Evolutionary Genetics: Concepts and Case Studies [1 ed.] 0195168178, 9780195168174

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EVOLUTIONARY GENETICS Concepts and Case Studies

Concepts and Case Studies AG = G(Y-PP) G + 2M M /=i

Edited by

Charles W. Fox Jason B. Wolf

Copyrighted mate

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EVOLUTIONARY GENETICS

Copyrighted material 1

*

EVOLUTIONARY GENETICS Concepts and Case Studies

Edited by Charles W. Fox Jason B. Wolf

OXFORD UNIVERSITY PRESS

2006

OXFORD Oxford University Press, I n c . publisher works that further Oxford University'* objective of excellence in research, scholarship* and education, Oxford New York Auckland i ape Town Dar es Salaam Hong Konp Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil U i i l r Crrch Republic France Greece Guatemala H u n g r y Italy japan Poland IVirtugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vsrmam C o p y r i g h t © 2 0 0 6 b y O x f o r d U n i v e r s i t y Press, I n c . Published by Oxford Unisrrsity Press, l o c 198 Madison Avenue, New York, New* York 10016 www.aupamn Oxford it a repstered trademark of Oxford University Pre» All right* reserved. N o part of t h n publication may be reproduced* stotcd in a retrieval system, or transmmrd. in any form or by any means* electronic, mechanical, photocopying* recording or otherwise, without thr prior permi**Hin of Oxford Uniteniry Prr** library of Congress Carak^Ln$*in-l\jhlicarion Data Evolutionary genets»; concepts and case srudhcVrdited by Oiaries V . Pox, Jason B. Wolf.

p. ion. Includes bibliographical rrtereiKev M N - I J 978*0-19-516817-4; 978-CM9-5I6818-1 jpbL) tSBNO J9 516817 8 ; 0 1 9 5 1 A S I 8 6 (phk.) L Kvotunonary genetics. | 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

QH390.E94 2005 572J'3S—dc22

2005011131

9 8 7 6 5 4 3 2 Printed ill the United States of America on acid-free paper

Preface

E

v 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 particularly r a p i d g r o w t h and 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 unified 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

availability of molecular d a t a .

genetic v a r i a t i o n w i t h i n and 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 evolutionary genetics

species and (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 variation l o r various evolu*

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.

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

At one extreme» evolutionary

genetics

o f D N A sequence e v o l u t i o n (e.g.. Chapters 7 and 9i

may he f i n d i n g and characterizing genes affecting

t o studies o f multivariate phenorypic evolution (e.g.,

traits, 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 ) , and across a c o n t i n u u m o f rime, f r o m

siou and 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 current species diversity

pretation o f associations between loci and 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 other

tively short t i m e scales in experimental 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 major cause o f the recent g r o w t h and 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 evolutionary genetics has been the modern

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

entitling

research

into

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

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

difficult

as

phenotype relationship, and genome e v o l u t i o n .

molecular biology permeates evolutionary 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 evolutionary genetics (e.g., since the M o d e r n

Evolutionary

Ecology:

Concepts

arul CMS*'

Studies

Synthesis), the availability 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 put genetic technology and 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

t o the emergence o f m a n y new 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

and 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 and c o n t e m p o r a r y

its c o m p a n i o n

v o l u m e , is

to

research

p r o g r a m s in evolutionary genetics. O u r hope w h e n

some o f the research areas and thus discover t h e

conceiving this volume was that it m i g h t be adopted

vast literature t h a t w c have been unable t o include

ai« a text f o r graduate courses and seminars* as ha*

here,

been the case for Evolutionary

Fxology.

We thus

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

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

this might suggest that there are six clearly defined

by advanced undergraduates, graduate students,

sets o f topics, such structuring is somewhat a r t i f i ­

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

cial. Evolutionary genetics is a highly

integrated

l o o k i n g for a concise i n t r o d u c t i o n t o evolutionary

field w i t h n o clear lines d i v i d i n g research topics.

genetics. Authors were asked t o target this audience

T h e structure o f t h e book is simply a convenient

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

w a y o f collecting m o r e related topics together. We

on n u k i n g the volume accessible t o this audience

start w i t h a collection o f chapters presenting many

w h i l e reviewing each chapter.

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

Chapter authors are all leading researchers in

as the f o u n d a t i o n for the rest o f the subject (Part I).

their fields and were chosen t o p r o v i d e their partic­

For this part readers need have o n l y a decent back­

ular perspectives on a topic. Chapters thus represent

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 ­

the current stage o f evolutionary genetics better than

tionary biology w i l l certainly be helpful. Later parts

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

o f the book assume an understanding o f b o t h general

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

concepts o f genetics and the concepts presented in

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

earlier p a n s . Parts I W V are ordered hierarchically

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

textbook

starting at the basic level o f biological c o m p l e x i t y ,

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

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

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

o p m e n t (Part I I I ) t o studies o f complex phenotypes

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

(quantitative genetics; P a n I V ) and on t o the inter­

Authors also vary in their w r i t i n g styles, t h e w a y

actions between i n d i v i d u a l s and their environment

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

(sexual and social selection; also Part I V ) . These

has a unique perspective o n the overall field. We

parts are f o l l o w e d by one on the genetics o f species

have attempted t o minimize this v a r i a t i o n t h r o u g h

differences and speciation (Part V ) that integrates

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

across the hierarchy o f complexity t o investigate wrhat

revising chapters. H o w e v e r , some variation a m o n g

is often considered the most f u n d a m e n t a l problem

chapters is unavoidable and reflects the variation in

in evolutionary 1 biology: the o r i g i n o f species, l a s t l y

styles and approaches c o m m o n t h r o u g h o u t science.

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

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

conceptual, and e m p i r i c a l approaches developed in

this book is not comprehensive. T o keep the length

previous chapters are applied t o specific p r o b l e m s

of the book practical, and the price a f f o r d a b l e , w c

in b i o l o g y (Part V I ) . T h e potential choice o f topics

had t o impose restrictions o n chapter length and the

here is e n o r m o u s but w e could choose only a couple

number o f references. T h i s a l l o w e d us t o increase

o f representative examples that w e find particularly

the diversity o f subjects covered but at the expense

exciting,

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

Because w c

enforced length

restrictions

on

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

chapters, many i m p o r t a n t and exciting topics were

books). Chapters are intended t o serve as introduc­

necessarily left o u t . O t h e r topics were outside the

tions t o their t o p i c , focusing o n basic concepts

expertise o f t h e authors o r w e r e i m p o r t a n t topics

rather than becoming comprehensive reviews (the

that did not fit well into the structure o f the chapters.

reference l i m i t was intended t o minimize t h e latter).

W c thus include a large number o f boxes focusing

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

on specific topics presented largely independently

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

o f the m a i n body of the text w i t h w h i c h they arc

the necessary omission o f missing topics and the

associated. W i t h the exception o f Box 24.1 { w h i c h

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

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

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

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

Chapters include a "Suggestions for Further Reading"

w h i c h they arc most relevant. M a n y w r crc w r i t t e n

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

by the same author as the chapter that they comple­

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

ment; these largely e x p a n d o n topics m e n t i o n e d in

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

the main body 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 in 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 Kirkpatrick, 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, llamish Spencer, Marc Tatar, Kric (Rick) Taylor, L i n d i Wahi, Cunrcr Wagner, John Wakeley, Bruce Walsh, Joe Williams, and a few others who 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 work! Charles W. Fox Jason B* Wolf

Copyrighted materi

J,

Contents

Conrrihnrnr*

^lll

Part I - Principles of Evolutionary Genetics 1. From Mendel to Molecules: A Brict History of Evolutionary Genetics Mich.wt

K

i

Motrirf,

2. Genetic Variation H Marta L. Wayne and Michael M» Box 2.1. Maternal Ff frets 19 3 . Mutation 12 David Houle and Alexcy

Miyamoto

Kondrashov

4. Natural Selection £2 Michael /. Wade Box 4 , 1 . Defining and Measuring Fttnev» Daphne h Vairbairn

52

V Stochastic Processes in Evolution til John H. Cillespie Box 5,1. The Probability of Extinction of an Allclc Box 5.2. Mutational Landscape Model 7Q

68

6 . Genetics and Evolution in Structured Populations 8 0 Charles /. Goodnight Box 6.1. Fpistasis and rhc Conversion ot Generic Variance Jason B. Wolf

S7

tx

Copyrighted material

Contents

x

Part II - Molecular Evolution

7. Detecting Selection at the Molecular Level Michael ffi Narhman

103

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 Ying Chen and Wolfgang Stepban 10. Evolution of Eukaryotic Genome Structure Dmitri A. Petrov and Jonathan R Wendel

133 144

11. New Genes» New Functions: Gene Family Evolution and Phylogenetics foe Thornton

157

12. Gene Genealogies 173 Noah A. Rosenberg Box 12.1. Horizontal Inheritancg

1Z&

Part III - From Genotype to Phenotype I V C*rnt* F n n r t i n n n n d Mnl**riilar F v n l u r i n n

jJiJ

Simon G I oiagfl ft**v i i I

I b e Bale ^ Gene Emccactioo M**wnrlfg in Enohitiop

2U0

Stephen R. Proulx 14. Evolution o f M n l r i d o m a i n Protein*

H I

U52/0 Pdtt/JV 15. Evolutionary Developmental Biology

222

Dfliad / Stem Box 15.2, Functional Assays in Nonmodcl Organisms

229

16. Canalization 215 Mark L* Siegal and Aviv Bergman Box 16.1. Computational Modeling of the Evolution of Gene Regulatory Networks

17. Evolutionary Epigcnctics 252 Eva fablonka and Marion h Lamb

Part IV - Quantitative Genetics and Selection

18. Evolutionary Quantitative Genetics Derek A. Roff ftr»* t f l . l

267

Individual T-irnres SllrfilCa -'"^ Mnlrivariaf^ SckctlQD

lasan B. Wolf

263

243

Contents

XI

19. Genetic Architecture of Quantitative Variation 2X8 fames At. Chevcrud Box 19.1. Genotvpic Values: Additivitv, Dominance, and Epkrasis ttox 1 f thr ditpint. Src Kim

Beginning in 1922, Haldane sought t o analyze the mathematical consequences o t natural selection, Starting f r o m simple Mendehan models using t w o

Copyrighted material

6

Principles o f Evolutionary Genetics

allelesat a single locus* Haldane went on t o consider

has resurfaced in recent years w i t h new protago­

selection w i t h self-fertilization, i n b r e e d i n g , over­

nists (Skipper 2 0 0 2 ) , but t h e o r i g i n a l debate was

lapping generations* incomplete dominance, isola­

especially influential because it occurred just as

t i o n , m i g r a t i o n , and fluctuating selection intensities

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

(Provinc 1971). Haldanc's scries o f nine papers o n

tionary synthesis (Provine 1992)*

selection c u l m i n a t e d in his 1932 book* The Causes of Evolution.

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

compares his views t o those o f Fisher and W r i g h t ,

THE EVOLUTIONARY

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

SYNTHESIS

Haldane differed f r o m Fisher by placing greater emphasis o n s t r o n g selection o f single genes, migra­

The evolutionary synthesis is identified by historians

t i o n , and cpisrasis. H e sided w i t h Fisher, however,

w i t h both the emerging discipline o f evolutionary

in t h i n k i n g t h a i W r i g h t put t o o much emphasis o n

biology and the integration of previously divergent

random generic d r i f t (Provine 1 9 7 1 ; Oillespie, C h . S

fields such as paleontology, zoology, botany, systcm-

of this volume),

atics, and genetics. According t o this interpretation,

W h i l e Fisher, W r i g h t , and Haldanc approached

the synthesis refers t o a time beginning in t h e 1930s

evolution and p o p u l a t i o n genetics f r o m different

when a range of arguments were offered t o show that

mathematical perspectives, their disagreements were

different fields relevant t o e v o l u t i o n were in fact

not about mathematics, but a b o u t

evolutionary

compatible w i t h each other. These c o m p a t i b i l i t y

processes and concepts and their representation in

arguments helped spur on the emergence o f e v o l u ­

different mathematical models. A c c o r d i n g t o W i l l

tionary b i o l o g y as a field o f i n q u i r y — a s a new a n d

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

centrally i m p o r t a n t discipline (Smocovitis 1 9 9 6 ) .

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

C o m p a t i b i l i t y arguments d o not necessarily i m p l y

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

that there was widespread agreement on a new*

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

synthetic theory o f e v o l u t i o n . A s Provinc and others

theories o f e v o l u t i o n : Wright's shifting

balance

have argued, there was little agreement a b o u t the

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

mechanisms o f e v o l u t i o n d u r i n g the 1930s and

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

1940s, Instead Provine suggests that w c reconsider

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

this p e r i o d as a n evolutionary

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

vast c u t - d o w n o f the variables considered i m p o r t a n t

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

process

and that large populations were the o p t i m u m . These

"Tlic

differences were most apparent a r o u n d the issue o f

understand t h a t evolutionists after

the relative importance o f r a n d o m genetic d r i f t .

disagree intensely w i t h each other a b o u t effective

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,

population

his early w o r k on the shifting balance rhcory gave

genetic d r i f t , levels o f hcrcrozygosiry,

random drift

rates, m i g r a t i o n rates, e t c , but all c o u l d agree t h a t

a considerable role in evolution,

term

'evolutionary

constriction—**a

constriction* helps

size, p o p u l a t i o n

1930

structure,

random mutation

T o counter Wright's view, Fisher and his colleague

these variables were o r c o u l d be i m p o r t a n t

E, B. Ford studied yearly fluctuations in the gene

e v o l u t i o n in nature, and that purposive

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

played n o role at a l l " (Provine 19881,

dommula

from 1941 t o 1946. They f o u n d that the fluctua­ tions 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 and 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 random d r i f t t o large, but subdivided populations where it could serve as a means f o r generating novel genotypic combinations (Provine 1986, 1992), T h e W r i g h t - F i s h e r debate

us

might

in

forces

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 art in animal 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 and influenced hv

hut was modeled o n D o h z h a n k y ' s Genetics and the

the w o r k o f N i c o l a i Vavilov and I u r i i Filipchenko,

Origin

Dobzhansky began his career s t u d y i n g v a r i a b i l ­

genetics w i t h evolutionary

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

and

concepts o f speciarion a n d species. Trained as an

Drosophila

mclitmgaster.

of Species, W h e r e Dobzhansky synthesized biology, M a y r

added

T o further his under*

ornithologist in G e r m a n y under Hans Strcsseman,

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

M a y r was the w o r l d ' s expert o n b i r d systemancs,

Rockefeller

Foundation t o join T. H .

Morgan's

A l t h o u g h developed w i t h avian exemplars» M a y r

1927 (Provine 1981). Ac

argued for the generality o f his Biological Species

C o l u m b i a and later C a l Tech, Dobzhansky excelled

Concept (Mallet, Species Concept* b o x , p p . 3 6 7 - 3 7 3

at the business o f Drosvphtla

genetics. First w i t h

of this volume) and model o f geographic speciation.

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

If Dobzhansky was the first t o set the intellectual

Sewall W r i g h t , Dobzhansky turned t o e v o l u t i o n a r y

agenda for evolutionary genetics, M a y r broadened

genetics—taking

famous Fly G r o u p in

the

rhat agenda. Moreover, M a y r was absolutely central

laboratory t o (he field. Dobzhansky's 1937 b o n k ,

Drosophila

genetics

from

t o the effort t o institutionalize and support the devel­

Genetics and the Origin

opment o f evolutionary

of Species, a r t i c u l a t e d a

biology

as a discipline,

program o f research for e v o l u t i o n a r y genetics. The

logether w i t h G. G . Simpson, w h o articulated the

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

contributions

were deliberately b o r r o w e d f r o m Wright's shifting

M a y r , Dobzhansky, and other

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

Northeastern United States discussed the similarities

D o b z h a n s k y s presentation was non-mathematical

and differences in their approaches t o evolution in

and served t o widely popularize the shifting balance

the Committee o n C o m m o n Problems in Genetics

theory (Provine 1981). Genetics and the Origin

of

and Paleontology, w h i c h met f r o m 1943 t o 1945

Species, thus, translated one o f the dominant general

when the Society for t h e Study o f Evolution was

theories o t evolution i n t o a research p r o g r a m for

founded (Smocovitis 1996; C a i n 1993). Because of

evolutionary genetics,

W o r l d War I I , M a y r , Simpson, and

Dobzhansky** evolutionary p r o g r a m was c h a l ­ lenged in Material

1940 by R i c h a r d Goldschmidt's

Basis of Evolution.

of paleontology

f o r the synthesis, scientists in

the

Dobzhansky

were somewhat isolated f r o m biologists i n Kngland

The

( H u x l e y and Fisher) and evolutionary biologists o n

G o l d s c h m i d t had been

the West Coast o f the U n i t e d States (Stehbins!. This

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

temporary

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

Dobzhansky, Simpson, and M a y r were so influential

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

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

the gradualist

Neo-Darwinism

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

isolation

may

be o n e reason

seemed particularly

why

focused

on

Dobzhpinksy and others. A c c o r d i n g t o Goldschmidt,

animal systems. The considerable effort o f Stchhins

Dobzhanksy had not demonstrated that his view fit

and others t o b r i n g plants i n t o the synthesis is surely

the evidence any better than the view that there

also a result o f the interesting differences between

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

plant and animal genetics (Smocovitis 1996).

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

of chromosomal

in dcvelopmentally

structure)

important

T h e architects o f

the evolutionary

synthesis

or

played a central role in the p r o m o t i o n of e v o l u t i o n ­

genes.

ary biology a n d especially e v o l u t i o n a r y genetics.

Goldschmidt's d e v e l o p m e n t a l ^ o r i e n t e d , saltation*

Dobzhanskys

ist alternative immediately inspired a hostile reac*

populations, in particular, was hailed as an exem­

rion by the N e o - D a r w i n i a n s * Subsequent e d i t i o n s

plar o f N c o - D a r w i n i s m ( M a y r 1 9 4 4 ; Stern 1944).

of Dobzhansky's Genetics and the Origin

of Sfrecies

Significantly, d u r i n g t h e 1940s Dobzhansky's o w n

devoted many pages t o Goldschmidt's r e f u t a t i o n ,

research p r o g r a m narrowed* F r o m 1938 t o 1976,

as did later w o r k by M a y r and Simpson. This nega­

Dobzhansky and his collaborators produced a series

tive response t o

o f 4 3 influential papers under the title of

Goldschmidt's

views

bolsters

work

on t h e genetics o f

natural

"The

Provinces interpretation of the synthesis as a cofistric-

Genetics o f N a t u r a l Populations" ( G N P ) ( L c w o m i u

tion. In fact, o p p o s i t i o n t o Goldschmidt's sattation-

1981), Early w o r k in the G N P series was often

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

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 and

[ D i e t r i c h 1995).

sought t o explore different aspects o f t h e s h i f t i n g

Hrnst M a y r ' s Systematic Species (1942/

of

balance theory using d a t a f r o m characteristic c h r o ­

responded t o Goldschmidt's claims*

and

the

Origin

mosomal inversion o f different natural populations.

Copyrighted material

s

Principles o f Evolutionary Genetics

Because Dobzhansky thought char selection had

should be heterozygous. Homozygotes w o u l d still

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

occur, but they w o u l d not be as advantageous a&

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

over-dominant heterozygous combinations. In terms

impact o f random d r i f t . As early as 1941* however,

of genetic v a r i a t i o n , the issue at stake between t h e

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

classical and balance positions was t h e relative

tion favoring hcterozygotes. By 1950, the G N P scries

number a n d importance o f heterozygous superior

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

o r o v c r d o m i n a n t loci. D o b z h a n s k y cast himself as

ingly t o address problems o f heterosis and balancing

the p r i m a r y advocate o f the balance position,

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

M u l l c r never agreed w i t h Dobzhansky's charac­

ro selection is emblematic of the emerging view in

terization o f the classical and balance positions, b u t

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

he had articulated something close t o the classical

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

position. A n o r i g i n a l member of M o r g a n ' s

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

G r o u p , M u l l c r was a w o r l d leader in genetics having

characteristic o f the synthesis period had produced

w o n a N o b e l Prize in 1948 for his research on

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

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,

evolutionary biology i n t o t h e 1970s ( G o u l d 1 9 8 . i l .

he published " O u r

Focusing o n selection t o the exclusion o f other

provided a new w a y t o assess the genetic damage

processes d i d not guarantee that consensus» Instead,

created by m u t a t i o n . Accepting t h e premise t h a t

new controversies emerged concerning the f o r m o f

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

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 .

degree, M u l l c r argued that i n a p o p u l a t i o n

lx>ad o f M u t a t i o n s , "

Fly

which

of

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. GENETIC VARIABILITY A N D T H E

T h e number of deleterious allcfes possessed by an

CLASSICAL-BALANCE

i n d i v i d u a l represented that individual's deviation

CONTROVERSY

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

In t h e 1950 and 1960s, Dobzhansky*s research on

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

balanced p o l y m o r p h i s m s fueled a major contro* vcrsy in evolutionary genetics concerning the genetic

adamant a b o u t the genetic loads that exposure t o

variability of n a t u r a l populations, the nature o f

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

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

and was motivated by the recent use o f a t o m i c

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

weapons in W o r l d War II and was heightened by the

Symposium on Q u a n t i t a t i v e Biology, Dohzhansky

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

articulated t w o diametrically opposed positions o n

T h u s , it was natural t h a t , w h e n M u l l c r discussed

these issues: the classical position and the balance

factors that w o u l d increase genetic loads and put

position. The

classical

Dohzhansky, held

that

position, according "evolutionary

to

changes

consist i n t h e m a i n in g r a d u a l substitution and

was

radiation c o u l d produce. This concern reflected the

human populations at risk, radiation was prominent (Beatty 1 9 8 7 b ) . M u l l e r ' s radiation fears w e r e exacerbated by

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

a scries o f a m b i g u o u s

the less favorable, gene alteles and c h r o m o s o m e

experiments conducted in t h e 1950s and 1960s.

structures." M o s t loci, according t o the classical posi­

Bruce Wallace, a student o f Dobzhansky's, had been

t i o n , should be homozygous. Hctcrozygotes were

collaborating w i t h J* C K i n g t o study the effects of

rare and had four possible sources; i l ) deleterious

radiation exposure i n Drosopbila.

results f r o m

irradiation

Setting a c o n t r o l

mutations that are eventually eliminated by selection,

p o p u l a t i o n as the standard, Wallace and

[2) adapnvely neutral mutations, (3) "adaptive poly­

exposed flies t o acute and chronic doses o f radiation.

King

morphisms maintained by the diversity o f the envi­

If M u l l e r was correct, the radiation should induce

ronments w h i c h t h e p o p u l a t i o n inhabits, w

and

deleterious mutations and lower the fitnesses of the

[4) rare beneficial mutants w h i c h are on their w a y

treated populations relative t o the c o n t r o l popula­

t o w a r d f i x a t i o n (Dobzhansky 1955)* A c c o r d i n g t o

tion. T h e flics receiving chronic irradiation did indeed

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

have a lower adaptive value, but the acutely irradi­

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

ated flics had a higher adaptive value. Interpreting

according t o

this

Dobzhansky, h e l d that

most

loci

result

in

light

of

the

balance

position,

From Mendel t o Molecutes 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 not merely in spite of hut 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 and King's results were meant t o invite further research, w h i c h they d i d , hut 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 Muller 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 experimental efforts 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 pin 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

9

Any 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 all o f the f o l l o w i n g criteria: (11 Phenotypic differences caused by allelic substitutions at single l o c i must be detectable i n single individuals. (2) Allelic suhstitutions at one locus must be distinguishahle from 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 must be an unbiased sample o t the genome w i t h respect t o the physiological effects and 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)

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 loci. Despite efforts t o b r i n g the disputants Together t o w o r k o u t their differences» by the 1960s

Hubby

and

Ixwonrin's

work

tried t o meet

the classical-balance controversy had stalemated

these criteria and provide a reliable measure o f the

(hcatty 1987b|. J

amount

o f heterozygosily

ubsatrj.

Their survey o f 18 loci revealed w h a t they

By linking genetic variability t o radiation, the

f o u n d i n />. />*rW'>-

stakes i n this controversy had been raised beyond

understood t o be a high degree o l p o l y m o r p h i s m ;

those of an intellectual dispute in evolutionary' genet*

the average hetcrozygosiry was 1 1 . 5 % . 1-cwontin

ics, Both M u l l e r and Dobzhansky saw themselves as

and I l u b h y proposed several alternatives t o explain

struggling tor the future o f h u m a n k i n d . Hope o f

this variation* The possibility o f neutral alleles was

some empirical resolution depended on a way o f

Considered, and ruled o u t because local popula­

detecting genetic differences more precisely. I h c tools

tions d i d not have the high levels o f homor.ygosity

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

predicted i f d r i f t were prevalent. They also consid­

biochemistry and molecular biology for a number o f

ered the possibility o f a large number o f o v e r d o in -

years. However» the introduction o f molecular tools

i n a n t loci» but recognized that so many heterotic

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

loci w o u l d c a m ' w i t h them a large segregational load

mentally alter

(Lewontin &i H u b b y

the classical-balance

controversy

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

1966). Almost

immediately

three different groups proposed truncation selection models t o address this problem* It looked as ifeleciTophoresis had provided important

evidence m

T H E ELECTROPHORETIC

favor o f the halance p o s i t i o n . This sense of resolu­

REVOLUTION

t i o n was short-lived, however, as t h e advocacy o f neutral molecular e v o l u t i o n , beginning i n 1968,

FJectrophorcsis had been developed i n biochem­ istry as a means for separating molecules by charge and size* In t h e early 1960s* geneticist Jack

redrew the conceptual landscape. A p a r t f r o m the classical-balance

controversy,

L

elect rophoresis had a tremendous impact upon the

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

experimental practice o f evolutionary gaieties* From

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

1966 t o 1984* the genetic variability o f 111) species

University o f Chicago t o collaborate w i t h h i m i n

was measured using electrophoresis. T h i s " f i n d *em

1964,

o f research

and g r i n d ' em** approach expanded the scope o f

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

Hubby's

original

program

evolutionary genetics, drew more people t o consider

Dob/hanslcyVs and had been f o l l o w i n g the classical-

the p r o b l e m o f explaining variability, and d e m o n ­

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

strated the power o f molecular techniques for evolu­

Chicago* he had a list o f criteria for experimentally

tionary biology ( L e w o n t i n 1991). H e a r o p l m r e s i s

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

was only a part o f the molecular biology

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

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

boom

and Francis Crick discovered the double helical 3

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

■r 1 i■ i I ■ du/hn/i volution/puMk/iuhivrVmtKyionfererwe1»1

mttcy.himl

structure o f D N A i n 1955, molecular

biologists

and biochemists began t o address the e v o l u t i o n of D N A , K N A , and proteins, as w e l l as their coding

Copyrighted material

10

Principles o f Evolutionary Genetics

properties and interrelations. I n t h e 1960s and

infinitely

1970s, the new field o f molecular e v o l u t i o n w o u l d

presented a m o d e l o f m u t a t i o n for neutral alleles,

incorporate

new

data

from

many

alleles m o d e l

which, while

it

clectrophorcsis,

was primarily aimed at demonstrating the high loads

i m m u n o l o g i c a l assays, h y b r i d i z a t i o n , and sequenc­

produced by m o r e c o m p l e x models o f o v e r d o m i -

ing. I n d o i n g so it w o u l d t r a n s f o r m significant parts

nant alleles. K i m u r a later shifted his perspective o n

o f evolutionary genetics (Dietrich 1998).

neutral alleles f r o m a mathematically tractable case t o a description o f a biological reality. H e did so in response t o both the high genetic variability observed

NON-DARWINIAN EVOLUTION

by L e w o n t i n and H u b b y and an array of biochemical

A N D THE NEUTRALIST-

evidence for neutral alleles being presented a n d

SELECTIONIST CONTROVERSY

discussed at the first conferences o n molecular evolu­ tion, such as the Evolving Genes and

Proteins

Molecular e v o l u t i o n a r y genetics developed in t h e

conference in 196S where Zuckerkandl and Pauling

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

christened the molecular c l o c k . Indeed

niques, such as electrophoresis, and w i t h theoretical

1968 argument for neutral molecular e v o l u t i o n is

developments that embraced these new molecular

based on data about rates o f molecular

data. T h e most significant theoretical o r conceptual

presented at the Evolving Genes and Proteins con­

developments associated w i t h t h e molecularizarion

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

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

by Z u c k e r k a n d l

rhc molecular clock and the advocacy o f neutral

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

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

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 ,

Non-Darwinian evolution.

primate h e m o g l o b i n , m a m m a l i a n and avian c y t o -

and Pauling (Dietrich

Kimuras change

1994).

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

chrome c, and triosephosphate dehydrogenase f r o m

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

rabbits and cattle. K i m u r a then calculated the rate

significant result o f research in molecular evolution**

of evolution for a mammalian genome. K i m u r a s esti­

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

mate o f 1.8 years f o r the average rime t a k e n f o r one

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

base p a i r replacement carried w i t h it an intolerable

Zuckerkandl and Pauling discovered that the differ­

cost o f selection. The only way t o avoid this high cost

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

o r substitutional l o a d was t o postulate that most

proportional

of the observed substitutions were i n fact selec­

in

number

to evolutionary

time"

( 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 constant.

Zuckerkandl

and

tively 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

P a u l i n g christened

next year by Jack K i n g and T o m Jukes w h o strongly

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

advocated the importance o f neutral mutations and

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

generic d r i f t . Jukes wTas a biochemist by t r a i n i n g

value o f the molecular clock for systcmatics was

and an early molecular evolutionist. H e had attended

quickly recognized, but the evolutionary mechanisms

the E v o l v i n g Genes and Proteins conference a n d

underlying the clock's constancy were a m b i g u o u s

had published a

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

Molecules

made their case for neutral molecular e v o l u t i o n ,

biochemists interested in e v o l u t i o n . Jukes recog­

book

and Evolution

o n the subject

entitled

in 1 9 6 6 . L i k e m a n y other

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

nized the existence o f neutral substitutions, but t o

had w o r k e d w i t h James C r o w and Sewall Wright i n

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

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

t i o n geneticist. Jukes sought out Jack K i n g , a y o u n g

ics* A s C r o w ' s student, K i m u r a was familiar w i t h

biologist w i t h t r a i n i n g i n evolutionary genetics.

the classical-balance controversy a n d was sympa­

Together they assembled a b r o a d range o f evidence

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

from

possibility of neutral alleles had been frequently

directly counter G . G . Simpson** and E m i l Smith's

mentioned in the course o f the classical-balance

claims f o r panselectionism at the molecular level

controversy, but none o f the participants seemed t o

(Dietrich 1994). Under the intentionally provocative

have taken them seriously as an alternative t o a

title 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

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

case for neutral molecular e v o l u t i o n t h a t included

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

K i m u r a ' s cost o f selection argument as w e l l as

biochemistry

and

molecular

evolution

to

From Mendel t o Molecules

11

arguments based on the significance o f synony­

A t t h e same s y m p o s i u m , G* L* Stebbms and

mous m u t a t i o n s , correlation between the generic

Richard L c w o n t i n attacked the neutral theory as a

code and t h e a m i n n acid c o m p o s i t i o n o f proteins,

testable hypothesis* A c c o r d i n g t o Stebhms

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

l e w o n t i n , the neutral theory in its simplest f o r m

and overall constancy of the rate of molecular evolu­

predicts that allele frequencies w i l l vary f r o m p o p u ­

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

lation t o p o p u l a t i o n , but in D. psettdtyobscura

immediate and hostile* Bryan Clarke and R o l l i n

D. tiillistoni,

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

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

terarguments

t o the evidence presented by K i n g and

low as one migrant per generation could account for

Jukes, thereby inaugurating the neutralist-selectionist

the similarity* Because assumptions a b o u t migration

controversy (Clarke 1 9 7 0 ; Richmond 1970)*

rate c o u l d always explain away allele frequency

widely separate populations

and

and show

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

data, Stchhins and I x w o n t i n charged that n o obscr*

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

vation c o u l d contradict the neutral theory's predic­

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

tion* They even directly appealed t o Karl Popper's

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

philosophy o f science and labeled the neutral theory

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

"'empirically void* because it has n o set of potential

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

falsifiers" l S t c b b i n s & I x w o n t i n 1972|- Yet, Stcbhins

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

and L c w o n t i n d i d not reject the idea o f neutral

ro forge a solid theoretical foundation for the neutral

mutation and rhe effects of random d r i f t ; instead they

theory; Kimura's diffusion equation method provided

claimed that the nature of evolutionary processes was

the theoretical f r a m e w o r k

unresolved and encouraged the diverse pursuits o f

he needed

formulate

specific models w h i c h in m m allowed h i m t o address

selectionists a n d neutralists (Stchbins &

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

|y72).

Ixwontin

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

Stebbms and l.ewontin's concerns a b o u t testing

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

rhe neutral theory w o u l d be c o m p o u n d e d over the

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

next 10 years. Despite an abundance o f data f r o m

extended the neutral theory t o encompass the prob*

electrophoretic surveys, using this data t o test predic­

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

tions from the neutral theory was not as straightfor­

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

w a r d as it had been supposed* Tests proposed by

and O h t a were able t o s h o w that protein p o l y m o r ­

Warren Kwens in 197.J a n d later refined by Geoff

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

Watterson in 1977 were designed for clccirnphorciic

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

data, but when applied d i d not have t h e statistical on

power t o discriminate between neutrality and selec­

devoted

t i o n [ I x w o n t i n 1 9 9 1 ) . T h e consequence o f this and

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 , and N o n -

other difficulties w i t h testing the neutral theory

Darwinian

was that neutralists put m o r e stock in the molecular

In

1 9 7 1 the S i x t h

Berkeley Symposium

M a t h e m a t i c a l Statistics and P r o b a b i l i t y e v o l u t i o n . By

this t i m e , rhe

debate

between the neutralists and selectionists was w e l l under way. A l t h o u g h (ew tests had been d o n e ,

clock as evidence in support o f neutrality. In

1 9 7 1 , T o m o k o O h t a and M o t o o

Kimura

there had been q u i t e a bit of t a l k a b o u t the ability

asserted that t h e " r e m a r k a b l e constancy of t h e rate

of r i v a l hypotheses t o explain a w i d e variety o f

of a m i n o acid substitutions in each p r o t e i n over a

data and the positions were w e l l articulated. James

vast p e r i o d o f geologic time constitutes so far the

C r o w was charged w i t h giving a review o f both

strongest evidence for the theory (Kimura 196S; King

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

and Jukes 1969) that the major cause o f molecular

C r o w was disposed t o w a r d t h e neutral theory, hut

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 neutral

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

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

a participant in t h e classical-balance controversy,

K i m u r a had s h o w n that l o r neurral changes the

C r o w had experienced the frustration o f t r y i n g t o

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

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

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

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

s t o o d t o be t h e result a stochastic process similar t o

tative predictions that c o u l d be tested and seemed 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

move beyond the classical-balance stalemate ( C r o w

also be understood as constant generated by an

1972K

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

'

Copyrighted material

12

Principles o f Evolutionary Genetics

substitutions, however, was subject t o changes in

Where earlier tests had been unable t o discriminate

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

between neutrality and selection, these rests applied

not be expected t o be constant over any long period

t o nucleotide sequence data succeeded. 1

[it t i m e .

A c c o m p a n y i n g the availability o f D N A

data

Whether recognized as a proxy f o r the neutralist-

was a significant change in attitude t o w a r d neutral­

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

ity* W h e n K i m u r a proposed the neutral theory in

the subject of intense debate. For instance, because

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

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

natural selection was the only i m p o r t a n t cause o f

variability in its rate was expected* By as early as

evolutionary change at any level o f o r g a n i z a t i o n .

1974, however, Walter Fitch and Charles Langley

This panselectionist attitude informed the early

argued that the rate o f substitution was nor as

opposition t o the possibility o f neutral molecular

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

evolution. By the raid-1980s, however, the dominant

the neutralist explanation was correct (Langley

&

attitude among evolutionary geneticists using molec­

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

ular data was that the neutral theory provided the

this line 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

starting place for investigation in the sense o f being

and speedups f r o m various lineages. In response,

the accepted null model (Kreitman 2000). W h y hypo­

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 ­

theses o f

tion was not perfectly u n i f o r m , but in his o p i n i o n ,

accepted as null hypotheses at this time has yet to

neutral molecular

evolution

became

'emphasizing local fluctuations as evidence against

be investigated by historians, but the rise o f neutral

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

null models seems t o coincide with increased avail­

the overall rare is intrinsically so regular o r constant

ability o f D N A sequence data, increasing use o f

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

molecular clocks i n systematic*, increasing use o f

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

coalescents, and t h e spread o f tests such as the

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

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

rate variability was much more pronounced than had been supposed, J o h n Gillespie proposed a selectionist episodic molecular clock chat he claimed

CONTROVERSY A N D THE

could explain patterns o f substitution better than

HISTORY OF EVOLUTIONARY

Kimura's neutralist explanation (Gillespie 1984). T o

GENETICS

answer Gillespte's claims, neutralists revised their models o f substitution ro accommodate greater

By emphasizing controversy, 1 have presented one

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

perspective on the history o f evolutionary genetics.

accommodated by the clock concept remains an

T h e controversies o f evolutionary genetics highlight

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

the interplay o f theory and experiment, the impact o f

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

new concepts and results, as w e l l as the power o f

T h e neutralist-selectionist controversy itself was

personality and politics. Controversies, such as those

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

between the Mendelians and Biomctricians o r Fisher

tion o f U N A sequence data. As a graduate student

and W r i g h t were often heated and sometimes q u i t e

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

personal. L i k e all criticism in science, however,

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

controversies also present the possibility of change.

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

T h e controversies of evolutionary genetics typically

A D H genes in Drosophila

l o o k i n g for evidence o f

began as highly polarized disputes, but the positions

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

in question developed, sometimes radical!); some*

phisms in the D N A sequences suggested that there

times more subtly. These nransformarions allowed the

was selection at the A D M locus and that differences

controversies t o depolarize by enabling some partic­

between synonymous and non-synonymous sites

ipants t o disengage, revise their o p i n i o n s , o r change

were significant. Kreitman w o u l d develop the analy­

their focus. Whether the future o f evolutionary

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 and 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).

*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 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 in 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

13

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 Crow, 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.

Copyrighted material

2 Genetic Variation M A R T A L WAYNE MICHAEL M . M I Y A M O T O

enetic 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

"sports"

m o d e r n biological

study o f e v o l u t i o n w i t h the s t u d y o f

G

thought*

From

evolutio­

(mutant

varieties); D a r w i n

began

his

heritable

nary biologists studying finches in the field» t o d r u g

pigeon varieties produced in response t o a r t i f i c i a l

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

selection by pigeon fanciers.

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

F r o m the perspective o f evolutionary biologists,

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

genetic variation is the fundamental r e q u i r e m e n t

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

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

variation gives us a h a n d h o l d on the phenotype,

concisely, particularly in t e x t b o o k s o r PhD qualify­

which is otherwise a complex and slippery construct»

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

Phcnotypcs arc produced by genes, the e n v i r o n ­

over 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

ment, a n d the interaction between genes and the

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

environment. T h e r e are few phenotypes for w h i c h

this chapter) is the i m p l i c i t requirement t h a t a locus

variation o c c u r r i n g in nature is entirely environ*

t h a t contributes t o e v o l u t i o n must not be fixed f o r

mental. H o w e v e r , beyond a c o n v i c t i o n that o r g a n ­

one allele, that is that genetic v a r i a t i o n must be

isms must ultimately be the products o f their genes,

present for e v o l u t i o n t o occur. Such a definition»

it is very difficult t o justify such a statement. This is

w h i l e precise i n some respects, fails t o capture

in part because we still can not describe the complete

several i m p o r t a n t details. First, w h a t is an allele?

genotype-phenotype m a p f o r any but the simplest

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 ­

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

t i o n , such as genome-wide duplications o r gross

for v i r t u a l l y every trait ever examined, suggesting

c h r o m o s o m a l rearrangements—do these not also

that genetic variation as a cause o f phenotypic v a r i ­

contribute t o evolution? Second, w h a t mechanisms

ation is likely t o be r a m p a n t .

cause the changes in allele frequency, however

It is impossible t o study the impact of the environ­

broadly w c m a y define an allele, and hence cause

ment on a trait if all organisms experience precisely

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

the same environment, that is the environment does

o f these different mechanisms?

not vary at all f r o m one i n d i v i d u a l t o a n o t h e r

This chapter w i l l concern itself first w i t h the

Likewise it is impossible t o study the role o f genes

question o f w h a t genetic variation consists o f : specif­

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

ically, w h a t is an allele? T h e definition o f an allele is

tion, that is i f all individuals are genetically the same.

far f r o m static, but rather changes w i t h every increase

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

in o u r knowledge about genetics and molecular b i o l ­

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

ogy, For example, an allele in the broadest sense may

the genetic and environmental factors responsible for

be a single nuclcotidc change o r a change in c h r o m o ­

specific traits. T h e origin of the study of genetics and

some number, structure, o r the d i s t r i b u t i o n o f genes

evolution began w i t h genetic v a r i a t i o n :

Mendel

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

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

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

14

Genetic Variation

IS

genetic v a r i a t i o n , combining molecular, mechanistic

genome-wide duplication t h r o u g h polyploidizauon,

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

T h u s , genetic v a r i a t i o n constitutes a

Functional properties o f alleles contribute t o their

diverse topic, a f f o r d i n g m a n y different ways t o

rich

and

roles in evolution, We begin by enumerating types o f

hierarchically organize this i n f o r m a t i o n . Given the

genetic variation identified at the molecular level.

current state o f biology, w i t h its emphasis o n mech­

including selective expectations for molecular varia­

anisms a n d thereby molecules, w e start the defini­

tion. N e x t , w e link this molecular variation t o genet*

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

ical properties such as dominance and additivity. The

D N A |or R N A ) molecule. O n e of the l u x u r i e s of

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

the post-genomic era is that w e now can precisely

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

describe far m o r e types o f sequence changes at the

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

molecular level, and estimate the relative abundance

o f genetic variation that w e see. Finally, w c consider

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

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

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

v a r i a t i o n challenges several classic

simplest (single base changes) t o the most c o m p l e x

evolutionary

paradigms.

(changes affecting entire genomes, such as genomew i d e duplications), A complementary discussion o f m u t a t i o n s and their effects is provided by H o u l e & Kondrashov (Ch* 3 o f this v o l u m e ) ,

V A R I A T I O N AT T H E M O L E C U L A R LEVEL

Single N u c l e o t i d e B a s e C h a n g e s

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

T h e most s t r a i g h t f o r w a r d type o f genetic v a r i a t i o n

single base substitution through p o i n t m u t a t i o n and

is t h e single nucleotide base m u t a t i o n (Figure 2.1).

Noncoding DNA

Co* ngDNA

N-Mel 5- A C ® G

1-

5'- AC(T)G

ATG

Pro CC®

•

Thr

Glu

Gin

lie

Ala

ACG

GAG

CA'G

ATA

GCC

•

'

GGA

TAG

CC .

*

■ •

Arg

-Stop-

.

i

J

ATO N-Met

1'

1

CC®

ACG

Pro

Thr

3

®AG I

*

Mutations 1. Transition substitution 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 proteincoding gene. At the t o p , the original D N A sequence o f this gene is s h o w n , along w i t h the a m i n o acid 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 and polypcptide sequences that result f r o m the four mutations are given at the b o t t o m . T o facilitate comparison, t h e coding regions o f the D N A sequences are labeled as such and arc presented as base triplets relative t o their encoded a m i n o acids* T h e four mutations are numbered and arc defined in the lower left c o m e r of the figure. In the case o f mutation 4 , the strikethrough highlights a deletion o f the marked " A " in the o r i g i ­ nal 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 frameshift m u t a t i o n i Insertion o Complex events*— l combine substitution >i and deletion or insertion

>i l

AGGC -*ATTC

% is the icngrti of rhc affected sequence Dcfore mutation, it is the length of lh* sequence NA sequences,

.1. N e u t r a l m u t a t i o n s d o not affect fitness m u c h , either positively o r negatively. These t o o are likely t o be c o m m o n .

ison of parents and o f f s p r i n g . A t a slightly longer

4. Advantageous m u t a t i o n s increase fitness. and therefore w i l l be favored by natural selection. These arc p r o b a b l y the rarest type of mutation.

p o p u l a t i o n under c o n d i t i o n s

Three different classes o f characteristics may be phenotypes, and fitness. Studies of m u t a t i o n almost invariably cover one o f three t i m e frames. First there is the direct study o f mutation through Compar­ time scale, one can set up a nuuatkwvaeeuniulation ( M A ) experiment. T o d o so, one maintains the that m i n i m i z e the

i m p a c t o f natural selection o n the fate o f an> m u t a ­ t i o n * that may arise (see Case Studies l o r examples). Finally, the comparative m e t h o d infers m u t a t i o n rate f r o m the rate of divergence between species.

T h i s categorization is c o n text -dependent.

An

1 he use o f different time frames allows different

may

aspects o f mutation t o he investigated. T h e chief

he neutral o r deleterious in other circumstances

reason for these differences is the degree t o w h i c h w e

(Schemer, C h . 21 o f this volume). A l s o , the fitness

can assume a realistic model (or the interaction

advantageous variant

in one e n v i r o n m e n t

Copyrighted material

36

Principles o f Evolutionary Genetics TABLE 3*3. Categorization o f approaches t o the study o f m u t a t i o n , with reviews or examples o f successful studies Generations separating samples

between

i Direct

\o to 10* Mutation accumulation

>io* Comparative

DNA

Weber and Wong 1991

Phenotype Fitness

Kondrashov 2002 Woodruff et al. 19S3

Denver et a l 2004; Schuget a l 1997 Houleet al. 1996 Mukal et a l 1972

Nachman and Cfowell 2OO0 Lynch 1990

With

depends on the effectiveness o f natural selection at

direct studies, the need for assumptions about n a t u ­

m u t a t i o n and

natural

selection.

influencing frequencies; this depends on the size of

ral selection is m i n i m a l . A l m o s t all rypes o f m u t a ­

the p o p u l a t i o n . In a p o p u l a t i o n where N is s m a l l ,

tions m a y he observed in the o f f s p r i n g . A s the time

genetic d r i f t (luck) w i l l be a relatively strong force,

frame o f t h e study lengthens, the necessary assump­

swamping o u t small differences in fitness. However,

tions about natural selection become more stringent.

w h e n N is large, even tiny differences i n fitness reli­

O n l y mutation rates t o neutral alleles can simply be

ably discriminate higher and lower fitness variants*

inferred over long time periods* A s a result, the same

M u t a t i o n - a c c u m u l a t i o n experiments are therefore

data can lead t o very different conclusions a b o u t the

designed t o m a x i m i z e t h e impact o f d r i f t , either by

overall m u t a t i o n rate, depending o n the assumptions

m a k i n g N as small as possible, o r by equalizing

chosen.

f a m i l y sizes (Shabalina et a l 1997). T h u s , the i n f l u ­

Despite the c o m p l i c a t i o n s i n a p p l y i n g models t o

ence o f natural selection is m i n i m a l in a direct study,

divergence data, t h e essential neutral theory b e h i n d

somewhat higher in a mutation-accumulation study,

such models is easy t o grasp. If w e consider a p o p u ­

and very large in a comparative study* T h e result is

l a t i o n o f generic varianrs w i t h no impact o n fitness,

that the neutral model can be applied t o an uncer­

that is neutral variants, whether they are lost f r o m

t a i n and decreasing p r o p o r t i o n o f variants as the

the p o p u l a t i o n o r w i l l become

(rise t o a

rime scale o f t h e study increases* Even at the D N A

frequency o f 1) depends o n l y o n generic d r i f t , the

level, it is difficult t o be sure that a particular segment

luck o f s a m p l i n g d u r i n g r e p r o d u c t i o n . Lucky v a r i ­

really evolves at the neutral rate. For example,

ants w i l l become f i x e d ; the vast majority' w i l l be

evolutionary biologists have treated pseudogenes,

lost just by chance* T h e chance t h a t each particular

altered sequences derived f r o m f u n c t i o n a l genes, as

variant w i l l be fixed in t h e future is p r o p o r t i o n a l t o

neutral (e.g. N a c h m a n and C r o w e l l in Case Studies,

its frequency r i g h t n o w : rare variants are likely t o

b e l o w ) . However, there are at least t w o possible

fixed

be lost, c o m m o n ones likely t o he f i x e d . N o w , let us

mechanisms for selection on pseudogenes. First,

consider ihe fate o f each new neutral variant. If

recombination

between

pseudogenes and

their

there are N d i p l o i d individuals in the p o p u l a t i o n ,

parent gene is deleterious, so deletions o f pseudo­

each new variant starts o u t at a frequency o f 1/2N,

genes m a y be favored by natural selection. Second,

and thus has a chance o f V2N o f rising t o

fixation.

t h e discover)* o f naturally o c c u r r i n g n o n p r o t c i n -

O n the other h a n d , w i t h a mutation rate m per

c o d i n g genes (such as m i c r o - R N A s ) that can regu­

gamete, the number o f new mutations in each gener­

late expression o f their h o m o l o g o u s genes suggests

ation is 2 N w . M u l t i p l y i n g thfse t w o together gives

t h a t some apparent pseudogenes may play such a

the surprisingly simple rate o f neutral e v o l u t i o n ;

selected role*

k = 2Nrtt x IflN

= w . T h i s fate is the divergence

A second major disadvantage o f c o m p a r a t i v e

f r o m the ancestral sequence; species diverge at

studies is that the number o f generations that sepa­

m i c e this rate because variants arise a l o n g borh

rate species is usually k n o w n only very a p p r o x i ­

branches t o the c o m m o n ancestor.

mately- A s the time scale o f any c o m p a r i s o n becomes

I n reality, variants have a range o f effects o n

longer, these uncertainties

become very

large.

fitness f r o m undetcctable t o lethality. T h e i r ability

T h e number o f generations i n a lineage since the

t o persist in t h e p o p u l a t i o n and so be detected also

Mesozoic era w i l l h a r d l y be ever k n o w n w i t h any

37

Mutation confidence at a l l A s a result, comparative data arc

responsible f o r

usually summarized as a m u t a t i o n rate per unit t i m e .

h u m a n genetic diseases, they can be used t o gain

W h i l e this may be useful in some contexts, such as

very detailed i n f o r m a t i o n a b o u t m u t a t i o n rates.

c a l i b r a t i n g a molecular

clock

(e.g.

Rodrigucz-

However,

t h e m , as explained

mutations

with

below

the very

tor

largest

Trcllcs et n l , C h . 8 o f this v o l u m e ) , it does not tell

phenotypic effects used in direct m u t a t i o n studies

us w h a t w e w a n t t o k n o w a b o u t m u t a t i o n rates tn

ate themselves rarely o f e v o l u t i o n a r y significance,

organismal terms.

as they usually reduce fitness. Quantitative trait locus

These considerations w o u l d seem t o make direct

and developmental studies o f species both

differences

studies preferable, were it not for the fact that the

suggest t h a t

longer the t i m e period» t h e greater the number o f

t o - l o o k - f o r and s m a l l effect variants are the m a j o r

detccrable-if-you-kim*v-what-

mutationat events that can be assayed» Because

sort of v a r i a t i o n t h a t allows e v o l u t i o n . Their c u m u ­

m u t a t i o n s are i n d i v i d u a l l y rare, direct studies can

lative effects are usually studied in a m u t a t i o n -

only be informative when there is an efficient mecha­

accumulation experiment. I n most such experiments.

nism for screening e n o r m o u s numbers o f i n d i v i d u ­

an initially inbred genotype is replicated and selection

als for mutations* Such screening is available f o r

on rach replicate minimized by lowering N iot each

m a n y inherited phenotypes in h u m a n societies w i t h

replicate, for example by sclfing o r brother-sister

advanced health care. At the other end of the biolog­

mating* T h e rare at w h i c h v a r i a t i o n in the pheno­

ical spectrum, m i c r o b i a l p o p u l a t i o n s can be rapidly

type accumulates is used t o measure the increase

screened for t h e converse sort o f m u t a t i o n s that

in phenotypic variance due t o a single generation o f

restore f u n c t i o n at a defective gene (reviewed in

m u t a t i o n , V M , In a d d i t i o n , a change in the mean

D r a k e 1991 >. For other species, the direct data are

o f the accumulation lines indicates that mutations arc

limited. Furthermore, because the phenotypic impact

biased in their effects* For example, fitness and its

o f most m u t a t i o n s is usually small, w e need t o be

key components o f viability, fecundity and m a t i n g

able t o inter f r o m t h e m i n o r i t y o f m u t a t i o n s that

ability, are m a x i m i z e d by n a t u r a l selection, suggest­

arc observable the properties o f the f u l l spectrum o f

ing that the (nutations chat arise w i l l on average

mutations.

decrease fitness. I n f o r m a t i o n o n VPM and m i i t a t i o n a l

O f the three different classes o f characteristic*

bias can sometimes be c o m b i n e d t o give a very crude

that may be used t o study m u t a t i o n , D N A sequences

estimate of the overall m u t a t i o n rate o f all genes

are die most conceptually straightforward. The chal­

affecting fitness, as in M u t a t i o n A c c u m u l a t i o n in

lenge w i t h the use o f sequence data is that care must

Drosophih

in the Case Studies section below.

b e taken t o account f o r the possibility o f errors in scoring. This has so far l i m i t e d t h e use o f sequence data in direct o r mutation accumulation studies, For example, t o detect a sample o f base pair mutations.

M u t a t i o n Rates T h e most detailed picture that w e have o f m u t a t i o n

w h i c h typically o c c u r at a rate o f 10 * per genera­

rates in enkaryotes is for humans. T h i s is due t o

t i o n , over a 100 generation m u t a t i o n - a c c u m u l a t i o n

several factors* First, human-chimpanzee is the only

experiment, one needs the a b i l i t y t o sequence many

species pair for w h i c h the t o t a l number o f genera­

m o r e than 10* nuclcotides w i t h an error rate w e l l

tions since their divergence is reasonably well k n o w n ,

b e l o w I D A The necessary methods are emerging

facilitating c o m p a r a t i v e studies (see Nachtnan and

and are starting t o be applied (Denver ct a l . 20041.

C r o w c l l in Case Studies, b e l o w ) . Second, data o n

Exceptions are provided by sequences w i t h espe­

Mendelian diseases provide t h e o n l y

cially high m u t a t i o n rates, such as microsatellites

phenotypic screenings for de n o w m u t a t i o n s in any

or mitochondria! D N A ,

eukaryottc species for direct estimates ( K o n d r a s h o v

large-scale

T h e other t w o categories of data (phenotypes

21 as i n d i c a t i n g demographic increase. Relative fitness, in contrast, provides n o i n f o r m a t i o n about demographic trajectories because d i v i s i o n by the mean absolute fitness (\V( necessarily results in a population mean relative fitness {w) o f unity, regardle&s o f the actual demographic trajectory o f the p o p u l a t i o n * Relative fitnesses [UK) therefore indicate only the relationship between the absolute fitness o f that individual or |*enotype and the population mean fitness ( W ^ * The)* imply nothing about the actual values o f r, RQ, o r any other measure o f absolute fitness, W h i l e b o t h r and R0 are used extensively in theoretical analyses o f adaptive e v o l u t i o n , the difficulty o f estimating either as a function o f phenotypc in w i l d populations has l i m i t e d their application in empirical studies* M o r e c o m m o n l y , researchers attempt t o measure only certain c o m p o n e n t s o f fitness. This approach is generally m o r e feasible and appropriate when ihe a i m is to ascertain the adaptive significance o f the trait i n ques­ tion, For example, the hypothesis that an exaggerated secondary sexual characteristic in males is favored by sexual selection for that t r a i t c o u l d be tested s i m p l y by measuring the covariance between the trait value and mating o r paternity success (Wade, C h . 4 o f this v o l u m e ; W o l f , Box 18.1 of this volume). I n some cases, the fitness parameter may itself he a component of lifetime fitness (i.e., survival, fecundity o r m a t i n g success). However, in other cases, surrogate fitness measures can he used on the assumption t h a t they correlate w i t h lifetime fitness. For e x a m p l e , behavioral ecologists m a y use energy intake rate as a surrogate measure o f fitness in studies c o m p a r i n g foraging strategics» T h e use o f surrogate measures o f fitness and studies o f only certain c o m p o n e n t s o f lifetime fitness has proven very valuable for testing adaptationist hypotheses* H o w e v e r , the dynamics o f t r a i t e v o l u t i o n i n response to selection (assuming h2> 0) arc ultimately determined by the relationship between trait values and lifetime fitness. Trade-offs between the fitness effects o f trait values d u r i n g different phases o f the life history often produce non linearities i n the relationship between trait values and lifetime fitness that w o u l d not be obvious f r o m studies l i m i t e d t o only a subset o f life history stages (Preziosi &£ Fairbairn 2 0 0 0 ) . Studies t h a t combine analyses o f fitness components w i t h estimates o f lifetime fitness o f f e r t h e best hope o f b o t h deducing the adaptive significance o f the t r a i t in question and understanding the e v o l u t i o n a r y dynamics o f the t r a i t d i s t r i b u t i o n .

TABLE 1 Definitions o f fitness found m the glossaries o f evolutionary biology textbooks Definition

Source

The success of an entity in reproducing; hence, the average contribution of an allele or genotype to the next generation or to succeeding generations The average number of offspring produced by individuals with a certain genotype relative to the number produced by individuals with other genotypes The extent to which an individual contributes genes to future generations, or ^n individual's score on a measure of performance that is expected to correlate with genetic contribution to future generations (such as lifetime reproductive success) 1. The ability of an individual or population to leave viable and re productively effective progeny, relative to the abilities of other individuals or populations. 2. The average contribution of ^t\ allele or genotype to the next or subsequent generations, compared with those of other relevant alleles or genotypes The relative reproductive success of individuals, within a population, in leaving offspring in the next generation. At the genetic level, fitness is measured by the relative success of one genotype (or allele) compared with other genotypes (or alleles)

Futuyma 1998 Ridley 2004 Freeman and Herron 2001

Price 1996

Kardong 2005

Natural Selection

55

TABLE 4 . 1 . Single-gene, twoallele models of natural selection in a randomly mating population C e notypic fi I nesses Genotype W to

Frequency before selection

Recessive deleterious allele

p* 2/Kf

1 l

Additive effects

Heterozygole advantage

General

l+i 1

WM W&

1+2$ 1+I

the genotypic httiess or | t t 7 A A C ^ * W'^JCMJ + W ^ G J J ) . T h e relative fitness of a genotype, say IVAA* equals its fitness relative to the population mean fitness o r the ratio, W ^ / W . As a result, G ' w equals U>\AGAA. I lencc. t h e relative genotypic fitnesses are a useful multiplicative transformation of i h c set of genotype frequencies before selection fu the set after selection. We can n o w calculate the allclc frequency after selection, p* or | G ' U + |0,5]G' A J } .isequal t o [wAjKGAy + [0.5\w^G^l The singlc-gcne. t w o a l l e l e models of natural selection specify t h e values u ( the genotypic frequencies (Table 4*1) to derive the textbook expressions for Ap. For example, a recessive deleterious allele evolves according t h e genotypic viability fitnesses of column three of Table 4.1 with mean fitness, IP, equal to (1 -sq2U As a result, we find

*4 = («•-*fi*A - |G„ + |0.5|C,U}. 14. Ibl

&q=lil-s)q**l(l.S)2pi,Uil-#?)- = V'U) - V{z) = iz2p'iz)dz - \\zp'{z)dz\l - \z*p[z)dz + \kpiz)dz\\ (4.14a) AV|z) ■ ]zLw{z)piz)dz - \izrtz)piz)dz}* - zlpiz)dz + \]zp\z)dz\\ AVU» - iz*uiz)piz)dz -[\z*piz)dz\\\wiz)p{z)dz\ -\iwiz)p{z)dz)^\lpiz)dz)\ A VU) = C o v ^ , w\z}) - |Z + AZ|2 + {Z|2, AV(z) = CovM wlzi) - 2ZA2 - {AZ[*, &V(z) = Covl*2, u\z\) - 2ZCov(c,«4zJ)

-Co\ &V(z) = Cov(U - Z\\

w\z\) -

Cav2tiMz)).

(4,14b) W i t h stabilizing selection, individuals with extreme phenotypes far from the mean (i.c., large values of [z - Z]1) have the lowest fitness so that Cov([r - Z]2t w\z\) is negative, reducing the pheno­ typic variance. Conversely, whenever individuals with extreme phenotypes have the highest fitnesses (i.e., disruptive selection), the phenotypic variance is increased by selection because Cov(|z — ZJ*, tv[z]l is positive. Even if the C o v ( | j — Z|*, w\z\\ is zero, changes in the mean in either direction, owing t o directional selection, will reduce the phenotypic variance because the term, Cov 2 ]*,!*^!) = |AZ| 2 , is always positive. This reduction in the phenotypic variance as a result of directional selection is conso­ nant with Darwin** pre-genetic discussion of natural selection's role in keeping characters "true and constant.**

Natural Selection The single-gene, two-allele model of balancing selection introduced above can also be viewed from fhis same covariance perspective. In this model, the necessary conditions for an intermediate equilib­ rium value of the allele frequency»?*, are identical to those for a notizero equilibrium value of V*(z) where, at equilibrium, dV(z) = 0, The variance in this model is defined as in Equation. 4.13 or* in words, as the difference between the mean of the squared values, that i s |{1) 1 IG^) + « W A G A , » + i0l : (G 4 i )|, and the square of the mean value, that is, \p)2. This gives us V[z) before selection equal to {pqll), Following the exposition above, we could derive an expression for AV{z). When the distribution of phenotypic values in a population is significantly skewed* the skew can he represented as Cov([£ — Z|, \z — ZJ : ) or, more simply, Covfc, [z - Z]1)* In this case, selection acting strictly on z will result in indirect selection on the variance in phenotype, V\z). This is one reason why mulnvariatc normality is so critical to the study of phenotypic selection in natural popu­ lations as a means of identifying agents of natural selection. The transformation of the observed phenotypic distribution to multivariatc normality' ensures that all covariances between linear and quad* ratic terms arc zero and facilitates analysis. Whether or not nature engages in the same kinds of transfor­ mations is open to question (Wade oc Kalis/ 1989, 1990), When one assumes that the phenotypic vari­ ance remains constant across generations despite directional selection, then one is implicitly making assumptions about the higher moments of the pheno­ typic distribution or the mating system and the underlying genetics. Unlike the linear multiplicative changes in the mean, Z. resulting from heredity, lrlt mating and transmission may increase or decrease the phenotypic variance of the offspring relative to the parents. For example, with stabilizing selection on additively determined phenotypes, the extreme individuals purged from the population will tend to be multilocus homozygotcs and the surviving parents will have an excess of multilocus hctcrozygotcs. Segregation from these heterozygous parents will reconstitute the extreme individuals leading to a dynamic balance between selection and segregation in their opposing effects on the phenotypic variance, The mating system affects this balance by influencing the frequency of hcrerozygores. On the other hand* with disruptive selection the surviving parents will consist of an excess of multilocus homozygotes and

59

random mating among the survivors will reduce the variance of rhe offspring phenotypc distribution. flie potential increase* or decreases in the phenotypic variance and covariance that attend transmission are more difficult to account for than the changes in the mean. This treatment can be extended to describe the effects of selection on the covariance between traits, OJV(.V, y), simply by noting that the variance is the special case of the covariance of a variable with itself. Thus, Equation. 4.14b becomes A Cov(ar, yj = Cov(|x - X||y - V|, w\x%y\) - CovBJ is the average value of NP fSt 1,1, GVNV). Furthermore» let .tir be the product of Al„ and J \ \ ; so that, xn = (A1,)(Nir). Also define */,, dz* d\> and d4 as the frequencies of the gametes AtBx, AxBzi A2BX* and A>B;* respectively, and note that (d} + Jz) is pwSy and (J, + d\) is pu\* Also note that, at the gametic level, the product of M and M is 1.0 for di but zero for all other gametes, so that X^mfu is d|. The gametic linkage disequilibrium* '^jmcr>.i N„) IK the value of the genotypic covariance after ««lection and transmission (recombination between loci A and B at rate c), that is, at the stan of the next generation. With random mating, the change in the genetic covariance, ACo^M^N^), that is, Cov"(A1^Nv) - C o v ^ A I ^ ) , caused by recombination equals -cf)72. The effect of trans­ mission on the genotypic covariance is always the opposite of the sign of D. Hence, it is always toward zero or no association. The evolutionary implication is that maintenance of a permanent, nonzero disequilibrium require* a balance between the effects of selection and transmission,

Partitioning the Variance in Fitness Variance in relative fitness is essential for the action of natural selection as wc saw above and this vari­ ance arises from multiple causes, environmental or genetic, as well as chance (see above). The variance in relative fitness sets an upper limit on the rate of all evolutionary change and the phenorypic covariances among different traits further limit the degree to which selection can be focused on a single trait without causing deleterious consequences for other traits. For these reasons, the partitioning of the total variance in relative fitness into different components is useful for determining where and to what extent the force of natural selection is focused on a particu­ lar trait, life history stage, or level of selection. Below, 1 partition the variance in relative fitness into components of natural and sexual selection, individ­ ual and group selection, and selling and outcrossing, to illustrate the range and utility of the approach.

Sexual Selection and the Sex Difference in Variance in Fitness The opportunities for selection in males, / m i l „, and in females, /^mjn, are defined as sex-specific ratios of fitness variance to the square of mean fitness, which is the variance in relative Fitness. The sex-specific variances in relative fitness arc related to one another through the sex ratio and mean fitness. Reproductive competition among the members of one sex can increase the variance in fitness of that sex so that selection in one sex can be stronger than selection in the other (Shuster & Wade 2003). To see this, let /' be the fraction of males that have i mates. The average number of mates per male, 2* jpp is the sex ratio, Jv, expressed as the ratio of the number of mating females over the number of mating males. " IvVnukt and V ^ ^ ^ are the mean and variance of offspring across females, then the variance in male reproductive fitness, V n ^ , is V - * = I ftO'V^^i + 1 W / W W , - R W W , ) 2 , 14.19a I V^-RVfc^+Wfc^'V^..

(4.19b)

Clearly, the variance in male reproductive fitness exceeds nSat of females whenever there is variation among males in the numbers of mates.

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Natural Selection Since mean male fitness» W,,,^, equals r!Wff;iuirt, dividing liquation 4.19b by the square of mean male fitness gives

61

With these definitions, we can rewrite / ll(Ul from Equation 4.22 as / ^ - ^ s ) ^ ) + - / s o K-23)

/ ^ . ( 1 / K K J ^ j W ^

(4.20)

2

where lmMin is the ratio I'^^/ft , or the opportu­ nity (or selection arising from the variance among males in mate numbers. When R is 1, the sex differ­ ence in the opportunity for selection* / m ^ - 'h^iei equals /p, u W Thus, lmMn is a standardized measure of the strength of sexual selection (Wade 1979; Wade & Arnold 1980; Wade 1995; Shyster 6c Wade 2003).

'%** - W3)Hh) + 0/3H(/o) + 2)2/3X1/3) C o - / » (4.24a)

Selfmg, Outerossing, and the Variance in Relative Fitness In a population of N hermaphrodites* let the ith individual have fitness \Vt. consisting of \V\. selfed offspring and (1/2)1 W n J outcrossed offspring* The factor of 11/2) discounts the outcrovsed offspring in proportion to the genetic contribution of the ith individual. The mean fitness of this population, W, equals |W\ + (1/2)Wo), where W s and WQ are the mean numbers o! selfed progeny and outcrossed progeny per individual, respectively. The variance in fitness, YV* is defined as VV = I, («s, + 11/2) Wo, - | \K\ + i 1/2)Wu|)-/N {4.21a)

= £({W«- WJ + d^JIWo,- WollW

- z, \\w* - ws(* + (i/4)i Wo, - w 0 j* -M2Hl/2)|\vV- W J I W o , - W 0 |p/N, Vw = l \ + and uncorrelarcd |Cov| W\,W 0 | - 0), rhen / \ equals (2/31 and po equals (1/3) and Equation 4.18 becomes

h**\ - (0.44)1« + (0.11 )Uo).

(4.24b)

Ik-causc the mean and variance t Thus, rhe contribution of selfed progeny co the total opportunity for selection is four times that of outcrossed progeny, hi this circumstance* phenorypes that improved selling would evolve much more rapidly than those that improved outerossing by a similar amount and the selection pressure to preserve selfing or vegetative growth as a means of reproduction is l o n g e r than that (o preserve outerossing. In this way* the differential contributions of selfed and outcrossed offspring to the opportunity for selection in hermaphroditic species share a simi* Janty wiih the differential opportunity for selection on males and females in species with separate sexes. More generally, if the mean number of selfed offspring equaled k times that of outbred offspring. then/\equals(2fc/|2k+ 1|1 and/'„ equals {1/U& + IJl and liquation 4.23 becomes / * „ ! = (2*/|2fc + l | r t W + {U[2k + Urtio» + 4 is 0..50, which is twice that of sclecnon on either selfed or

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Principles of Evolutionary Genetics

outcrossed offspring. As a result* when selection is equally strong on traits producing selfed offspring as it is on traits producing outcrossed offspring (see intersection of the lines in Figure 4.1), the fitness trade-off between selfing and outcrossing becomes the most predominant factor in mating system evolution.

I T Zt (W,,)/MN, then the variance in fitness can be partitioned into w o components. Beginning with the definition of die variance in fitness, we have: Vw = ft E, ( * ; - Wy\/MNt

Vw-1^5 Croup and Kin Selection and the Variance in Fitness among Groups Group selection is a controversial topic because it is difficult to establish that groups have the neces­ sary properties of replication, variation, and heredity. The processes of group formation, dispersion, colo­ nization, fission, and local extinction, together with environmental variation, determine the amount of phenotypic variation, among groups and the extent to which it is heritable (Wade 1996), When groups fission or disperse along lines of kinship, they are more likely to have the requisite heritable variation than groups formed in other ways. The variance in relative fitness can be parti­ tioned into within-and among-group components in a manner similar to that above for the separate sexes. For simplicity of derivation, let each of the M groups contain N individuals, that is, the same fraction, ( l / M ) , o f the total population, ( M N ) . If the lifetime fitness of the nh individual in the /th group is W^, and mean finiess, W T , equals

(4,26a)

(W; - W > W, - Wf )/MN, (4.26b)

by adding and subtracting the / t h group mean fitness» W, (= Z, WJNl Recognizing that both sums, X, ( W j - W_) and I , I , (vP„ - WJt are zero, the square can now be separated into two components:

w

Vw ^ {2,1, {V„-W/\/MN * {Z, lAW.-WtfVMK

(4.26c)

V r = II, V.J/M + {Z, (W4 - WfW,

(4.26d)

hich reduces to

'W

m

• iTirhin CWuuft *

" Among ,

(432)

by equating Equation 4,29b with (1/N r ) from stan­ dard theory, we then derive the effective population

which can be applied to maternally inherited mito­

iizc with natural selection as

chondrial haplotypcs, Fmt, or paternally inherited Y-linked haplotypcs by adding the appropriate sex-

Nt={N-l)/t.

(4.30)

specific subscripts When the sex ratio is even ^ N ' ^ . ^ - NiraieJ and

Thu:*, the greater the opportunity for natural

ihe sex-specific migration rates are equal \mmAk =

selection, f, the smaller the effective population size,

^"'trnuin where A. a constant of proportionality, is set

N f , and» thereby, the stronger the force of random

to 1,0), then the ratio of the difference, { ( l ' / w ) -

genetic drift. This means that current natural selec­

[1/Fi )|, to the sum, Ifl/Fyl + { 1 / F J - 2», gives

tion acting on one trait will diminish necessarily the future opportunity for a response to selection at a

UUF^-iUFyMiUty) + 0/Fm) - 2)

later time on another, independent trait. Thus, hered­ itary variation is not simply an independent "multi­ plier** of natural selection hut is necessarily affected by it. With

Thus, a function of maternally inherited and paternally inherited diversity can be used to esti­

sexual selection, the opportunity for

mate the fraction of total selection represented

selection on males, / n u j f t 1 tends to exceed that of

by sexual selection. (Note that, whenfe> 1, the

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Principles of Evolutionary Genetics

migration rate o f females exceeds that of males, And Equation 4.33 is an underestimate of the proportion of sexual selection. The comparable nonequilibrium solution is similar (see Wade & Shuscer 2004).)

SUMMARY A N D C O N C L U S I O N The KJMV logic of evoluiion hy natural selection was discovered and discussed in derail by Darwin, but the quantitative investigation of his theory required additional theoretical developments. Key developments were Fisher's (1930) insight that the phenotypic process o f natural selection could be formally separated from the problem of inheritance and Crow's insight (1958) that the variance in rela­ tive fitness or the opportunity for selection sets an upper bound on the rate of adaptive evolution. Robertson (1966) and Price (1970, 1972) made the important discovery that natural selection is the co variance between phenotypic value and relative fitness, a relationship which greatly facilitates the study of phenotypic selection in natural populations (e.g., Shuster & Wade 2003). In the sections above, I have tried to show the conceptual utility and the empirical potential of these fundamental contributions t o the theory of evolution by natural selection. They can be used t o formally connect quantitative genetic theory with population genetic theory and thereby illustrate the similarity and differences in these two theoretical approaches to evolutionary genetics. The opportu­ nity for selection is particularly useful since it can be applied to so many different aspects of natural selection. I illustrated its utility in partitioning selec­ tion between males and females» between selfcd and outcrossed offspring, and between different levels of selection. These partionings reveal an interesting similarity between selection acting on males and females in species with separate sexes and the action

of selection on selfcd and outcrossed offspring in hermaphroditic species. The opportunity for selection is also useful for illustrating the necessary interaction between natural selection and random genetic drift. The variance in offspring numbers with directional selection tend*. t o be greater than random and* thus, to reduce the effective population size and enhance drift. This effect can be employed in the interpretation of patterns of molecular diversity of maternally and paternally inherited genes to estimate the propor­ tional strength of sexual selection.

SUGGESTIONS FOR FURTHER READING To further explore these concepts, I recommend as an excellent and broader introduction to evolution­ ary genetic theory» the chapter hy Kirkpatrick (1996) entitled "Genes and adaptation: a pocket guide t o theory/ For a more nuanced and detailed introduction to the topics covered in this chapter, the first nine chapters of the hook Introduction to Quantitative Genetics hy Falconer and Mackay (1996) arc recommended; this book should be required reading for all graduate students interested in evolutionary genetics. 1 also highly recommend Hcdrick's (2005) Genetics of Populations* espe­ cially chapters 2 and 3, Falconer DS & TFC Mackay 1996 Introduction to Quantitative Genetics. Addison Wesley. Hedrick P\V 2005 Genetics of Populations- Jones and Bartlett. Kirkpatrick M 1996 Genes and adaptation: a pocket guide to theory, pp. 125-146 in M R Rose Si G Laudcr, eds. Evolutionary Biology and Adaptation. Sinauer Assoc.

Stochastic Processes in Evolution JOHN KCILLESPIE

ity the poor mutation: it* most likely (ate is extinction even i( it is more fit than any other allele at its Incus* When lost, these mutations play no significant role in evolution and evolutionists have no record of (heir short-lived existence. On the other hand, when an advantageous mutation is lucky enough to fix in the population, there are a number of consequences that excite evolutionists of various stripes. Darwin focused on the idea that the species is better adapted t o its environment as a result of the substitution. A population geneticist might note thai there is reduced variation around the site of the fixed mutation; a molecular evolu­ tionist might use the substitution as a basis (or a new phylogeny; a functional evolutionist might wonder why ihis particular substitution rather than another one that would seem t o be even more fit; a statistician might use the timing of the substitution as pan of a description of the temporal sequence of evolution* At the core of all of this interest is a random event that includes the time at which the substitution occurred, the functional properties of the substituted allele, and the neighboring pirevs til the genome that were carried along with the allelc as it swept though the population. In this chapter, we will be particularly interested in the random times at which alleles enter the population and in their subsequent dynamics as well as those of linked portions o l the genome. These arc arguably the most important stochastic processes in evolution. The source of the random­ ness is somewhat mysterious, but obviously includes demographic stochasticity—the apparent

P

randomness in the numbers of offspring among individuals—and the random nature of mutations, including both their probabilities of occurrence and the particular alterations in their DNA sequence. I he source must also include random temporal and spatial variation in fitness* mutation and migration rates as well as changes induced by events in neigh­ boring regions of the genome. When episratic inter­ actions from other evolving loci are added t o the mix, ihe stochastic landscape for alleles becomes unimaginably complex. O u r confidence that we do understand some aspects of this landscape comes Irom an examination of each source of randomness in isolation followed by a judgment call on its relative importance. In doing this, there is a major schism hctween the dynamics of very rare alleles—new mutations being the prime example—and more common alleles. The first two sections in this chapter are concerned with rare alleles, which are said to lorm a boundary process. The ncxr three sections deal with common alleles, which are alleles that leave the boundary region to begin a calmer sojourn. The randomness of evolution is nearly impos­ sible t o investigate through observation or experi­ mentation. Most of our understanding comev from mathematical and computer modeling. This is precisely what we shall use in this chapter. Beyond baste algebra, there arc only three critical prerequi­ sites for this chapter: ^m understanding of the Poisson and geometric distributions and of the Taylor series expansion of a function. As a special case ol the latter* wc will use the geometric series in a couple of places.

65

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Principles of Evolutionary Genetics

CONCEPTS The Fate o f a New Mutation

When a new mutation appears in a population it is likely to disappear within very few generations even if it carries a substantial fitness advantage. This simple statement adumbrates much of what is to follow. But first wc must sec that it is true. A simple warm-up problem is as follows: What is the probability that a new4 neutral mutation in a population of N haploid individuals will be lost in a single generation? Assume (or simplicity' that there will be exactly *V individuals in the next gener­ ation as well* We could imagine that the next gener­ ation is obtained by simply reaching into the current generation and drawing out iV gametes at random with replacement, (In this context» "with replace­ ment" captures the idea that individuals arc send­ ing random numbers of offspring into the next generation.) As the frequency of the new mutation is UN, the probability that it will fail to cross into the next generation in a single draw* is the probabil­ ity that some other allele is chosen, 1 - 1/N. As the draws are independent, the probability that the mutation is never drawn is

e~l = 03678.

(The convergence of the expression on the left to Me for large N may be found in a basic calculus book that discusses the definition of e* You can prove it yourself by writing out the binomial expan­ sion of (1 - UN\S\ letting N~t « and noting that the resulting power series is the Taylor series expansion ot r \) From this wc conclude that the probability that a new neutral mutation is lost in its first gener­ ation of life is about one third* Our calculation has one major surprise: The population size does not appear in the final answer even though it was an integral part of the underlying model. Given this, it should be possible to restate the problem in such a way that N plays no role in the model or the calculation* The simplest approach is to assume that each individual has, on average, one offspring» and that the number of offspring is Poisson-distributed: Probjfoffspring} = — ■

A mean of 1 is chosen because we are modeling a stable population whose mean size is not chang­ ing. The probability that our new mutation has no offspring is e*1 just as wfc saw with the previous calculation. If you jumped to the conclusion that this implies there was a hidden assumption in the previous approach that the number of offspring is Poisson-distrihutcd, you are correct! The second approach allows an immediate generalization to the case where the new mutation has a slight selective advantage accrued through A larger mean number of offspring. /J ■ 1 + st where s is small and positive* Now the probability' of no offspring is

where the final approximation uses the first tvo terms of the Taylor series expansion of f~*. The surprising aspect of this result is that mutations with a considerable selective advantage still have a significant probability of being lost in the first generation. For example» the probability of loss in a Single generation of an allele with a 1 % selective advantage (s = 0.01) is 0.99/e = 0.3642, which is very close to the probability* for a neutral allele I* = 0). Mont evolutionists would consider 1% selection to be very strong selection. The reason there is always a substantial probability that a new mutation is lost in a single generation is traceable to the assumption that the mean number of offspring per individual is close to 1- The probabilities of two. three» four, or more offspring must be balanced by the probability of zero offspring to keep the mean near 1. It should be obvious that the larger the variance in offspring number, the higher will be the probability of zero offspring. I have a strong preference for the second approach to the problem. The dynamics of mre alle­ les, including new mutations, arc essentially inde­ pendent of the size of the population* The contrary view is hard to defend: Why should the immediate fate of a new mutation be different in a population of 10,000 versus 10 million individuals? When allcles do become common, their dynamics are influ­ enced by the population size* We turn now to the fate of new mutations for more than the first generation. Figure 5.1 graphs the probability of ultimate extinction for neutral alleles and alleles with 2 % and 10% selective advantages over 100 generations* As is evident» the probability

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Stochastic Processes in Evolution

67

:00

50 Gererat^r

5.1. The probability Thar a new mutanon will have been lost by a particular generation* FIGURE

of extinction within the first few generations is remarkably similar among all three mutations. In particular; the probability of loss in the first gener­ ation is close to one third* as we already know* After a few generations, the extinction probabilities of advantageous mutations appears t o asymptote while that for the neutral allele continues on toward I . The fixation probability of the mutation with a 10% selective advantage is particularly striking as, even though this would be considered very strong selection, 8 0 % of the time rhis wonderful mutation is lost. As these extinction probabilities are among the most important quantities that we have in evolution* it is imponant to know how they were obtained* The curves in Figure 5.1 come from the theory of branching processes, which is beyond the scope of this chapter. Feller (1968) remains one of the clear­ est expositions of these processes ami is highly recommended. A derivation of the probability of ulti­ mate extinction, the asymptotic values in Figure 5.1, may be found in Box 5.1. There it is shown that the probability of ultimate survival of a new mutation with a selective advantage of s is approximately 2$toz* where « 1 . Thus, the probability that a new mutation will enter the popu­ lation in a particular generation and ultimately fix is 2NYj. We could call it a success when a new mutation arises that ultimately fixes in a particular generation and a failure when this doe* noi occur. This language shows that the time until the appear­ ance of the first mutation that ultimately fixes has a geometric distribution. That is, the probability that ihc origination time is i generations is 2Nrs\t ~ 2NrsY~\

69

This approach has one conspicuous peculiarity; Why should the selection coefficients of all ongin.it* mg mutations be the same* If a substitution increases the level of adaptation of a species, would not subse­ quent advantageous mutations have smaller selec­ tion coefficients? Kxplicif models of adaptive evolution from KisherS (1958) original geometric model up through O r r s (2002) recent work all have the property that a sequence of substituting alleles has decreasing selection coefficients. I See Box 5,2 lor a simulation of one of Orr's models,) In fact. they all have the property that evolution stagnates after a few substitutions either because the supply of advantageous mutations has been exhausted or because the selection coefficients become so small that originations fail to appear in an e v o l u t i o n a r y reasonable span of time. Under these models, evolution produces a small burst of substitutions and then . . . nothing. An intriguing aspect of these models is chat the number of substitutions in a burst is insensitive t o the mutation rate, population size, M\K\ selection coefficients, l o r example, in some of the models the mean depends on the loga­ rithm of the population size; in others ir is inde­ pendent of population sue (Gillespie 2002), box 5.2 shows how t o study some properties of a hurst using computer simulations. I'or continuous evolution we need only add one new element: a changing environment. If the envi­ ronment changes, a new hurst of substitutions can occur. We expect a similar burst of substi rut urns to follow each change in the environment. If A is the

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Principles of Evolutionary Genet IC5

70

Alan O r r (e.g., O r r 2002) has been w o r k i n g o n some fascinating properties o f a simple model o f adaptive e v o l u t i o n called the m u t a t i o n a l landscape model* Under this m o d e l , w c imagine rhac some allcle w i t h fitness w$ is currently fixed in the p o p u l a t i o n * Suppose that there are n alleles one m u t a t i o n a l step away f r o m the fixed allcle a n d that t h e fitnesses o f these n allclcs arc assigned at r a n d o m and independently f r o m the same p r o b a b i l i t y d i s t r i b u t i o n . (A n o r m a l d i s t r i b u t i o n w o r k s fine here*} T h e neighboring allc­ lcs arc labeled such that A} is the most fit allcle, Y is the next most fit* and so f o r t h . If selection is sufficiently s t r o n g , then only alleles that are m o r e fit t h a n the f i x e d alle­ les can themselves become fixed* The p r o b a b i l i t y that the « h allcle fixes is

-, J = l,2,*.*,m 5,+s2

.« + *_

if there happen t o be m allclcs that arc m o r e fit than t h e fixed allcle. I n this expression 5, = wt-u\x is just the selection coefficient o f the i t h allcle. T h u s , the p r o b a b i l i t y that a particular allcle fixes is p r o p o r t i o n a l t o its selection coefficient* as seems o b v i o u s . A s i m u l a t i o n o f this model begins w i t h n + 1 alleles w i t h r a n d o m fitnesses and the fixed allcle being the / t h most fit allcle. / should be viewed as a parameter o f the modcL Figure I shows the results o f 10 replicate evolutions o f the model w i t h n = 10,000, / = 2 0 , and fitnesses d r a w n f r o m a n o r m a l d i s t r i b u t i o n w i t h standard deviation 0 . 0 1 , N o t i c e that even t h o u g h there are 19 alleles that are m o r e fit t h a n the originally f i x e d allclcs, e v o l u t i o n usually (7 o u t o f 10 times) stops after one o r t w o substitutions. W h i l e , on average, the biggest j u m p in fitness occurs w i t h the first substitution, the repli­ cates show a great deal o f scatter in the fitnesses o f f i x e d allclcs*

0,05

0.045

i

004

0035

003

0.Q2S

2

Step FIGURE 1 . Ten trajectories f r o m the m u t a t i o n a l landscape m o d e l .

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Stochastic Processes in Evolution

BOX 5.2.

71

(cent.)

T h e p y t h o n a i d e (or ( h i * s i m u l a t i o n is below. Readers- are encouraged t o p i a \ a r o u n d w i t h the model and f i n d its properties. P y t h o n code for m u t a r i o n a l landscape s i m u l a t i o n front random import * f r o m math i m p o r t * randont_fitness - l a m b d a : gausstO.0,0.01) del titncss_array(w, n , rngh " R e t u r n s a list o f those allclcs m o r e fit rhan w " hetrcr_alleles = |\vj f o r i in xrangcln):

r = mgO if r > w : better_allclcs,appcndfr) bcncr_allelcs.sonO return bettcr_aHcles defchoosc_allc)c( fitnesses): " " R e t u r n s the i n d e x o f the f i x e d allele T h e first allele in fitnesses is the s t a n d a r d / " " * selection_eoe(s = [f - f i t n e s s o | 0 | l o r f in fitnesses] sum_sc ^ sum(sclection_eoefs) probabilities = [s I sum_sc (or s in selection_cotfs| running_sum - 0.0 r - random!) i 0 for p in probabilities: running_sum + = p if r u n n i n g sum > r: return i i

•

I

def e v o l u t i o n a l , «tart, r n g ) : initial_alleles - |rngO for i in x r a n g e ( n + D | initial_alleles.sorr(i allclcs ■ i n i t i a l allclcs|-siart:| n x e d _ a U e l c s M ( 0 , allclcs|0])l while lenialleta) > I : lixed_allele = (chwsc_alIele(allelcsM fixed_alleles,appendMfixed_allele T alldes|li*ed__allelc|)}

alleles = fiincs*_array(fixtd.alleles[-l][l| % n, rnj** return fixed alleles

rate o f change per generation in those aspects of

We have arrived at a rate o f substitution that is

rhe e n v i r o n m e n t t h a t affect o u r locus, then the rate

essentially independent o f the p o p u l a t i o n size, the

of substitution per generation is just the rate of

m u t a t i o n rare, and the strength o f selection and

change o f the e n v i r o n m e n t , K

about as different from o u r previous rate, p - 2Nvs^

times the mean

number o f f i x a t i o n s f o l l o w i n g a change,

as w e c o u l d imagine. There is n o consensus in p o p u ­ lation genetics a b o u t w h i c h race is better or, in fact, whether either is w o r c h v of o u r a t t e n t i o n ,

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72

Principles of Evolutionary Genetics

In this section wc have given a description of the stochastic dynamics of originations of advanta­ geous mutations. This is an important stochastic process not only because of its consequences for adaptation, but because of the hitchhiking of genome segments that invariably accompanies the substitu­ tion of a new mutation. In the next three sections wc will look at the stochastic forces that impact mutations once they leave the caldron and begin their sojourn in the realm of common alleles.

Genetic Drift The origins o f much of mathematical population genetics, including the stochastic theory, can be found in Fisher's monumental 1922 paper* In this paper. Fisher considers two models that incorpo­ rate randomness. The first appears in a treatment of the survival probability of "individual genes*1 as described previously. Fisher went on to treat "Factors not acted on by selection." and, in so doing, intro­ duced genetic drift t o population genetics: If p be the proportion of any gene, and q its allelomorph in a dimorphic factor, then in n individuals of any generation we have 2np genes scattered at random . . . Further, if a second generation of n individuals be now formed at random, the standard departure of p from its previous value will be

*Jpql2rt for a diploid population. The reason for using binomial sampling is not at all obvious or even plausible. In this section will we (1) illustrate the problem with binomial sampling, (2) show that Fisher's standard deviation is reasonable without binomial sampling, and (3) discuss some of the prop­ erties of genetic drift. The motivation for mathematical models of genetic drift is usually somewhat contrived. The hagof-marbles metaphor that is often used in teaching genetic drift is a wonderful device for learning rhc consequences of binomial sampling» but the biolog­ ical underpinnings are not at all clear. To see this, imagine a haploid population with two allcles, A\ and A ; , with frequencies p and q = I -p. If there are rV individuals in the population, then Np o f these will be A | and Nq will be A2* To form the next gener­ ation, we imagine that the number of offspring for each individual is chosen at random from the same probability distribution. 1 ct the number of offspring from the i t h At be X, and from the ith A» be Y r The allele frequency in the next generation will be

Number of A{ offspring

X

Total number of offspring

X + Y

where X = Xl+X2+..,+XNf Y = Yl+Y1

o\ ■ He went on t o conclude that the rate of loss o f genetic variation is 1/4«. (Later, Sewall Wright corrected this result t o 1/2«.) The loss of genetic variation due to this "Hagcdoorn effect" he thought was insignificant: As few specific groups contain less than 10,000 individuals between whom interbreeding takes place, the period required for the action of the Hagedoorn effect, in the entire absence of muta­ tion, is immense» Curiously, Fisher does not motivate or attempt to justify his assertion that the "standard departure of p' is yfpqfln. (Standard departure is an old name for standard deviation.) Today, we typi­ cally model genetic drift with binomial sampling and from this obtain a standard deviation of

+

.„+Vwr

The bag-of-marbles metaphor suggests that the distribution of the number of / \ ( allcles in the next generation, J, is the binomial distribution

Pro b{x^

= (yW-'.

But why? in our model, the number of Ax indi­ viduals in the next generation is called X and its distribution can be that of any positive integer-valued random variable. For example, X could have a geometric, negative binomial, Poisson, or some other distribution. And why should the total number of individuals, X + Y, be N? In fact, a binomial distri­ bution is only appropriate when two conditions arc met: The total number of offspring is set at some fixed number and the distributions of X and Y are Poisson. Biologically, we are in trouble because stud­ ies of offspring distributions in natural populations

Stochastic P r o c e w s in Evolution

seldom* if ever, find Poisson distributions. In general, the variance in the number of offspring is larger than the mean. The idea of fixing the total number of offspring at N before forming the next generation is strange as well. Population sizes of most species fluctuate significantly over relatively small numbers of generations, In our model, that fluctuation is embodied by the distribution of X + Y, which cannot be set at a fixed number N without disrupting the biological appeal of the model* Docs this mean that genetic drift is a flawed concept? Nut at all; it only means thai binomial sampling is not a good mirror of the demography of natural populations. Fortunately, much of theo­ retical population genetics does not deal directly with the binomial distribution but uses large N approx­ imations such as diffusion models. For these* ihe binomial distribution is only used to obtain the variance ot p\ which can be obtained directly with­ out any reference to a binomial distribution. To see this* first rewrite p ' a s

X-E{X} E[XL X-E\X}*Y-E{Y) 1+

E{X]

? = E(x}.f:{v|

E{X) + £{V1 (5.4) where the notation E\X] refers to the expected value (or mean I of X. An application of the delta method of statistics will allow us to obtain useful approximations of p\ Toward this end, define

X-EJXJ

ind

• *y

X-E{X} + Y-ti{Y) h{X\+E{Y)

(The 8s are small when N is large because of the law of large numbers.) Note that H| 1/2N. As .1 consequence, the a m o u n t o f

genetic v a r i a t i o n .it the neutral locus w i l l also even­ tually

decrease w i t h increasing p o p u l a t i o n size.

11

Random Environments 1 he last stochastic process TO be discussed is selec­

A n y o n e familiar w i t h genetic d r i f t w i l l recoil f r o m

t i o n in a r a n d o m environment. O u r goal is not t o

the idea t h a t neutral v a r i a t i o n can decrease w i t h

give an extensive treatment of this rich area, but

increasing p o p u l a t i o n size. T h e reason tor tins i*

rather t o give a few simple results that can l>e used

that the rate o f hitchhiking is increasing w i t h increas­

t o c o m p a r e the role o f this source o f randomness

ing p o p u l a t i o n size ( p = 4Nvs)

a n d , as a conse­

w i t h those discussed earlier. All o u r w o r k w i l l focus

quence. neutral v a r i a t i o n is reduced* T h e nature of

o n a two-nllelc, a d d i t i v e d i p l o i d model in w h i c h the

the f u n c t i o n a l relationship between p and N

fitnesses of the three genotypes are:

in

e v o l u t i o n is not at all clear A l t h o u g h w e frequently use p ^ 4Nvs

in discussions o f adaptive e v o l u t i o n ,

AtA}

this may w e l l he a p o o r choice as the underlying

U U ,

model is so at variance w i t h o u r usual notions of

A , ^

A ^

l+|U, +V,)/2

l + V/

adaptive evolution. It is clear that w e cannot under* stand the relationship between neutral variation and

Assume that the selection coefficients (.'. and V,

p o p u l a t i o n size w i t h o u t k n o w i n g m o r e about p.

change at r a n d o m t h r o u g h t i m e and that their

relationship

values in a particular generation arc independent o f

between p and \ \ o u r results on genetic draft suggest

all values in previous generations. That is, assume

that levels o f genetic v a r i a t i o n w i l l not necessarily

t h a t \it and V, are not autocorrelated. If p is the

show a s t r o n g dependency on p o p u l a t i o n size. This

frequency o f the \ \ allele, then the change in its

is a g o o d t h i n g as one conspicuous c o n u n d r u m in

frequency in a single generation is

No

matter

what

the functional

p o p u l a t i o n genetics has been that o u r drift-based theories predict a strong dependency of level* o f v a r i ­

Ap

ation on population size but observations generally show a weak dependency at best. This is often called

2l + p ( t/ ( +