PRINCIPLES OF

POPULATION
GENETICS
FOURTH EDITION

Daniel L. Hartl
Harvard University
Andrew G. Clark
Cornell University

UniversitSts- und Landes-

bibliothek Darmstadt
Bibliothek Biologie
Sinauer Associates, Inc. Publishers
Sunderland, Massachusetts
TABLE OF CONTENTS

PREFACE xii

1 GENETIC AND PHENOTYPIC VARIATION 3

1.1 RELEVANCE OF POPULATION GENETICS 4 Allele Frequencies and Genotype
Frequencies 18
1.2 PHENOTYPIC VARIATION IN NATURAL Polymorphism and Heterozygosity 20
POPULATIONS 5 Allozyme Polymorphisms 21
Continuous Variation: The Normal Inferences from Allozyme
Distribution 5 Polymorphisms 23
Mean and Variance 6
1.6 POLYMORPHISMS IN DNA
The Central Limit Theorem 8
SEQUENCES 25
Discrete Mendelian Variation 10
Restriction Enzymes 25
1.3 MULTIPLE-FACTOR INHERITANCE 12 The Polymerase Chain Reaction 28
1.4 MAINTENANCE OF GENETIC Single Nucleotide Polymorphisms 32
VARIATION 14
Synonymous and Nonsynonymous
Polymorphisms 32
1.5 MOLECULAR POPULATION GENETICS 15 Segregating Sites and Nucleotide
Electrophoresis 16 Mismatches 34
1.7 UTILITY OF GENETIC POLYMORPHISMS 38
 Contents vii

2 ORGANIZATION OF GENETIC VARIATION 45

2.1 RANDOM MATING 46 2.4 EXTENSIONS OF THE HARDY-WEINBERG
Nonoverlapping Generations 47 PRINCIPLE 67
Three or More Alleles 67
2.2 THE HARDY-WEINBERG PRINCIPLE 48
X-Linked Genes 70
Random Mating of Genotypes versus
Random Union of Gametes 50 2.5 LINKAGE AND LINKAGE
Implications of the Hardy-Weinberg DISEQUILIBRIUM 7 3
Principle 52 Difficulties in Testing for Linkage
2.3 TESTING FOR HARDY-WEINBERG Equilibrium 82
EQUILIBRIUM 54 Relative Measures of Linkage
Difficulties in Testing for Hardy-Weinberg Disequilibrium: D' and rs 83
Equilibrium 54 2.6 CAUSES OF LINKAGE
Complications of Dominance 62 DISEQUILIBRIUM 8 4
Frequency of Heterozygotes 66 Linkage Disequilibrium Due to Population
Admixture 85
Linkage Disequilibrium Due to Reduced
Recombination 86

3 RANDOM GENETIC DRIFT 95

3.1 RANDOM GENETIC DRIFT AND Unequal Sex Ratio, Sex Chromosomes,
BINOMIAL SAMPLING 95 Organelle Genes 123
Variance in Offspring Number 126
3.2 THE WRIGHT-FISHER MODEL OF
Effective Size of a Subdivided
RANDOM GENETIC DRIFT 102 Population 127
3.3 THE DIFFUSION APPROXIMATION 105 3.6 GENE TREES AND COALESCENCE 128
An Approach Looking Forward 106 Coalescent Effective Size 133
An Approach Looking Backward 11O Coalescence with Population Growth 134
Absorption Time and Time Coalescent Models with Mutation 136
to Fixation 112 Applications of Coalescent Methods 137
3.4 RANDOM DRIFT IN A SUBDIVIDED 3.7 THEORETICAL IMPLICATIONS OF
POPULATION 113 COALESCENCE 138
3.5 EFFECTIVE POPULATION SIZE 121 Coalescent Models with
Fluctuation in Population Size 121 Recombination 14O
Linkage Disequilibrium Mapping 143

4 MUTATION AND THE NEUTRAL THEORY 151

4.1 MUTATION 151 4.3 THE NEUTRAL THEORY OF MOLECULAR
Irreversible Mutation 152 EVOLUTION 161
Reversible Mutation 156 4.4 THE INFINITE-ALLELES MODEL 162
4.2 MUTATION AND RANDOM GENETIC The Ewens Sampling Formula 166
DRIFT 158 The Ewens-Watterson Test 168
Probability of Fixation of a New Neutral
Mutation 160
viii Contents

4.5 INFINITE-SITES MODEL 172 4.6 MUTATION AND RECOMBINATION 182

Nucleotide Polymorphism and Nucleotide A Model for the Evolutionary Benefit of
Diversity 175 Recombination 183
Tajima's D Statistic 176 Muller's Ratchet 185
The Fu and Li Test of Fit to Neutral Piecewise Recombination in Bacteria 187
Coalescence 178 Animal Mitochondrial DNA 189

5 DARWINIAN SELECTION 199

5.1 SELECTION IN HAPLOID 5.5 MORE COMPLEX TYPES OF
ORGANISMS 200 SELECTION 229
Discrete Generations 2OO Differential Selection in the Sexes 229
Continuous Time 204 X-Linked Genes 230
Change in Allele Frequency in Haploids 205 Frequency-Dependent Selection 230
Darwinian Fitness and Malthusian Density-Dependent Selection 231
Fitness 206 Fecundity Selection 231
5.2 SELECTION IN DIPLOID ORGANISMS 206 Age-Structured Populations 232
Heterogenous Environments and
Change in Allele Frequency in Diploids 208
Clines 232
Marginal Fitness and Selection with
Diversifying Selection 534
Multiple Alleles 212
Gametic Selection 236
Application to the Evolution of Insecticide
Meiotic Drive 236
Resistance 215
Multiple Loci and Gene Interaction:
5.3 EQUILIBRIA WITH SELECTION 215
Epistasis 239
Overdominance 216 Evolution of Recombination Rate 241
Local Stability 220 Sexual Selection 241
Heterozygote Inferiority 222 Kin Selection 243
Stable Equilibria with Multiple Alleles 223
Adaptive Topography and the Role of 5.6 INTERDEME SELECTION IN
Random Genetic Drift 225 GEOGRAPHICALLY SUBDIVIDED
POPULATIONS 245
5.4 MUTATION-SELECTION BALANCE 226
Equilibrium Allele Frequencies 226 5.7 SELECTION IN A FINITE POPULATION 248
The Haldane-Muller Principle 228 Weak Selection and the Nearly
Neutral Theory 248
Genetic "Draft" 251

6 INBREEDING, POPULATION SUBDIVISION,

AND MIGRATION 257
6.1 INBREEDING 257 6.2 POPULATION SUBDIVISION 275
The Inbreeding Coefficient 258 Reduction in Heterozygosity Due to
Genotype Frequencies with Inbreeding 259 Population Subdivision 276
Genetic Effects of Inbreeding 265 Average Heterozygosity 278
Calculation of the Inbreeding Coefficient Wright's F Statistics 281
from Pedigrees 268 Linanthus Revisited: Evidence for Selection
Regular Systems of Mating 272 Associated with Flower Color 285
 Contents ix

Inference of Population Structure from 6 . 4 ASSORTATIVE MATING 2 9 4

Multilocus Genotype Data 286
6.5 MIGRATION 2 9 5
6.3 THE WAHLUND PRINCIPLE 288
One-Way Migration 295
Wahlund's Principle and the Fixation
The Island Model of Migration 297
Index 291 •
How Migration Limits Genetic
Genotype Frequencies in Subdivided
Populations 291 Divergence 299
Relation between the Inbreeding Coefficient Estimates of Migration Rates 303
and the F Statistics 293 Coalescence-Based Estimates of
Migration 303
Migration-Selection Balance 307

7 MOLECULAR POPULATION GENETICS 317

7.1 THE NEUTRAL THEORY AND 7.5 POLYMORPHISM AND DIVERGENCE
MOLECULAR EVOLUTION 3 1 8 IN NUCLEOTIDE SEQUENCE—
Theoretical Principles of the Neutral THE MCDONALD-KREITMAN AND
Theory 318 HKA TESTS 3 5 1
7.2 ESTIMATING RATES OF MOLECULAR Polymorphism and Divergence in
SEQUENCE DIVERGENCE 3 2 1 Noncoding Sequences 354
Rates of Amino Acid Replacement 322 Impact of Local Recombination Rates 354
Rates of Nucleotide Substitution 326 Substitution Models for Structural RNA
Statistical Fitting of Nucleotide Substitution Genes 356
Models 329 7.6 GENE GENEALOGIES 358

7.3 THE MOLECULAR CLOCK 329 Hypothesis Testing Using Trees 358
Variation among Genes in the Rate of the 7 . 7 MlTOCHONDRIAL AND CHLOROPLAST
Molecular Clock 332 DNA EVOLUTION 362
Variation across Lineages in Clock Chloroplast DNA and Organelle
Rate 334 Transmission in Plants 363
The Generation-Time Effect 337 Maintenance of Variation in Organelle
The Overdispersed Molecular Clock and Genomes 364
the Neutral Theory 338 Evidence for Selection in mtDNA 365
The Nearly Neutral Theory 339
7.8 MOLECULAR PHYLOGENETICS 366
7.4 PATTERNS OF NUCLEOTIDE AND AMINO
Algorithms for Phylogenetic Tree
ACID SUBSTITUTION 3 4 0 Reconstruction 366
Calculating Synonymous and Non- Distance Methods versus Parsimony 369
synonymous Substitution Rates 34O Bootstrapping and Statistical Confidence
Codon Substitution Models 343 in a Tree 370
Observations of Synonymous and
Bayesian Methods 370
Nonsynonymous Substitution Rates 345
Trans-Species Polymorphism 371
Polymorphism within Species 347
7.9 MULTIGENE FAMILIES 3 7 2
Implications of Codon Usage Bias 349
Concerted Evolution 374
Subfunctionalization 375
Birth-and-Death Process 376
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8 EVOLUTIONARY QUANTITATIVE GENETICS 385

8.1 TYPES OF QUANTITATIVE TRAITS 387 8.7 NORM OF REACTION, THRESHOLD TRAITS,
AND GENETIC CORRELATION 433
8.2 RESEMBLANCE BETWEEN RELATIVES AND
Norm of Reaction and Phenotypic
THE CONCEPT OF HERITABILITY 388
Plasticity 433
8.3 ARTIFICIAL SELECTION AND REALIZED Threshold Traits: Genes as Risk Factors
HERITABILITY 394 in Disease 437
Contribution of New Mutations to the Genetic Correlation and Correlated
Response to Selection 396 Response 439
Prediction Equation for Individual 8.8 EVOLUTIONARY QUANTITATIVE
Selection 397 GENETICS 4 4 3
Limits to Selection 400 Inference of Selection from Phenotypic
8.4 GENETIC MODELS FOR QUANTITATIVE Data 443
TRAITS 4 0 3 Evolution of Multiple Intercorrelated
Traits 444
Change in Allele Frequency 412
Random Genetic Drift and Phenotypic
Change in Mean Phenotype 413 Evolution 446
Linearity of Response 415 Mutational Variance and Mutation-
8.5 COMPONENTS OF PHENOTYPIC Accumulation Experiments 448
VARIANCE 4 1 6 Mutation-Selection Balance for
Quantitative Traits 449
Genetic and Environmental Sources of
Variation 416 8.9 GENES THAT AFFECT QUANTITATIVE
Components of Genotypic Variation 422 TRAITS 4 5 2
8 . 6 COVARIANCE AMONG RELATIVES 4 2 6 The Number of Genes Affecting
Quantitative Traits 453
Twin Studies and Inferences of Heritability
in Humans 430 Methods for Mapping QTLs 455
Estimation of Genetic Variance Components
in Natural Populations 432

9 POPULATION GENOMICS 469

9.1 EVOLUTION OF GENOME SIZE Decline of Linkage Disequilibrium with
AND COMPOSITION 4 7 0 Genetic Distance 483
Organismic Complexity and the C-Value 9.3 DIFFERENCES BETWEEN SPECIES 484
. Paradox 470 Comparison of Nonsynonymous and
Base Composition of Genomic DNA 471 Synonymous Divergence 484
9.2 GENOME-WIDE PATTERNS OF Positive Selection 486
POLYMORPHISM 4 7 3 Exploiting a Phylogenetic Signal 487
Excess Polymorphism in Subtelomeric Polymorphism and Divergence 487
Regions 473 Compensated Pathogenic
Deviations 489
Polymorphism and Rates of
Structure-Function Analysis 491
Recombination 475
Hitchhiking versus Background 9.4 SEXUAL SELECTION AND THE SEX
Selection 477 CHROMOSOMES 492
Linkage Disequilibrium and Haplotype Faster-Male Molecular Evolution 493
Structures 481
 Contents xi

Molecular Evolution of Genes in the, Factors Controlling the Population

X Chromosome 495 Dynamics of Transposable
Haldane's Rule 495 Elements 5O1
Demasculinization of the Insertion Sequences and Composite
X Chromosome 497 Transposons in Bacteria 502
9.5 TRANSPOSABLE ELEMENTS 498 Transposable Elements in Eukaryotes 505
Diverse Types of Transposable Population Dynamics of Transposable
Elements 498 Elements 505
Nonuniformity of Transposition Rates 506
Horizontal Transmission of Transposable
Elements 511

10 HUMAN POPULATION GENETICS 519

10.1 HUMAN POLYMORPHISM 520 Linkage Disequilibrium in Admixed
Public SNP Resources and the HapMap Populations: Admixture Mapping 544
Project 521 Inbred Populations and Homozygosity
Mapping 544
10.2 POPULATION GENETIC INFERENCES
FROM HUMAN S N P S 524 10.5 MENDELIAN DISEASE AND
POPULATION GENETICS 547
Ascertainment Bias of SNP
Genotypes 524 Mutation-Selection Balance 548
Departures from Hardy-Weinberg ' Dating the Origin of Mutant Alleles 548
Frequencies 527 10.6 GENETIC BASIS FOR VARIATION IN
Site Frequency Spectrum and Human RISK OF COMPLEX DISEASE 550
Population Growth 527 Mapping Methods Based on Linkage 55O
Rooting Human Polymorphism 529 Linkage Disequilibrium Mapping 552
Inference of Inhomogeneities in the Genome-Wide Association Studies 553
Mutation Process 530
10.7 SEEKING SIGNATURES OF HUMAN-
Inferences about Male and Female
SPECIFIC GENETIC ADAPTATIONS
Mutation Rates 531
554
10.3 LINKAGE DISEQUILIBRIUM ACROSS THE
HUMAN GENOME 532
Interspecific Divergence 554
The Landscape of Human Linkage McDonald-Kreitman and Poisson
Disequilibrium 532 Random Field Tests 555
Inferences about Local Rates of Local Distortions in Linkage
Recombination 537 Disequilibrium 556
10.4 POPULATION STRUCTURE INFERRED FST Tests 557
FROM HUMAN POLYMORPHISM 539 Genome Scans for Selection-Skewed
Multilocus Methods of Inference of Site Frequency Spectrum 557
' Stratification 540 10.8 HUMAN ORIGINS 558
Heterogeneity in Linkage Disequilibrium Neanderthal Genome Sequence 562
across Human Populations 542

ANSWERS TO CHAPTER-END PROBLEMS 567 AUTHOR INDEX 629

BIBLIOGRAPHY 597 SUBJECT INDEX 635