o r d i n g t o this interpretation, the synthesis refers t o a t i m e b e g i n n i n g in t h e 1930s when a range of arguments were offered t o show that different fields relevant t o e v o l u t i o n were in fact

c o m p a t i b l e w i t h each other These c o m p a t i b i l i t y arguments helped s p u r on the emergence o f e v o l u ­

t i o n a r y b i o l o g y as a field o f i n q u i r y — a s a n e w a n d centrally i m p o r t a n t discipline (Smocovitis 1 9 9 6 )

C o m p a t i b i l i t y arguments d o n o t necessarily i m p l y that there was widespread agreement on a new* synthetic t h e o r y o f e v o l u t i o n A s Provinc a n d others have a r g u e d , there was little agreement a b o u t the mechanisms o f e v o l u t i o n d u r i n g the 1930s a n d 1940s, Instead Provine suggests that w c reconsider this p e r i o d as a n e v o l u t i o n a r y constriction—**a vast c u t - d o w n o f the variables considered i m p o r t a n t

t o t h e e v o l u t i o n a r y process,** A c c o r d i n g t o P r o v i n c ,

" T l i c t e r m ' e v o l u t i o n a r y c o n s t r i c t i o n * helps u s understand t h a t evolutionists after 1930 m i g h t disagree intensely w i t h each o t h e r a b o u t effective

p o p u l a t i o n size, p o p u l a t i o n s t r u c t u r e , r a n d o m genetic d r i f t , levels o f hcrcrozygosiry, m u t a t i o n rates, m i g r a t i o n rates, e t c , b u t a l l c o u l d agree t h a t these variables were o r c o u l d be i m p o r t a n t in

e v o l u t i o n in n a t u r e , a n d that purposive forces played n o role at a l l " (Provine 19881,

The foundation for the evolutionary synthesis was communicated in a number of now classic texts:

R A Fisher's The Genetical Theory of Natural Selection (1930), Thcodosius Dohzhansky's Genetics

and the Origins of Species (1937), Julian Huxley's

Evolution: The Modern Synthesis (1942), Ernst Mayr's Systematic* and the Origin of Species (1942),

G G Simpson's Tempo and Mode in Evolution (1944), and G L Stebbins* Variation and Evolution

m Plants (1950)

Dobzhansky's w o r k represented the state o f the a r t in a n i m a l genetics a n d p o p u l a t i o n genetics

From Mendel t o Molecules 7

[ r a i n e d in the Soviet U n i o n a n d influenced hv

the w o r k o f N i c o l a i V a v i l o v a n d I u r i i F i l i p c h e n k o ,

D o b z h a n s k y began his career s t u d y i n g v a r i a b i l ­

ity in n a t u r a l p o p u l a t i o n s ot Coccinellidae a n d

Drosophila mclitmgaster T o further his under*

standing o f genetics, he received f u n d i n g f r o m the

Rockefeller F o u n d a t i o n t o j o i n T H M o r g a n ' s

famous Fly G r o u p in 1 9 2 7 (Provine 1981) Ac

C o l u m b i a a n d later C a l Tech, D o b z h a n s k y excelled

at the business o f Drosvphtla genetics First w i t h

A H Sturtevant a n d later i n c o l l a b o r a t i o n w i t h

Sewall W r i g h t , D o b z h a n s k y t u r n e d t o e v o l u t i o n a r y

g e n e t i c s — t a k i n g Drosophila genetics f r o m the

laboratory t o (he field Dobzhansky's 1 9 3 7 b o n k ,

Genetics and the Origin of Species, a r t i c u l a t e d a

p r o g r a m o f research for e v o l u t i o n a r y genetics The

theoretical underpinnings o f Dobzhansky's p r o g r a m

were deliberately b o r r o w e d f r o m W r i g h t ' s s h i f t i n g

balance theory U n l i k e W r i g h t s papers» however,

D o b z h a n s k y s presentation was n o n - m a t h e m a t i c a l

a n d served t o widely popularize the shifting balance

theory ( P r o v i n e 1981) Genetics and the Origin of

Species, thus, translated one o f the d o m i n a n t general

theories o t e v o l u t i o n i n t o a research p r o g r a m for

e v o l u t i o n a r y genetics,

Dobzhansky** e v o l u t i o n a r y p r o g r a m was c h a l ­

lenged in 1 9 4 0 by R i c h a r d G o l d s c h m i d t ' s The

Material Basis of Evolution G o l d s c h m i d t h a d been

D i r e c t o r o f the Kaiser W i l h c l m Institute o f Biology

in Berlin before he was forced t o emigrate in 1936,

Once in the U n i t e d States, G o l d s c h m i d t challenged

the gradualist model o f e v o l u t i o n p r o m o t e d by

Dobzhpinksy a n d others A c c o r d i n g t o G o l d s c h m i d t ,

D o b z h a n k s y h a d n o t demonstrated that his view fit

the evidence a n y better than the view that there

were bridgeless gaps between species w h i c h c o u l d

only be crossed by either systemic m u t a t i o n s (large

of Dobzhansky's Genetics and the Origin of Sfrecies

devoted many pages t o G o l d s c h m i d t ' s r e f u t a t i o n ,

as d i d later w o r k by M a y r a n d S i m p s o n This nega­

t i v e response t o G o l d s c h m i d t ' s views bolsters

Provinces interpretation of the synthesis as a

cofistric-t i o n In faccofistric-t, o p p o s i cofistric-t i o n cofistric-t o G o l d s c h m i d cofistric-t ' s sacofistric-tcofistric-tacofistric-tion-

sattation-ism became a d e f i n i n g feature o f N e o - D a r w i n i s m

[ D i e t r i c h 1995)

Hrnst M a y r ' s Systematic and the Origin of

Species (1942/ responded t o G o l d s c h m i d t ' s claims*

h u t was modeled o n D o h z h a n k y ' s Genetics and the

Origin of Species, W h e r e D o b z h a n s k y synthesized

genetics w i t h e v o l u t i o n a r y biology, M a y r added concepts o f speciarion a n d species T r a i n e d as an

o r n i t h o l o g i s t in G e r m a n y under Hans Strcsseman,

M a y r was the w o r l d ' s e x p e r t o n b i r d systemancs,

A l t h o u g h developed w i t h avian exemplars» M a y r argued for the generality o f his Biological Species Concept (Mallet, Species Concept* b o x , p p 3 6 7 - 3 7 3

of this volume) and model o f geographic speciation

If Dobzhansky was the first t o set the intellectual agenda for evolutionary genetics, M a y r broadened rhat agenda Moreover, M a y r was absolutely central

t o the effort t o institutionalize a n d support the devel­opment o f evolutionary biology as a discipline, logether w i t h G G Simpson, w h o articulated the contributions of paleontology f o r the synthesis,

M a y r , Dobzhansky, a n d o t h e r scientists in the Northeastern United States discussed the similarities and differences in their approaches t o e v o l u t i o n in the C o m m i t t e e o n C o m m o n Problems in Genetics and Paleontology, w h i c h met f r o m 1 9 4 3 t o 1945 when the Society for t h e Study o f E v o l u t i o n was founded (Smocovitis 1996; C a i n 1993) Because of

W o r l d War I I , M a y r , Simpson, a n d Dobzhansky were somewhat isolated f r o m biologists i n Kngland ( H u x l e y a n d Fisher) and evolutionary biologists o n the West Coast o f the U n i t e d States (Stehbins! This

t e m p o r a r y i s o l a t i o n m a y be o n e reason w h y Dobzhansky, Simpson, a n d M a y r were so influential

in the development o f N e o - D a r w i n i s m , a n d w h y

N e o - D a r w i n i s m seemed p a r t i c u l a r l y focused o n

a n i m a l systems The considerable effort o f Stchhins and others t o b r i n g plants i n t o the synthesis is surely also a result o f the interesting differences between plant a n d a n i m a l genetics (Smocovitis 1996)

T h e architects o f the e v o l u t i o n a r y synthesis played a central r o l e in the p r o m o t i o n of e v o l u t i o n ­ary biology a n d especially e v o l u t i o n a r y genetics

D o b z h a n s k y s w o r k on t h e genetics o f n a t u r a l

p o p u l a t i o n s , in particular, was hailed as an exem­plar o f N c o - D a r w i n i s m ( M a y r 1 9 4 4 ; Stern 1944) Significantly, d u r i n g t h e 1940s D o b z h a n s k y ' s o w n research p r o g r a m n a r r o w e d * F r o m 1938 t o 1976, Dobzhansky a n d his collaborators produced a series

o f 4 3 influential papers under the title of " T h e Genetics o f N a t u r a l Populations" ( G N P ) ( L c w o m i u 1981), Early w o r k in the G N P series was o f t e n conducted m c o l l a b o r a t i o n w i t h Sewall W r i g h t a n d sought t o explore different aspects o f t h e s h i f t i n g balance t h e o r y using d a t a f r o m characteristic c h r o ­

m o s o m a l inversion o f different n a t u r a l populations

s Principles o f Evolutionary Genetics

Because D o b z h a n s k y t h o u g h t char selection h a d

little effect on inversion frequency* his w o r k w i t h

b r i g h t concentrated o n breeding structures a n d the

impact o f r a n d o m d r i f t As early as 1941* however,

Dobzhansky's attention begins t o shift t o w a r d selec­

tion favoring hcterozygotes By 1950, the G N P scries

and Dobzhansky's research p r o g r a m began increas­

ingly t o address problems o f heterosis a n d balancing

selection (Beatty I987a)_ T h i s transition f r o m d r i f t

ro selection is emblematic of the emerging view in

the 1950s that n a t u r a l selection is the p r e d o m i n a n t

process o f e v o l u t i o n D u b b e d the " h a r d e n i n g o f t h e

synthesis" by Stephen Jay G o u l d , the c o n s t r i c t i o n

characteristic o f the synthesis period had produced

n type o f pan-sclccrionistn t h a t w o u l d d o m i n a t e

e v o l u t i o n a r y biology i n t o t h e 1970s ( G o u l d 1 9 8 i l

Focusing o n selection t o the exclusion o f o t h e r

processes d i d n o t guarantee that consensus» Instead,

new controversies emerged c o n c e r n i n g the f o r m o f

selection a n d the a v a i l a b i l i t y o f genetic v a r i a t i o n

selection, a n d the genetic effects o f a t o m i c r a d i a t i o n

In 1955 at the meeting o f the C o l d Spring H a r b o r

eventual f i x a t i o n o f the m o r e favorable, in place of

the less f a v o r a b l e , gene alteles a n d c h r o m o s o m e

structures." M o s t l o c i , according t o the classical posi­

t i o n , should be homozygous Hctcrozygotes were

rare a n d h a d four possible sources; i l ) deleterious

mutations that are eventually eliminated by selection,

[2) adapnvely neutral m u t a t i o n s , (3) " a d a p t i v e poly­

morphisms m a i n t a i n e d by the diversity o f the e n v i ­

ronments w h i c h t h e p o p u l a t i o n i n h a b i t s ,w a n d

[4) r a r e beneficial m u t a n t s w h i c h are on their w a y

t o w a r d f i x a t i o n ( D o b z h a n s k y 1955)* A c c o r d i n g t o

Dobzhansky, the m a i n p r o p o n e n t o f the classical

position was I L J M u l l e n T h e balance p o s i t i o n ,

a c c o r d i n g t o Dobzhansky, h e l d that most l o c i

should be heterozygous H o m o z y g o t e s w o u l d still occur, b u t they w o u l d n o t be as advantageous a& over-dominant heterozygous combinations In terms

of genetic v a r i a t i o n , the issue at stake between t h e classical a n d balance p o s i t i o n s was t h e relative

n u m b e r a n d i m p o r t a n c e o f heterozygous superior

o r o v c r d o m i n a n t l o c i D o b z h a n s k y cast himself as the p r i m a r y advocate o f the balance p o s i t i o n ,

M u l l c r never agreed w i t h Dobzhansky's charac­terization o f the classical a n d balance positions, b u t

he had articulated s o m e t h i n g close t o the classical

p o s i t i o n A n o r i g i n a l member of M o r g a n ' s Fly

G r o u p , M u l l c r was a w o r l d leader in genetics h a v i n g

w o n a N o b e l Prize in 1948 for his research on the p r o d u c t i o n o f m u t a t i o n s w i t h X-rays I n 1950,

he published " O u r lx>ad o f M u t a t i o n s , " w h i c h

p r o v i d e d a n e w w a y t o assess the genetic damage created by m u t a t i o n A c c e p t i n g t h e premise t h a t the vast m a j o r i t y o f m u t a t i o n s are h a r m f u l t o some degree, M u l l c r argued that i n a p o p u l a t i o n o f constant size, each m u t a t i o n leads t o one "genetic

d e a t h " — t o one i n d i v i d u a l that fails t o reproduce

T h e n u m b e r of deleterious allcfes possessed by an

i n d i v i d u a l represented that individual's d e v i a t i o n

f r o m a genetic ideal—that person's genetic load Because he had pioneered m u c h o f the early w o r k

on the genetic effects o f r a d i a t i o n , M u l l c r was

a d a m a n t a b o u t the genetic loads that exposure t o

r a d i a t i o n c o u l d produce This concern reflected the

d a m a g i n g effects o f r a d i a t i o n on genetic material

a n d was m o t i v a t e d by the recent use o f a t o m i c weapons in W o r l d War I I a n d was heightened by the

o n g o i n g C o l d War arms race a n d testing programs,

T h u s , it was n a t u r a l t h a t , w h e n M u l l c r discussed factors that w o u l d increase genetic loads a n d p u t human p o p u l a t i o n s at risk, radiation was prominent (Beatty 1 9 8 7 b )

M u l l e r ' s r a d i a t i o n fears w e r e exacerbated by

a scries o f a m b i g u o u s results f r o m i r r a d i a t i o n experiments conducted in t h e 1950s a n d 1960s Bruce Wallace, a student o f Dobzhansky's, h a d been

c o l l a b o r a t i n g w i t h J* C K i n g t o study the effects of

r a d i a t i o n exposure i n Drosopbila Setting a c o n t r o l

p o p u l a t i o n as the standard, Wallace a n d K i n g exposed flies t o acute a n d chronic doses o f r a d i a t i o n

I f M u l l e r was c o r r e c t , the r a d i a t i o n s h o u l d induce deleterious mutations a n d lower the fitnesses of the treated populations relative t o the c o n t r o l popula­

t i o n T h e flics receiving chronic irradiation d i d indeed have a lower adaptive value, but the acutely irradi­ated flics had a higher adaptive value Interpreting this r e s u l t in l i g h t o f the balance p o s i t i o n ,

From Mendel t o Molecutes 9

Wallace a n d K i n g argued that i m p r o v e m e n t o f the

acutely irradiated population "cciuld exist n o t merely

in spite of h u t because of the o r i g i n a l t r e a t m e n t "

(Wallace & K i n g 1951) Wallace a n d King's results

were meant t o i n v i t e further research, w h i c h they

d i d , h u t they also invited controversy Wallace

himself c o n t i n u e d t o refine his r a d i a t i o n experi­

ments, w h i l e M u l l e r w o r k e d w i t h a graduate student,

Raphael Palk, t o p e r f o r m similar experiments N o n e

of these e x p e r i m e n t a l e f f o r t s were c o n v i n c i n g in t h e

end, in part because i t was impossible t o p i n d o w n

the exact effects o f the i r r a d i a t i o n — i t was unclear

then that i r r a d i a t i o n was p r o d u c i n g new o v c r d o m

-i n a n t l o c -i Desp-ite e f f o r t s t o b r -i n g the d-isputants

Together t o w o r k o u t t h e i r differences» by the 1960s

the classical-balance controversy h a d stalemated

(hcatty 1 9 8 7 b | J

By l i n k i n g genetic variability t o r a d i a t i o n , the

stakes i n this controversy had been raised beyond

those of an intellectual dispute in evolutionary' genet*

ics, Both M u l l e r a n d Dobzhansky saw themselves as

struggling tor the f u t u r e o f h u m a n k i n d Hope o f

some empirical resolution depended on a way o f

detecting genetic differences more precisely I h c tools

for addressing this issue had been developing w i t h i n

biochemistry and molecular biology for a number o f

years However» the i n t r o d u c t i o n o f molecular tools

and data i n t o evolutionary genetics w o u l d funda­

mentally alter the classical-balance controversy

rather than settle it (Dietrich 1994; L e w o n t i n 1974)

T H E E L E C T R O P H O R E T I C

R E V O L U T I O N

FJectrophorcsis h a d been developed i n biochem­

istry as a means for separating molecules by charge

and size* I n t h e early 1960s* geneticist Jack L

H u b b y began t o a d a p t electrophoresis for use w i t h

Drosophila W h e n R i c h a r d L e w o n t i n m o v e d t o the

University o f C h i c a g o t o c o l l a b o r a t e w i t h h i m i n

1 9 6 4 , H u b b y ' s o r i g i n a l p r o g r a m o f research

changed significantly L e w o n t i n was a student o f

Dob/hanslcyVs a n d h a d been f o l l o w i n g the

classical-balance debate closely W h e n l e w o n t i n arrived i n

Chicago* he h a d a list o f criteria for e x p e r i m e n t a l l y

resolving h o w m u c h heterozygosiry there was per

locus in a p o p u l a t i o n * In his w o r d s ,

3Scc thi" iranwfipi *>f the MACY Conference J< http^

■ r 1 i■ i I ■ du/hn/i volution/puMk/iuhivrVmtKyionfererwe 1 » 1

mttcy.himl

A n y technique that is t o give the k i n d o f clear i n f o r m a t i o n w e need must satisfy a l l o f the

f o l l o w i n g c r i t e r i a : (11 Phenotypic differences caused by allelic substitutions at single l o c i m u s t

be detectable i n single i n d i v i d u a l s (2) Allelic suhstitutions at one locus must be distinguishahle

f r o m substitutions at other loci ( ! ) A substantial

p r o p o r t i o n o f (ideally* all) allelic substitutions must be distinguishable f r o m each other (4) Loci studied m u s t be an unbiased sample o t the genome w i t h respect t o the physiological effects

a n d degree o f v a r i a t i o n ( M u b b v & L e w o n t i n

1966, p >7fl)

H u b b y a n d I x w o n r i n ' s w o r k tried t o meet these criteria a n d provide a reliable measure o f the

a m o u n t o f heterozygosily f o u n d i n />

/>*rW'>-ubsatrj T h e i r survey o f 18 loci revealed w h a t they

u n d e r s t o o d t o be a h i g h degree o l p o l y m o r p h i s m ; the average hetcrozygosiry was 1 1 5 % 1-cwontin

a n d I l u b h y proposed several alternatives t o e x p l a i n this v a r i a t i o n * The possibility o f neutral alleles was Considered, a n d ruled o u t because local popula­tions d i d n o t have the h i g h levels o f homor.ygosity predicted i f d r i f t were prevalent They also consid­ered the possibility o f a large n u m b e r o f o v e r d o in -

i n a n t loci» b u t recognized that so many heterotic loci w o u l d c a m ' w i t h them a large segregational load

( L e w o n t i n &i H u b b y 1966) Almost immediately

three different groups proposed truncation selection models t o address this problem* It l o o k e d as ifelec-iTophoresis had p r o v i d e d i m p o r t a n t evidence m favor o f the halance p o s i t i o n This sense of resolu­

t i o n was s h o r t - l i v e d , however, as t h e advocacy o f

n e u t r a l molecular e v o l u t i o n , beginning i n 1968, redrew the conceptual landscape

A p a r t f r o m the classical-balance controversy, elect rophoresis h a d a tremendous impact u p o n the experimental practice o f evolutionary gaieties* F r o m

1966 t o 1984* the genetic variability o f 111) species was measured using electrophoresis T h i s " f i n d *em

a n d g r i n d ' em** approach expanded the scope o f evolutionary genetics, d r e w more people t o consider the p r o b l e m o f e x p l a i n i n g variability, a n d d e m o n ­strated the power o f molecular techniques for evolu­

t i o n a r y biology ( L e w o n t i n 1991) H e a r o p l m r e s i s was o n l y a p a r t o f the molecular biology b o o m

g o i n g o n in the 1960s, however After James Watson

a n d Francis C r i c k discovered the d o u b l e helical structure o f D N A i n 1955, molecular biologists

a n d biochemists began t o address the e v o l u t i o n of

D N A , K N A , a n d p r o t e i n s , as w e l l as their c o d i n g

10 Principles o f Evolutionary Genetics

late 1960s w i t h the spread o f experimental tech­

niques, such as electrophoresis, a n d w i t h theoretical

developments that embraced these n e w m o l e c u l a r

d a t a T h e most significant theoretical o r conceptual

developments associated w i t h t h e molecularizarion

o f e v o l u t i o n a r y genetics were the i n t r o d u c t i o n o f

rhc molecular c l o c k a n d the advocacy o f n e u t r a l

molecular e v o l u t i o n or, as it was called at the t i m e

N o n - D a r w i n i a n e v o l u t i o n

I n 1965 Emilc Z u c k e r k a n d l a n d L i n u s Pauling

articulated w h a t was later referred t o as " t h e most

significant result o f research in molecular evolution**

[ W i l s o n et a l , 1977) A f t e r c o m p a r i n g the a m i n o

acid sequences o f proteins f r o m different lineages*

Z u c k e r k a n d l a n d Pauling discovered that the differ­

ences in a m i n o acid sequence were " a p p r o x i m a t e l y

p r o p o r t i o n a l in n u m b e r t o e v o l u t i o n a r y t i m e "

( Z u c k e r k a n d l & Pauling 1965) In other w o r d s , t h e

rate o f a m i n o acid s u b s t i t u t i o n was a p p r o x i m a t e l y

c o n s t a n t Z u c k e r k a n d l a n d P a u l i n g christened

this constancy the molecular clock ( M o r g a n 1 9 9 8 ;

Rodrigucz-Trelles ct a l , C h 8 of this v o l u m e ) T h e

value o f the molecular c l o c k for systcmatics was

quickly recognized, b u t the evolutionary mechanisms

u n d e r l y i n g the clock's constancy were a m b i g u o u s

until M o t o o K i m u r a , Jack K i n g , a n d T h o m a s Jukes

made t h e i r case for n e u t r a l m o l e c u l a r e v o l u t i o n ,

M o t o o K i m u r a was a Japanese biologist w h o

had w o r k e d w i t h James C r o w a n d Sewall W r i g h t i n

the United States on mathematical p o p u l a t i o n genet­

ics* A s C r o w ' s s t u d e n t , K i m u r a was f a m i l i a r w i t h

the classical-balance c o n t r o v e r s y a n d was s y m p a ­

thetic t o the classical p o s i t i o n , as was C r o w T h e

possibility of n e u t r a l alleles had been frequently

m e n t i o n e d in the course o f the classical-balance

controversy, but n o n e o f the participants seemed t o

have taken them seriously as an alternative t o a

system o f alleles under some f o r m o f selection

Indeed in 1 9 6 4 , C r o w a n d K i m u r a developed the

i n f i n i t e l y m a n y alleles m o d e l w h i c h , w h i l e i t presented a m o d e l o f m u t a t i o n for neutral alleles, was p r i m a r i l y aimed at demonstrating the high loads produced by m o r e c o m p l e x models o f o v e r d o m i -nant alleles K i m u r a later shifted his perspective o n neutral alleles f r o m a mathematically tractable case

t o a description o f a biological reality H e d i d so in response t o both the high genetic variability observed

by L e w o n t i n a n d H u b b y and an array of biochemical evidence for neutral alleles being presented a n d discussed at the first conferences o n molecular evolu­

t i o n , such as the Evolving Genes a n d Proteins conference in 196S where Z u c k e r k a n d l and Pauling christened the m o l e c u l a r c l o c k Indeed K i m u r a s

1 9 6 8 argument for neutral molecular e v o l u t i o n is based on data about rates o f molecular change presented at the Evolving Genes and Proteins c o n ­ference, i n c l u d i n g the h e m o g l o b i n d a t a presented

by Z u c k e r k a n d l a n d P a u l i n g ( D i e t r i c h 1 9 9 4 )

K i m u r a *s colleague T o m o k o O h t a estimated the rate

of a m i n o acid change i n m a m m a l i a n h e m o g l o b i n , primate h e m o g l o b i n , m a m m a l i a n a n d avian c y t o -

chrome c, a n d triosephosphate dehydrogenase f r o m

rabbits a n d cattle K i m u r a then calculated the rate

of e v o l u t i o n for a m a m m a l i a n genome K i m u r a s esti­mate o f 1.8 years f o r the average rime t a k e n f o r one base p a i r replacement c a r r i e d w i t h it an intolerable cost o f selection The o n l y way t o avoid this high cost

o r s u b s t i t u t i o n a l l o a d was t o postulate that m o s t

of the observed substitutions were i n fact selec­tively neutral { K i m u r a 1968)

K i m u r a ' s p o s i t i o n was strongly reinforced the next year by Jack K i n g a n d T o m Jukes w h o strongly advocated the importance o f neutral mutations a n d generic d r i f t Jukes wTas a biochemist by t r a i n i n g and an early molecular evolutionist H e had attended the E v o l v i n g Genes a n d Proteins conference a n d

h a d published a b o o k o n the subject entitled

Molecules and Evolution in 1 9 6 6 L i k e m a n y o t h e r

biochemists interested in e v o l u t i o n Jukes recog­nized the existence o f n e u t r a l substitutions, b u t t o

develop his views he needed rhc help ot A p o p u l a ­

t i o n geneticist Jukes s o u g h t o u t Jack K i n g , a y o u n g biologist w i t h t r a i n i n g i n e v o l u t i o n a r y genetics Together they assembled a b r o a d range o f evidence

f r o m biochemistry a n d molecular e v o l u t i o n t o directly counter G G Simpson** a n d E m i l Smith's claims f o r panselectionism at the m o l e c u l a r level (Dietrich 1994) Under the intentionally provocative

t i t l e o f N o n - D a r w i n i a n E v o l u t i o n , the)' presented a case for neutral m o l e c u l a r e v o l u t i o n t h a t included

K i m u r a ' s cost o f selection a r g u m e n t as w e l l as

From Mendel t o Molecules 11

arguments based on the significance o f synony­

mous m u t a t i o n s , c o r r e l a t i o n between the generic

code a n d t h e a m i n n acid c o m p o s i t i o n o f p r o t e i n s ,

higher rates o f change at t h i r d positions o f codons*

and overall constancy of the rate of molecular evolu­

t i o n T h e response t o K i m u r a , K i n g , a n d Jukes w a s

immediate a n d hostile* Bryan C l a r k e a n d R o l l i n

R i c h m o n d , for instance, offered point by point c o u n ­

terarguments t o the evidence presented by K i n g a n d

Jukes, thereby inaugurating the neutralist-selectionist

controversy (Clarke 1 9 7 0 ; R i c h m o n d 1970)*

I n 1 9 6 9 , K i m u r a used t h e constancy o f t h e rate

of a m i n u acid substitutions in h o m o l o g o u s proteins

ro argue p o w e r f u l l y for n e u t r a l m u t a t i o n s a n d t h e

i m p o r t a n c e o f r a n d o m d r i f t in molecular e v o l u t i o n

i K i m u r a 1969b) A t the same time, K i m u r a was also

calling o n his earlier w o r k on stochastic processes in

population genetics (Gillcspic, C h 5 o f this volume)

ro forge a solid theoretical f o u n d a t i o n for the neutral

theory; Kimura's diffusion equation method provided

the theoretical f r a m e w o r k he needed f o r m u l a t e

specific models w h i c h in m m a l l o w e d h i m t o address

issues such as the p r o b a b i l i t y a n d t i m e t o f i x a t i o n

of a m u t a n t substitution as well as the rate o f mutant

substitutions i n e v o l u t i o n ( K i m u r a 1970) W o r k i n g

in c o l l a b o r a t i o n w i t h T o m o k o O h t a , K i m u r a also

extended the n e u t r a l theory t o encompass the p r o b *

lem o f e x p l a i n i n g p r o t e i n p o l y m o r p h i s m s T h i s was

a central concern o f p o p u l a t i o n genetics, a n d K i m u r a

a n d O h t a were able t o s h o w that p r o t e i n p o l y m o r ­

phisms were a phase in mutations* journey t o f i x a ­

t i o n ( K i m u r a & O h t a 1971a),

I n 1 9 7 1 the S i x t h Berkeley Symposium on

M a t h e m a t i c a l Statistics a n d P r o b a b i l i t y devoted

a session t o D a r w i n i a n , N e o D a r w i n i a n , a n d N o n

-D a r w i n i a n e v o l u t i o n By this t i m e , rhe debate

between the neutralists a n d selectionists was w e l l

under w a y A l t h o u g h (ew tests h a d been d o n e ,

there h a d been q u i t e a b i t of t a l k a b o u t the a b i l i t y

of r i v a l hypotheses t o e x p l a i n a w i d e variety o f

data a n d the positions were w e l l a r t i c u l a t e d James

C r o w was charged w i t h g i v i n g a r e v i e w o f both

sides o f t h e debate t o start the conference session

C r o w was disposed t o w a r d t h e n e u t r a l theory, h u t

was m o r e skeptical than cither K i m u r a o r O h t a A s

a p a r t i c i p a n t in t h e classical-balance controversy,

C r o w h a d experienced the f r u s t r a t i o n o f t r y i n g t o

f i n d d e f i n i t i v e tests for either p o s i t i o n ; as a result he

valued the neutral theory because it offered q u a n t i ­

tative predictions that c o u l d be tested a n d seemed t o

m o v e b e y o n d the classical-balance stalemate ( C r o w

1972K '

A t t h e same s y m p o s i u m , G* L* Stebbms a n d Richard L c w o n t i n attacked the n e u t r a l t h e o r y as a testable hypothesis* A c c o r d i n g t o Stebhms a n d

l e w o n t i n , the n e u t r a l theory in its simplest f o r m predicts that allele frequencies w i l l vary f r o m p o p u ­

l a t i o n t o p o p u l a t i o n , b u t in D psettdtyobscura a n d

D tiillistoni, w i d e l y separate p o p u l a t i o n s s h o w

very similar allele frequencies A m i g r a t i o n rate as

l o w as one migrant per generation could account for the similarity* Because assumptions a b o u t m i g r a t i o n rate c o u l d always e x p l a i n away allele frequency data, Stchhins a n d I x w o n t i n charged that n o obscr* vation c o u l d contradict the neutral theory's predic­tion* They even directly appealed t o K a r l Popper's philosophy o f science a n d labeled the neutral t h e o r y

" ' e m p i r i c a l l y void* because it has n o set of potential falsifiers" l S t c b b i n s & I x w o n t i n 1972|- Yet, Stcbhins and L c w o n t i n d i d n o t reject the idea o f neutral

m u t a t i o n and rhe effects of r a n d o m d r i f t ; instead they claimed that the nature of evolutionary processes was unresolved a n d encouraged the diverse pursuits o f selectionists a n d neutralists (Stchbins & I x w o n t i n

| y 7 2 ) Stebbms a n d l.ewontin's concerns a b o u t testing rhe neutral theory w o u l d be c o m p o u n d e d over the next 10 years Despite an abundance o f data f r o m electrophoretic surveys, using this data t o test predic­tions f r o m the neutral theory was n o t as straightfor­

w a r d as it had been supposed* Tests proposed by Warren Kwens in 197.J an d later refined by Geoff Watterson in 1977 were designed for clccirnphorciic

d a t a , b u t when applied d i d n o t have t h e statistical

p o w e r t o d i s c r i m i n a t e between n e u t r a l i t y a n d selec­

t i o n [ I x w o n t i n 1 9 9 1 ) T h e consequence o f this and other difficulties w i t h testing the n e u t r a l t h e o r y was that neutralists p u t m o r e stock in the molecular clock as evidence in s u p p o r t o f neutrality

In 1 9 7 1 , T o m o k o O h t a a n d M o t o o K i m u r a asserted that t h e " r e m a r k a b l e constancy of t h e rate

of a m i n o acid substitutions in each p r o t e i n o v e r a vast p e r i o d o f geologic t i m e constitutes so far the strongest evidence for the theory (Kimura 196S; K i n g

a n d Jukes 1969) that the m a j o r cause o f molecular

e v o l u t i o n is r a n d o m f i x a t i o n o f selectively n e u t r a l

o r nearly neutral mutations*" l O h t a 5c K i m u r a 19711,

K i m u r a had s h o w n that l o r neurral changes the rate o f s u b s t i t u t i o n was equivalent t o t h e rate o l

m u t a t i o n Because the r3tc o f m u t a t i o n was under*

s t o o d t o be t h e result a stochastic process similar t o radioactive decay, the rate o f s u b s t i t u t i o n c o u l d also be u n d e r s t o o d as constant generated by an

u n d e r l y i n g stochastic process* T h e rate o f selected

12 Principles o f Evolutionary Genetics

substitutions, however, was subject t o changes in

selection intensity a n d p o p u l a t i o n size a n d so c o u l d

not be expected t o be constant over any l o n g period

[it t i m e

Whether recognized as a proxy f o r the

neutralist-selectionist debate o r n o t , the molecular clock was

the subject of intense debate For instance, because

the molecular clock was a stochastic c l o c k , some

variability in its rate was expected* By as early as

1974, however, Walter Fitch a n d Charles Langley

argued that the rate o f substitution was nor as

u n i f o r m across different lineages as it ought t o be i f

the neutralist e x p l a n a t i o n was correct (Langley &

hitch 19741 M o r r i s G o o d m a n a n d others joined i n

this l i n e o f c r i t i c i s m , a d d i n g evidence o f s l o w d o w n s

and speedups f r o m various lineages In response,

K i m u r a a d m i t t e d that the rate o f molecular e v o l u ­

tion was n o t perfectly u n i f o r m , b u t in his o p i n i o n ,

'emphasizing local fluctuations as evidence against

the n e u t r a l theory, w h i l e neglecting t o i n q u i r e w h y

the overall rare is intrinsically so regular o r constant

Is picayunish It is a classic case o f "not seeing the

forest f o r the trees"" { K i m u r a 1983), Selectionist

critics were undeterred W i t h g r o w i n g evidence that

rate v a r i a b i l i t y was m u c h more pronounced than

had been supposed, J o h n Gillespie proposed a

selectionist episodic molecular clock chat he claimed

could explain patterns o f substitution better than

Kimura's neutralist e x p l a n a t i o n (Gillespie 1984) T o

answer Gillespte's claims, neutralists revised their

models o f substitution ro accommodate greater

variability The a m o u n t o f variability that can be

accommodated by the clock concept remains an

open question (although see Rodrigucz-Trcllcs ct a l ,

Ch 8 o f this v o l u m e )

T h e neutralist-selectionist controversy itself was

transformed d u r i n g the 1980s w i t h the i n t r o d u c ­

tion o f U N A sequence d a t a As a graduate student

w o r k i n g w i t h Richard I x w o n t i n , M a r t i n K r e i t m a n

learned h o w t o sequence D N A in Walter Gilbert's

laboratory at H a r v a r d K r e i t m a n then sequenced

A D H genes in Drosophila l o o k i n g for evidence o f

p o l y m o r p h i s m s , k r e i t m a n s detection of p o l y m o r ­

phisms in the D N A sequences suggested that there

was selection at the A D M locus a n d that differences

between synonymous a n d n o n - s y n o n y m o u s sites

were significant Kreitman w o u l d develop the analy­

sis o f patterns o f nucleotide sequence comparisons

i n t o the H u d s o n - K r c i t m a n - A g u a d e test a n d the

M c D o n a l d - K r c i t m a n test These statistical tests and

others allowed evolutionary geneticists t o detect

selccrion ar the molecular level ( K r e i t m a n 2000)

Where earlier tests h a d been unable t o discriminate between n e u t r a l i t y a n d selection, these rests applied

t o nucleotide sequence data succeeded.1

A c c o m p a n y i n g the availability o f D N A data was a significant change in a t t i t u d e t o w a r d neutral­ity* W h e n K i m u r a proposed the neutral t h e o r y in

1968, the d o m i n a n t a t t i t u d e o f biologists was that

n a t u r a l selection was the o n l y i m p o r t a n t cause o f evolutionary change at any level o f o r g a n i z a t i o n This panselectionist a t t i t u d e informed the early opposition t o the possibility o f neutral molecular evolution By the raid-1980s, however, the d o m i n a n t attitude among evolutionary geneticists using molec­ular data was that the neutral theory p r o v i d e d the starting place for investigation in the sense o f being the accepted null model ( K r e i t m a n 2000) W h y hypo­theses o f n e u t r a l m o l e c u l a r e v o l u t i o n became accepted as n u l l hypotheses at this t i m e has yet to

be investigated by historians, but the rise o f neutral

n u l l models seems t o coincide w i t h increased avail­

a b i l i t y o f D N A sequence d a t a , increasing use o f molecular clocks i n systematic*, increasing use o f coalescents, a n d t h e spread o f tests such as the

a n d W r i g h t were o f t e n heated a n d sometimes q u i t e personal L i k e a l l c r i t i c i s m in science, however, controversies also present the possibility of change

T h e controversies of e v o l u t i o n a r y genetics typically began as highly polarized disputes, b u t the positions

in question developed, sometimes radical!); some* times more subtly These nransformarions allowed the controversies t o depolarize by enabling some partic­ipants t o disengage, revise their o p i n i o n s , o r change their focus Whether the f u t u r e o f e v o l u t i o n a r y

*Thc hittorv of tbetc te«* a» wdl a* a diwwwon of their development And ligniricjncc by Mmin Krritnun and R>JI»TJ Lrwoniin arc Jviibbk *l htrp^/hr%t.mit.cJu*f*/oolui»oci/puWiJ krtitnuflJitmL

Copyrighted mate

From Mendel to Molecules 13

genetics is doomed ro persistent controversy is hard

to iay, but controversy has been an unavoidable

failure of its past

SUGGESTIONS FOR

FURTHER READING

Provine (19861 provides an excellent overview of

the development of evolutionary genetics as it traces

the life of Scwall Wright* The earlier debate between

the Mcndclians and Biometncians is expertly

analyzed in Kim (1994), Because it also includes

commentaries by other historians of genetics, Kim

(1994) provides a useful introduction to the debates

among historians, sociologists, and philosophers

over scientific controversy l*cwontin et at* 11981)

is a collection of Thcodosius I)obzhansky\ papers

i n the Genetics of Natural Population series This

very influential set of papers is comextualtzed by

i w o extensive introductions, one by Provine and

the other hy I-ewonrin The impact of molecular

biology on evolutionary genetics and the rise of molecular evolution are examined in Dietrich

(1994)

Dietrich MR 1994 The Origins of the Neutral Thvory of Molecular Evolution J I list Biol 27:21^59

Kim K 1994 Explaining Scientific Consensus: The Ca*c of Mendelian Genetics Guilford Press Lcwontm RC, Moore JA Provine W l l fcx

Wallace B teds) 1981 Dobzhan sky's Genetics

of Natural Populations [ - X L I I I Columbia Univ- Press

Provine W 1986 Scwall Wright and Evolutionary Biology Univ o f Chicago Press

Acknowledgments I am grateful t o James K

C r o w , Richard C Lcwontin, William Provine, Robert Skipper, and Michael J Wade for their thoughtful comments on earlier drafts of this chapter Any remaining errors are my own

2

Genetic Variation

M A R T A L WAYNE MICHAEL M M I Y A M O T O

Genetic v a r i a t i o n provides the u n d e r p i n n i n g o f

m o d e r n biological thought* F r o m e v o l u t i o ­

nary biologists s t u d y i n g finches in the field» t o d r u g

development in the pharmaceutical i n d u s t r y ; f r o m

[he developmental geneticists t r y i n g t o understand

the b o d y p l a n o f a mouse, t o the researchers inves­

t i g a t i n g t h e genetic basts for a l c o h o l i s m ; genetic

v a r i a t i o n gives us a h a n d h o l d on the p h e n o t y p e ,

which is otherwise a complex a n d slippery construct»

Phcnotypcs a r c p r o d u c e d by genes, the e n v i r o n ­

ment, a n d the interaction between genes a n d the

e n v i r o n m e n t T h e r e are few phenotypes for w h i c h

v a r i a t i o n o c c u r r i n g in nature is entirely e n v i r o n *

m e n t a l H o w e v e r , b e y o n d a c o n v i c t i o n that o r g a n ­

isms must u l t i m a t e l y be the products o f t h e i r genes,

it is very d i f f i c u l t t o justify such a statement This is

in part because we still can n o t describe the complete

g e n o t y p e - p h e n o t y p e m a p f o r a n y b u t the simplest

traits Regardless, genetic v a r i a t i o n has been f o u n d

for v i r t u a l l y every trait ever e x a m i n e d , suggesting

that genetic v a r i a t i o n as a cause o f p h e n o t y p i c v a r i ­

ation is l i k e l y t o be r a m p a n t

It is impossible t o study the impact of the environ­

ment on a trait if a l l organisms experience precisely

the same environment, that is the environment does

n o t vary at a l l f r o m one i n d i v i d u a l t o a n o t h e r

L i k e w i s e it is impossible t o study the role o f genes

in producing a phenotype w i t h o u t any genetic varia­

t i o n , that is i f a l l individuals are genetically the same

Thus, variation is central, as the differences a m o n g

individuals serve as markers that a l l o w one t o study

the genetic and environmental factors responsible for

specific traits T h e origin of the study of genetics a n d

e v o l u t i o n began w i t h genetic v a r i a t i o n : M e n d e l

began his study o f sweet peas w i t h the study o f

" s p o r t s " ( m u t a n t varieties); D a r w i n began h i s study o f e v o l u t i o n w i t h the s t u d y o f h e r i t a b l e pigeon varieties produced in response t o a r t i f i c i a l selection by pigeon fanciers

F r o m the perspective o f e v o l u t i o n a r y biologists, genetic v a r i a t i o n is the fundamental r e q u i r e m e n t

f o r e v o l u t i o n , E v o l u t i o n is frequently defined quite concisely, p a r t i c u l a r l y in t e x t b o o k s o r PhD q u a l i f y ­

i n g e x a m i n a t i o n s , as a change in allele frequencies

o v e r time* C o n t a i n e d in this d e f i n i t i o n ( w h i c h is a very n a r r o w one that w i l l be expanded t h r o u g h o u t this chapter) is the i m p l i c i t requirement t h a t a locus

t h a t c o n t r i b u t e s t o e v o l u t i o n m u s t n o t be fixed f o r one allele, that is that genetic v a r i a t i o n m u s t be present for e v o l u t i o n t o occur Such a definition»

w h i l e precise i n some respects, fails t o c a p t u r e several i m p o r t a n t details First, w h a t is an allele?

W h a t a b o u t larger changes in c h r o m o s o m a l e v o l u ­

t i o n , such as g e n o m e - w i d e d u p l i c a t i o n s o r gross

c h r o m o s o m a l rearrangements—do these n o t also

c o n t r i b u t e t o e v o l u t i o n ? Second, w h a t mechanisms cause the changes in allele frequency, however broadly w c m a y define an allele, a n d hence cause

e v o l u t i o n ; a n d w h a t are the relative c o n t r i b u t i o n s

o f these different mechanisms?

This chapter w i l l concern itself first w i t h the question o f w h a t genetic variation consists o f : specif­ically, w h a t is an allele? T h e definition o f an allele is far f r o m static, b u t rather changes w i t h every increase

in o u r knowledge about genetics a n d molecular b i o l ­ogy, For e x a m p l e , an allele in the broadest sense may

be a single nuclcotidc change o r a change in c h r o m o ­some number, structure, o r the d i s t r i b u t i o n o f genes

t h r o u g h o u t the genome T h r o u g h o u t the chapter,

w c strive t o emphasize a synthesis o f f u n c t i o n a l

14

Genetic Variation I S

genetic v a r i a t i o n , c o m b i n i n g molecular, mechanistic

definitions o f alleles w i t h their genetical properties,

Functional properties o f alleles contribute t o their

roles in e v o l u t i o n , We begin by enumerating types o f

genetic v a r i a t i o n identified at the molecular level

i n c l u d i n g selective expectations for molecular varia­

t i o n N e x t , w e link this molecular variation t o genet*

ical properties such as dominance and additivity The

o r i g i n o f genetic variation is also briefly discussed

f r o m a f u n c t i o n a l perspective, as is the inseparable

a c t i o n o f selection a n d d r i f t t o create the spectrum

o f genetic v a r i a t i o n that w e see Finally, w c consider

h o w a f u n c t i o n a l , synthetic perspective o n genetic

v a r i a t i o n challenges several classic e v o l u t i o n a r y

p a r a d i g m s

V A R I A T I O N A T T H E

M O L E C U L A R LEVEL

N e w molecular v a r i a t i o n arises t h r o u g h a spectrum

o f changes in a genome sequence, encompassing

single base substitution t h r o u g h p o i n t m u t a t i o n a n d

genome-wide d u p l i c a t i o n t h r o u g h p o l y p l o i d i z a u o n ,

T h u s , genetic v a r i a t i o n constitutes a rich a n d diverse t o p i c , a f f o r d i n g m a n y different ways t o hierarchically organize this i n f o r m a t i o n Given the

c u r r e n t state o f b i o l o g y , w i t h its emphasis o n mech­anisms a n d thereby molecules, w e start the defini­

t i o n o f an allele at the m o s t reductionist level: the

D N A | o r R N A ) m o l e c u l e O n e of the l u x u r i e s of the post-genomic era is that w e n o w can precisely describe far m o r e types o f sequence changes at the molecular level, a n d estimate the relative abundance

o f such events, at least w i t h i n the genome o f an

i n d i v i d u a l M o l e c u l a r alleles are presented f r o m t h e simplest (single base changes) t o the most c o m p l e x (changes affecting entire genomes, such as genome-

Thr

A C G

A C G Thr

GGA Arg

2 Transversion, synonymous substitution

3 Transition, nonsynonymous* missense substitution

4 Frameshtft deletion (introducing one nonsynonymous missonse and one nonsynonymous nonsense change)

FIGURE 2 1 Four different types o f mutations as illustrated w i t h the 5'-end of a hypothetical

protein-c o d i n g gene At the t o p , the original D N A sequenprotein-ce o f this gene is s h o w n , along w i t h the a m i n o aprotein-cid sequence for the a m i n o ( N H e r m i n u s o f its encoded polypeptide product* In t u r n , the D N A a n d polypcp-

tide sequences that result f r o m the four mutations are given at the b o t t o m T o facilitate c o m p a r i s o n , t h e

c o d i n g regions o f the D N A sequences are labeled as such a n d arc presented as base triplets relative t o their

encoded a m i n o acids* T h e four mutations are numbered a n d arc defined in the l o w e r left c o m e r of the figure In the case o f m u t a t i o n 4 , the strikethrough highlights a deletion o f the marked " A " in the o r i g i ­

n a l sequence In a d d i t i o n t o representing a p o i n t d e l e t i o n , this m u t a t i o n also constitutes a f r a m e s h i f t

m u t a t i o n <i.e., one that alters the d o w n s t r e a m reading f r a m e o f this gene)* I n this case, this fcimcshift

m u t a t i o n results in a n e w a m i n o acid a n d p r e m a t u r e t e r m i n a t i o n (as i n d i c a t e d by "stop**) o f the encoded m u t a n t polypeptide

16 Principles of Evolutionary Genetics

These include heritable substitutions o f one base

for another* Substitutions may be b r o a d l y classed

i n t o transitions (purine t o p u r i n e , i.e., adenosinc t o

f^iuninc or the reverse; pyrimidine t o pyrimidine, i.e.,

cytosine t o thymine o r the reverse) o r transversions

(purine t o p y r i m i d i n e o r vice versa) Relative rates

of transitions and transversions are well under*

stood for a w i d e range o f organisms (Graur & L i

2 0 0 0 ) ; in general, transitions are m o r e c o m m o n

rhan transversions because o f 11} rare t a u t o m c r i c

shifts (proton shifts) that result in noncanomcal base

p a i r i n g (e.g., G w i t h T ) ; a n d (2) the relatively fast

rate of m u t a t i o n o f C t o T in C p G dinucleotide pairs

(where the 5' C is methylated) Base changes are an

extremely c o m m o n type o f m u t a t i o n , and arc caused

by errors in genome replication Although D N A

polymerase has a p r o o f - r e a d i n g f u n c t i o n , most base

substitution mutations arise f r o m D N A replication

( D r a k e et a l 19981 Thus* spontaneous m u t a t i o n s

for base substitutions are inevitable a n d universal,

Base substitutions are also caused by a variety of

mutagens, including that favorite mutagen o f classi­

cal geneticists, ethylmethane sulfonatc, o r E M S

Base substitutions m a y occur in the n o n c o d i n g

sequence chat comprises the majority of most organ*

isms' genomes, o r in the p r o t e i n c o d i n g sequence

(CDS) o f the D N A o r R N A (Figure 2.1 K Genes that

occur i n the n o n c o d i n g sequence, w h i c h is defined

t o be sequence that is never transcribed o r else is

transcribed b u t not translated i m t r o n s , untranslated

regions o r U T R s ) , have t r a d i t i o n a l l y been expected

t o be e v o l u t i o n a r i l y u n i m p o r t a n t a n d irrelevant t o

the phenotype o f the o r g a n i s m Recent advances in

o u r understanding o f the sources o f v a r i a t i o n f o r

regulation o f p r o t e i n abundance have challenged

this view (see Phcnotypcs at the M o l e c u l a r Level:

Regulatory Variants, b e l o w ) In contrast, the e v o l u ­

tionary relevance o f base substitutions in the c o d i n g

sequence is expected t o be specific t o the c o n t e x t o f

the base Some c o d i n g sequence substitutions result

in a m i n o acid replacements, a n d these are generally

expected t o be under stronger selection than those

coding sequence changes that d o n o t result in protein

changes Because the genetic code is redundant f o r

many codons at the first a n d t h i r d positions, many

first a n d t h i r d position m u t a t i o n s d o n o t result in

changes t o the a m i n o acid sequence; some, however,

arc also replacement changes* Base m u t a t i o n s a t

second positions always lead t o a m m o acid replace*

ments o r stop codons M u t a t i o n s that change the

amino acid sequence arc referred t o as replacement o r

non-synonymous changes In t u r n , nonsynonymous

mutations that result in a m i n o acid replacements versus the incorporation of premature stop codons arc k n o w n as missense m u t a n o n s versus nonsense

m u t a t i o n s , respectively Those that d o n o t a r c referred t o as synonymous m u t a t i o n s

S y n o n y m o u s c o d i n g changes are g e n e r a l l y assumed t o be under weaker selection than nonsyn­onymous c h a n g e s even weaker than base changes

in untranslated regions o f genes (Graur & Li 2000) Nevertheless, even these w e a k l y selected changes can leave their marks at the molecular level when

p o p u l a t i o n sizes are large a n d selection is thereby most efficient For e x a m p l e , in yeast (where popu­

l a t i o n sizes are large), the use o f synonymous codons for the same a m i n o acids (e.g., C U A , C U C , C U G ,

C U D , U U A , a n d U A A for leucine) is n o t u n i f o r m bur is skewed such that their frequencies are corre­lated w i t h the relative abundances o f their corre­

s p o n d i n g cognate t R N A s (Ikemura 1985) Such codon usage biases ( c o d o n bias) are most evident in highly expressed genes (i.e., those m o s t l i k e l y under the strongest selection)

L e n g t h C h a n g e s Genetic v a r i a t i o n at the molecular level may also he caused by v a r i a t i o n i n sequence length Sequence length v a r i a t i o n i t caused by insertions o r deletions

t o the sequence a n d is m o r e generally referred t o as indcl v a r i a t i o n Collectively, base substitutions o r indels o f a single nucleotide that arc p o l y m o r p h i c

at the p o p u l a t i o n level are k n o w n as SNPs (single nucleotide p o l y m o r p h i s m s ) There are three m a j o r mechanistic models f o r indel v a r i a t i o n (transpose able elements, unequal crossing over, a n d D N A slippage), t h o u g h o r i g i n o f length variants is n o t considered t o be exclusive co these mechanisms Transposable elements fTEs) a r c genetic units that

d o not have a fixed place in the genome, b u t rather can move f r o m one locus t o another, sometimes by

d u p l i c a t i n g themselves a n d sometimes by excising themselves f r o m the D N A (Pctrov and W e n d c l ,

C h 10 o f this volume), T E variation is considered t o

be a ma tor source o f indel variation, as well as a m a j o r source o f genetic variation in natural populations (Kazazian 2004) T h e genetic differences between TEs themselves is a fascinating subject w h i c h is

b e y o n d the scope o f this chapter In brief, the inser­

t i o n o f a T E in a n e w site, p a r t i c u l a r l y by duplica­tion of the element, can result in a local increase in sequence length Shorter insertions are more c o m m o n , and may be due t o the imprecise excision of TEs f r o m

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Genetic Variation 17

genes ( M c D o n a l d 2000) Short deletions may also

result f r o m imprecise excision of T F A M a n y classical

m u t a t i o n s are c o m m o n l y caused by insertions,

i n c l u d i n g m u l t i p l e illicit-* o ( the white locus in

Drasopbila metattogaster (the first visible m u t a t i o n

isolated in t h i s species) U n e q u a l crossing o v e r is

another c o m m o n source of length p o l y m o r p h i s m

U n e q u a l crossing o v e r is caused by m i s p a i r i n g of

genes d u r i n g meiosis a n d subsequent recombina­

t i o n I K t w e e n the genes Such crossing over requires

that there I K extensive similarity between sequences,

so it is generally restricted t o t a n d e m l y d u p l i ­

cated genes, o r genes c o n t a i n i n g t a n d e m repeated

sequences (resulting in g a i n o r loss o f the area

between a n d / o r i n c l u d i n g the repeats) Unequal

crossing over is a m a i o r source o f indels for longer

D N A sequences a n d c h r o m o s o m a l regions* I n t u r n ,

f o r s h o r t , t a n d e m l y repeated sequences l i c , m i c r o

-satellite repeats a n d h o m o n u c l c o r i d e runs», indels

are p r i m a r i l y the result o f strand slippage a n d

mis-p a i r i n g o f the temmis-plate versus remis-plicating strands

d u r i n g D N A replication ( D X A slippage) I lere loops

can f o r m in either t h e template a n d / o r r e p l i c a t i n g

strands» i n such a w a y that the tandem repeals of

the f o r m e r p a i r w i t h repeats o f the latter w h i c h are

n o t t h e i r d i r e c t c o u n t e r p a r t s The end result is that

subsequent rounds o f replication can then lead t o

m u t a n t D N A duplexes w i l h increased o r decreased

n u m b e r s o f these short t a n d e m repeals

G e n e a n d G e n o m e

M u l t i p l i c a t i o n Events

I n a d d i t i o n ro single gene d u p l i c a t i o n events n o t

infrequently entire genomes have been duplicated

one o r more times in evolutionary history

(autopoly-p l o i d y ) , W h i l e i n d i v i d u a l genes have l o n g been

t h o u g h t t o be duplicates of one another ( T h o r n t o n ,

C h 11 o l t h i s v o l u m e l » the first o r g a n i s m t h a t was

proposed t o be the p r o d u c t o f an ancient

genome-w i d e d u p l i c a t i o n event is Saccharomyccs cerevmac*

the c o m m o n l a b o r a t o r y species o f yeast ( W o l f e t v

Shields 1997) Evidence f o r the a u t o i c t r a p l o i d state

o f yeast comes first f r o m many genes w i t h apparently

redundant f u n c t i o n , that is» no assayable phenotypc

on k n o c k o u t ; a n d second a n d m o r e convincingly*

f r o m t h e discovery o f 55 regions o f colinear, d u p l i ­

cated genes w i t h w h o l e gene deletions interspersed

w i t h i n these regions

Polyploidy events are generally m o r e c o m m o n in

plants t h a n in a n i m a l s , perhaps o c c u r r i n g in up t o

7 0 % o f angiosperms tSoltis & Soltis 1999; A r n o l d &

B u r k e , C h 26 o f this v o l u m e ) In general, plants are

m o r e tolerant o f changes in p l o i d y than a n i m a l s , perhaps because they arc m o r e tlevible in devel­

o p m e n t and therefore more tolerant of differences

in gene dosage* In particular, plants are c o m m o n l y allopolyploids i p o l y p l o i d s created f r o m interspecific

h y b r i d i z a t i o n ! , while the more rare p o l y p l o i d animals are usually autopolyploids, w h i c h an* frequently parthcuogeoetic due t o mciotic problems Moreover, plant species are frequently p o p u l a t i o n s of lineages

o f m u l t i p l e allopolyploidy events Genome restruc­

copies o f certain hnx genes in vertebrates were derived f r o m invertebrates such as Drosophiht a n d

p r i m i t i v e vertebrates l i k e Amphinxus* a n d was due

t o t w o serial g e n o m e - w i d e d u p l i c a t i o n s r e s u l t i n g in

an o c t o p l o i d geuomic state in vertebrates* H e also

n o t e d that for many genes, b o t h members o f the

I lox cluster a n d members o f gene families, o n l y three

copies are extant* H e suggested that because inter­specific h y b r i d i z a t i o n events are rare in vertebrates (other t h a n certain fish o r a m p h i b i a n s ) , a u t o p o l y -ploidy c o u l d be a major source of evolutionary novel­ties E le f u r t h e r suggested that ihis novelty was likely

t o be the o u t c o m e o f regulatory changes rather than

c o d i n g sequence changes, such that r e d u n d a n t func­

t i o n s might he rendered tissue*specific There are

n o w studies in multiple laxa s u p p o r t i n g the auto*

o c t o p l o i d hypothesis in ehordatcs, including humans ( M c l y s a g h t et ak 2 0 0 2 ! ; further, strong evidence exists for a subsequent d u p l i c a t i o n event in the

o f biological diversity A s n o t e d above, gene a n d genome d u p l i c a t i o n s p r o v i d e the new c o d i n g a n d regulatory sequences f o r t h e o r i g i n s of new p r o t e i n functions a n d s u b f u n c t i o n a l i / a t i o n s o f their ances­tral roles H o w e v e r , a n u m b e r o f o t h e r m u t a t i o n s are k n o u n that i n v o l v e changes in c h r o m o s o m e

13 Principles o f Evolutionary Genetics

structure a n d / o r n u m b e r a n d these are also often of

evolutionary a n d biological significance

In a d d i t i o n t o duplications and deletions, c h r o ­

mosome structure can also change by inversions

a n d t r a n s l a t i o n s In an i n v e r s i o n , a c h r o m o s o m a l

segment becomes flipped by 180° such that it is n o w

oriented in the reverse d i r e c t i o n If the centromere

is included in t h e inverted segment, then the inver­

sion is k n o w n as periccntric O t h e r w i s e , it is called

a paracentric inversion Inversions are considered

p a r t i c u l a r l y interesting because r e c o m b i n a t i o n is,

suppressed in inversion hctcrozygotcs, a l l o w i n g f o r

the possibility of ratchet-like m u t a t i o n accumulation

a n d / o r co-adapted gene complexes (Powell 1997)

I n t u r n , translocations refer t o the p r o d u c t s

of crossing over between n o n h o m o l o g o u s c h r o m o ­

somes Such crossing over can involve a unidirec­

t i o n a l transfer o f c h r o m o s o m a l material from one

nonhomologous chromosome t o the other o r a bidi­

rectional exchange o f segments between the t w o

T h e t w o types of translocations are k n o w n as n o n

-reciprocal a n d -reciprocal, respectively T w o special

types o f reciprocal translocations arc Robertsonian

fissions and fusions I n Robcnsonian fissions, a c h r o ­

mosome w i t h a m o r e central centromere (i.e., m e i a

-centric or submeta-centric) interacts w i t h a m i n u t e

" d o n o r " chromosome t o split the former i n t o t w o

smaller a n d separate acrocentnc chromosomes (those

w i t h near-terminal centromeres) In Robertsonian

fusions, t w o acrocentnc chromosomes interact such

that the t w o become united i n t o one larger metacen*

trie o r submetacentric chromosome In the process*

a minute " d o n o r " chromosome is generated as w e l l

I n contrast t o p o l y p l o i d y , a n e u p l o i d y refers t o

the g a i n o r loss o f i n d i v i d u a l w h o l e chromosomes

(rather than t o the duplication of the entire genome)

Trisomy is the gain of a whole chromosome, whereas

monosomy corresponds t o its loss In a d d i t i o n ,

changes in chromosome number can be l i n k e d t o

R o b e r t s o n i a n fissions a n d fusions o f d i f f e r e n t

nonhomologous chromosomes H e r e , as the m i n u t e

" d o n o r " chromosomes are readily lost, Robertsonian

fissions a n d fusions can lead relatively quickly t o a

subsequent increase o r decrease in c h r o m o s o m e

number, respectively Such a mechanism has been

invoked t o e x p l a i n the difference in c h r o m o s o m e

number between humans a n d great apes, w i t h t h e i r

2iV counts of 46 versus 4 8 c h r o m o s o m e s , respec­

tively <de P o n t b r i a n d et a l 2 0 0 2 )

O f these a d d i t i o n a l sources o f change i n

chromosome structure and/or number, inversions,

translocations, a n d Robertsonian translocations

are most i m p o r t a n t t o studies o f n a t u r a l v a r i a t i o n , Such changes in c h r o m o s o m e s t r u c t u r e a n d

n u m b e r arc frequently present as p o l y m o r p h i s m s in natural p o p u l a t i o n s a n d geographic p o p u l a t i o n s

a n d closely related species are often distinguished

by such c h r o m o s o m a l differences

Epigenetic C h a n g e s Epigenetic changes may be defined as heritable changes in gene expression that are not the result

o f sequence alterations ( M u r p h y & Jirtle 2 0 0 3 ; JablonkaSc 1-amb, C h , 17 of this volume) Epigenetic changes can often be reset every generation, in contrast t o sequence changes, w h i c h are reset accord­

i n g t o the site-specific m u t a t i o n rate o f the o r g a n ­

i s m (ue., rarely) T h u s , epigenetic effects arc often transient M e t h y l a t i o n is believed t o be the p r i m a r y mechanism of epigenetic effects, b u t the exact mechanism by w h i c h methylation occurs a n d is reset remains an open question (Vcrmaak et a l 2003)

W h y d i d epigenetic effects evolve? O n e i n t r i g u ­ing hypothesis is that m e t h y l a t i o n evolved as a host response t o intragenomic c o n f l i c t , specifically, t o silence TEs <Mcl>onald 1999), M c D o n a l d p o i n t s

o u t that m u t a t i o n rates caused by TEs are far lower

in mammals, w h i c h have sophisticated genome-wide

mechanisms o f i m p r i n t i n g ^ than in Drosophila^

w h i c h does n o t However, this hypothesis has been criticized for failing t o address directly the role o f sexual d i m o r p h i s m in m e t h y l a t i o n patterns by genomic i m p r i n t i n g (i.e., w h y silence TEs in o n l y one parent rather than in b o t h ; see below) {Spencer

c t a l 1999)

One especially interesting example o f cpigenerics

is genomic i m p r i n t i n g , w h i c h is defined as a specific expression pattern, o r parent-of-origin effect

parental-T h a t is, o n l y the allele f r o m one o f the parents

is expressed in the o f f s p r i n g rather than biallelic expression U p w a r d of 7 0 genes are k n o w n t o be

i m p r i n t e d in m a m m a l s , a n d probably closer to 2 0 0

( M u r p h y & Jirtle 2 0 0 3 ) I m p r i n t i n g is an e x c i t i n g area o f research for several reasons: it may be an

i m p o r t a n t evolutionary mechanism for intersexual conflict o v e r reproductive investment ( H a i g 2 0 0 0 ) ,

a n d / o r for silencing TEs o r enabling genome-wide duplications (see b e l o w )

A n o t h e r interesting argument is that methyla­

t i o n resulting in gene silencing was a necessary

c o n d i t i o n for the successful maintenance of ploid genomes (Bird t 9 9 5 a , b ) The idea is that silencing could preserve the appropriate gene dosage

poly-Copyrighted materi

BOX 2 1 M a t e r n a l Effects

Timothy A MQUSSCQU

M o s t biologists consider that individual phenorype results f r o m genes inherited f r o m ihe

mother a n d the father, together w i t h the direct influence» o f the environment experienced

by the developing o f f s p r i n g H o w e v e r , inherited genes a n d direct e n v i r o n m e n t a l effects

are only a few o f the many factors underlying the phenotypic v a r i a t i o n that is subject t o

naair.1l selection (Mousscau & Pox 1998) In particular, mothers can profoundly influence

the phenotype o f their offspring above a n d beyond the genes they contribute a n d these

maternally effected sources o f phenotypic variation can play a m a j o r role in trait evolution*

A l t h o u g h maternal effects are defined in a variety o f ways d e p e n d i n g o n the ques­

t i o n a n d a p p l i c a t i o n , I w i l l b r o a d l y define t h e m as a l l sources o f o f f s p r i n g p h e n o t y p i c

variance due t o mothers above a n d b e y o n d the genes that she herself c o n t r i b u t e s

(Figure I ) As such, most maternal effects are associated w i t h v a r i a t i o n in propagule si/e

o r quality, parental c a r e , host choice, o r m a t e choice I n genetic t e r m s , maternal effects

are usually described as a source o f e n v i r o n m e n t a l variance a m o n g o f f s p r i n g that is

mediated by either genetic o r e n v i r o n m e n t a l influences o n the maternal p h e n o t y p e Sec

R o f f (Ch* 18 in this v o l u m e ) for genetic methods o f q u a n t i f y i n g maternal effects

Sources o f M a t e r n a l Effects V a r i a t i o n

Maternal Effects on Propagule Size or Composition

I n many species there is a positive relationship between maternal s i / e a n d neonatc size

a n d this v a r i a t i o n may sometimes influence o f f s p r i n g development a n d fitness

Offspring FIGURE 1 A few o f the many sources o f o f f s p r i n g p h e n o t y p k v a r i a t i o n that a r c medi­

ated by mothers* Both mothers a n d fathers c o n t r i b u t e nuclear genes M o t h e r s also

directly influence the a m o u n t a n d q u a l i t y (i.e., constituents) o f cytoplasm allocated t o

each o f f s p r i n g w h i c h can be influenced by her environment, the a m o u n t o f provision­

i n g (i.e., n u p t i a l gift) given t o her hy her mate, and her ability t o differentially allocate

resources among offspring Mothers may also influence the q u a l i t y o f e n v i r o n m e n t

experienced by developing young via maternal care, choice o f host, t i m i n g o f p r o p a g ­

ule dissemination, a n d the social setting i n t o w h i c h o f f s p r i n g are placed Female mate

choice can influence the q u a l i t y a n d quantity o f paternal p r o v i s i o n i n g t o both mother

a n d o f f s p r i n g , the q u a l i t y o f paternal care, a n d the genetic c o n t r i b u t i o n s t o o f f s p r i n g

f r o m fathers T h e size o f the a r r o w s does n o t necessarily reflect relative importance

Principles o f Evolutionary Genetics

BOX 2 1 (COM.)

I n many species, maternal diet w i l l influence the number, size, a n d / o r q u a l i t y o f her

o f f s p r i n g rhough the adaptive significance o f such effects has rarely been assessed However* in s o m e cases, mothers are able t o adaptively adjust propagulc size in response t o predicted e n v i r o n m e n t a l c o n d i t i o n s for developing y o u n g For e x a m p l e , in

the seed beetle, Siator Umbatus* mothers can r a p i d l y change egg size a c c o r d i n g t o t h e

host u p o n w h i c h eggs are l a i d ( M o u s s c a u & Fox 1998)

A l t h o u g h propagulc size per se is likely t o be i m p o r t a n t under many conditions* m o t h ­ers also control the deposition o f extranuclcar developmental messages in the egg (e.g., hormones, m R N A s , immunofactors) These cytoplasmic factors are often influenced by the environment experienced by the mother (e.g., p h o t o p e r i o d , temperature, resource quality; Mousseau &: Fox 1998; Roach & W u l f f 1987), and can lead t o significant devel* opmental effects including variation in offspring g r o w t h rate, diapause o r dormancy, w i n g and color polymorphisms, a n d o f f s p r i n g behavior (e.g propensity t o disperse) There have been many recent studies w i t h birds suggesting that mothers can m o d i f y allocation o f hormones (e.g., androgens) that subsequently affect offspring development a n d behavior, Recent developments in developmental b i o l o g y indicate t h a t m a t e r n a l l y derived

t r a n s c r i p t i o n factors play a m a j o r role in o f f s p r i n g development a n d u l t i m a t e

pheno-type- For e x a m p l e , in Drosophila* asymmetrically d i s t r i b u t e d maternal factors i n i t i a t e

a cascade o f spatially organized zygotic gene action t h a t provides the b l u e p r i n t for t h e

l a r v a l b o d y at the blastoderm a n d subsequent stages o f development i A k a m 1987),

I n a d d i t i o n , it has been suggested that maternal messages that p r o g r a m t e r m i n a l differ­

e n t i a t i o n o f germ a n d soma cell lines may have been instrumental in the e v o l u t i o n o f

m u l t t c e l l u l a r organisms (Buss 1987)

Parental Cart and Maternal Effects

There are many examples o f the importance o f postzygotie maternal effects on o f f s p r i n g fitness T h e most o b v i o u s include provisioning o f developing embryos in m a m m a l s ; there arc even examples o f " i n u t e r o " care in insects (e.g., roaches, H o l b r o o k flc Schal 2 0 0 4 )

P o s t - p a r t u r i t i o n care is c o m m o n l y observed a n d can include lactation in mammals»

a n d p r o v i s i o n i n g i n birds» reptiles, fish, a n d insects T h e i m p o r t a n c e o f such care has

o b v i o u s consequences a n d has been w e l l documented for a w i d e variety o f organisms,

Maternal Host Choice and Offspring Fitness

For m a n y species, the most i m p o r t a n t d e t e r m i n a n t o f o f f s p r i n g survival w i l l be t h e choice o f e n v i r o n m e n t in w h i c h o f f s p r i n g are deposited by m o t h e r s T h i s is especially

t r u e for parasites a n d parasitoids w h i c h tend t o specialize o n a l i m i t e d range o f hosts Females able t o d i s c r i m i n a t e a n d select high-quality* e n v i r o n m e n t s for their developing

y o u n g w i l l have higher inclusive fitness It seems l i k e l y t h a t host preferences have o f t e n evolved in response t o v a r i a t i o n i n host q u a l i t y t o developing y o u n g A similar effect

is observed i n turtles a n d crocodilians in w h i c h nest temperature can influence the gender o f o f f s p r i n g (environment sex d e t e r m i n a t i o n ; ESD)

Sexual arid Social Influences on Maternal Effects

M a t e r n a l c o n d i t i o n tand its subsequent effects o n egg constituents) can be influenced by nutritive c o n t r i b u t i o n s f r o m t h e sire o r helpers in the social g r o u p I n many species males

w i l l provide females w i t h n u p t i a l gifts prior t o , a n d d u r i n g , c o p u l a t i o n a n d thevr n u t r i ­ents are incorporated in the eggs prior t o o v u l a r i o n T h e q u a l i t y o r quantity o f these gifts can influence female choice w i t h subsequent effects on o f f s p r i n g f r o m b o t h direct n u t r i ­ent investment bv the male a n d the indirect influence of his genes o n offspring

Genetic Variation

BOX 2.1 (com.)

T h e r e is g r o w i n g evidence that in m a n y species mothers can respond ro i h c genetic

o r p h e n o t y p i c q u a l i t y o f lathers by differential l a n d preferential) a l l o c a t i o n o f egg

constituents t o o f f s p r i n g o f high-quality mates Studies o f m a l l a r d duck<; suggest that

females m a t e d t o h i g h - q u a l i t y males produce larger eggs n u t that such investment

comes at a cost ro later r e p r o d u c t i o n ( C u n n i n g h a m &: Russell 20l>0| A recent study

of crickets has f o u n d that females m a t e d t o h i g h - q u a l i t y males produce h i g h - q u a l i t y

sons h u t l o w - q u a l i t y daughters ( r e d o r k a Sc Mousscau 2 0 0 4 } a n d that such differential

investment is an adaptive response t o fitness v a r i a t i o n a m o n g o f f s p r i n g ( h i g h - q u a l i t y

sons have higher lifetime fitness t h a n h i g h - q u a l i t y daughters)

M a t e r n a l effects c a n also be mediated via social m i l i e u For e x a m p l e , in C l u t t o n

-Brock er a l / 5 (19841 classic study o f red deer, male o f f s p r i n g h o r n t o h i g h - r a n k i n g

mothers have significantly higher l i f e t i m e reproductive success than those h o r n ro

subordinate females a n d mothers adjust the sex r a t i o o f t h e i r o f f s p r i n g t o increase their

inclusive fitness Social status a n d numbers o f helpers in a g r o u p have also been f o u n d

t o influence o f f s p r i n g development a n d fitness (e.g., Russell et a l 2 0 0 3 ) Conversely,

recent studies o f b i r d s ( e g , Badyacv c t a ) 2<N>2) have f o u n d t h a t m a n y b i r d s have t h e

ability t o adjust the sex r a t i o (or b i r t h o r d e r of diftcrent-sexed offspring) in response to

a m b i e n t e n v i r o n m e n t a l c o n d i t i o n s o r social selling I n these examples, the environment

experienced by the mother leads t o p h e n o t y p i c a n d fitnes* effects on o f f s p r i n g

M a t e r n a l Effects a n d E v o l u t i o n a r y Response t o S e l e c t i o n

TTie e v o l u t i o n a r y significance o f maternal effects stems f r o m b o t h the fitness conse­

quences o f transgencrational plastic responses t o e n v i r o n m e n t a l heterogeneity a n d the

longer t e r m e v o l u t i o n a r y responses o f adaptive t r a i t s t o e n v i r o n m e n t a l change M a n y

matern.il effects are h o m o l o g o u s t o the w e l l - s t u d i e d p h e n o m e n o n o f p h e n o t y p i c plas­

t i c i t y except that w i t h maternal effects the e n v i r o n m e n t a l trigger is experienced by t h e

maternal generation a n d the p h e n o t y p i c consequences a r c expressed by o f f s p r i n g

( M o u s s c a u & Fox 1998) I n the case where the genes associated w i t h maternal recep­

t i v i t y a n d o f f s p r i n g response are independent, n a t u r a l selection a c t i n g across genera­

t i o n s w i l l favor linkage d i s e q u i l i b r i u m between "cause a n d e f f e c t " t o p r o m o t e an

a p p r o p r i a t e response (e.gM W o l f & Brodie 1998) I n o t h e r cases, linkage between

generations may result f r o m p l e i o t r o p y Longer i c r m consequences o f maternal effects

result f r o m the expectation t h a t maternally effected traits w i l l have higher amounts o f

additive genetic v a r i a t i o n as a result o f sex l i m i t e d expression ( W o l f Sc B r o d i e 1998J,

a n d t h e fact t h a t t o t a l h c r i t a b i l i f y o f a given trait w i l l reflect t h e s u m m a t i o n o f b o t h

maternal a n d direct (i.e., in the o f f s p r i n g ) a d d i t i v e genetic influences a n d t h e i r genetic

covariancc If rhis covariancc is negative» then maternal a n d direct genetic influences

may cancel each other, thus d e t e r r i n g e v o l u t i o n a r y response t o selection ( K i r k p a t r k k

&; Landc 1989), H o w e v e r , i f the covariancc is positive, response t o selection can be

dramatically enhanced* This p r o p e r t y o f m a t e r n a l l y effected traits has l o n g been c a p i ­

talized o n by a n i m a l a n d plant breeders as a means for r a p i d selection for e c o n o m i ­

cally i m p o r t a n t t r a i t s I n recent studies of r e d squirrels ( e g , , M c A d a m & B o u t i n

20O4)> it lias been f o u n d that a large p o s i t i v e genetic covariancc between direct and

maternal genetic influences o n o f f s p r i n g development can generate responses t h a t are

up t o 5 times that p r e d i c t e d by simple, single-generation genetic models

A l t h o u g h it is o f t e n d i f f i c u l t t o assess t h e adaptive significance o r even measure the

fitness consequences of maternal effects, it is apparent that they are displayed by a

w i d e variety o f organisms a n d can influence a great n u m b e r of t r a i t s T h u s , given this

diversity, it is always necessary t o consider the possible impact o f maternal effects o n

evolutionary response ro selection*