Genetic constraints on adaptation: a theoretical primer for the genomics era

Genetic constraints are features of inheritance systems that slow or prohibit adaptation. Several population genetic mechanisms of constraint have received sustained attention within the field since they were first articulated in the early 20th century. This attention is now reflected in a rich, and still growing, theoretical literature on the genetic limits to adaptive change. In turn, empirical research on constraints has seen a rapid expansion over the last two decades in response to changing interests of evolutionary biologists, along with new technologies, expanding data sets, and creative analytical approaches that blend mathematical modeling with genomics. Indeed, one of the most notable and exciting features of recent progress in genetic constraints is the close connection between theoretical and empirical research. In this review, we discuss five major population genetic contexts of genetic constraint: genetic dominance, pleiotropy, fitness trade‐offs between types of individuals of a population, sign epistasis, and genetic linkage between loci. For each, we outline historical antecedents of the theory, specific contexts where constraints manifest, and their quantitative consequences for adaptation. From each of these theoretical foundations, we discuss recent empirical approaches for identifying and characterizing genetic constraints, each grounded and motivated by this theory, and outline promising areas for future work.

[1]  D. Bachtrog,et al.  Y-chromosome evolution: emerging insights into processes of Y-chromosome degeneration , 2013, Nature Reviews Genetics.

[2]  Claudia Bank,et al.  A systematic survey of an intragenic epistatic landscape , 2014, bioRxiv.

[3]  R. Lewontin The Genetic Basis of Evolutionary Change , 1974 .

[4]  J. Hadfield,et al.  DIRECTIONAL SELECTION IN TEMPORALLY REPLICATED STUDIES IS REMARKABLY CONSISTENT , 2012, Evolution; international journal of organic evolution.

[5]  Philipp W. Messer,et al.  Evidence that Adaptation in Drosophila Is Not Limited by Mutation at Single Sites , 2010, PLoS genetics.

[6]  J. B. S. Haldane,et al.  The Effect of Variation of Fitness , 1937, The American Naturalist.

[7]  J. Welch,et al.  Fisher’s Microscope and Haldane’s Ellipse , 2005, The American Naturalist.

[8]  T. Lenormand,et al.  A GENERAL MULTIVARIATE EXTENSION OF FISHER'S GEOMETRICAL MODEL AND THE DISTRIBUTION OF MUTATION FITNESS EFFECTS ACROSS SPECIES , 2006, Evolution; international journal of organic evolution.

[9]  T. Prout,et al.  Antagonistic Pleiotropy, Reversal of Dominance, and Genetic Polymorphism , 1994, The American Naturalist.

[10]  L. Rowe,et al.  The Effect of Sexual Selection on Offspring Fitness Depends on the Nature of Genetic Variation , 2012, Current Biology.

[11]  B. Charlesworth,et al.  Effective Population Size and the Faster-X Effect: An Extended Model , 2009, Evolution; international journal of organic evolution.

[12]  Marcel Dicke,et al.  Plant interactions with multiple insect herbivores: from community to genes. , 2014, Annual review of plant biology.

[13]  D. Bolon,et al.  Experimental illumination of a fitness landscape , 2011, Proceedings of the National Academy of Sciences.

[14]  A. Kondrashov,et al.  Classification of hypotheses on the advantage of amphimixis. , 1993, The Journal of heredity.

[15]  H. A. Orr,et al.  Does diploidy increase the rate of adaptation? , 1994, Genetics.

[16]  D. Aanen,et al.  The costs of being male: are there sex-specific effects of uniparental mitochondrial inheritance? , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[17]  J. Conner Genetic mechanisms of floral trait correlations in a natural population , 2002, Nature.

[18]  Matthew W. Hahn,et al.  Reanalysis suggests that genomic islands of speciation are due to reduced diversity, not reduced gene flow , 2014, Molecular ecology.

[19]  M. Kimura Attainment of Quasi Linkage Equilibrium When Gene Frequencies Are Changing by Natural Selection. , 1965, Genetics.

[20]  M. Kirkpatrick,et al.  Chromosome Inversions, Local Adaptation and Speciation , 2017, Genetics.

[21]  J. Haldane A Mathematical Theory of Natural Selection. Part VIII. Metastable Populations , 1931, Mathematical Proceedings of the Cambridge Philosophical Society.

[22]  A. Barbadilla,et al.  Adaptive Evolution Is Substantially Impeded by Hill–Robertson Interference in Drosophila , 2015, Molecular biology and evolution.

[23]  J. Gillespie The causes of molecular evolution , 1991 .

[24]  J. Stinchcombe,et al.  How much do genetic covariances alter the rate of adaptation? , 2009, Proceedings of the Royal Society B: Biological Sciences.

[25]  L. Knowles,et al.  Recombination rate and protein evolution in yeast , 2007, BMC Evolutionary Biology.

[26]  S. Otto,et al.  Two steps forward, one step back: the pleiotropic effects of favoured alleles , 2004, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[27]  H. Levene,et al.  Genetic Equilibrium When More Than One Ecological Niche is Available , 1953, The American Naturalist.

[28]  M. Blows,et al.  Evolutionary Constraints in High-Dimensional Trait Sets , 2014, The American Naturalist.

[29]  S. Yeaman Genomic rearrangements and the evolution of clusters of locally adaptive loci , 2013, Proceedings of the National Academy of Sciences.

[30]  H. A. Orr,et al.  The rate of adaptation in asexuals. , 2000, Genetics.

[31]  B. Charlesworth,et al.  Rapid fixation of deleterious alleles can be caused by Muller's ratchet. , 1997, Genetical research.

[32]  H. A. Orr,et al.  Haldane's sieve and adaptation from the standing genetic variation. , 2001, Genetics.

[33]  Nigel F. Delaney,et al.  Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins , 2006, Science.

[34]  L. Hurst,et al.  Protein Rates of Evolution Are Predicted by Double-Strand Break Events, Independent of Crossing-over Rates , 2009, Genome biology and evolution.

[35]  Alex Wong,et al.  Evolution of protein-coding genes in Drosophila. , 2008, Trends in genetics : TIG.

[36]  W. E. Ritter AS TO THE CAUSES OF EVOLUTION. , 1923, Science.

[37]  S. Otto,et al.  Polyploid incidence and evolution. , 2000, Annual review of genetics.

[38]  E. Pollak,et al.  On the theory of partially inbreeding finite populations. I. Partial selfing. , 1988, Genetics.

[39]  Matthew Hall,et al.  Direct selection on male attractiveness and female preference fails to produce a response , 2004, BMC Evolutionary Biology.

[40]  B. Charlesworth,et al.  The effect of deleterious mutations on neutral molecular variation. , 1993, Genetics.

[41]  D. Presgraves,et al.  Recombination Enhances Protein Adaptation in Drosophila melanogaster , 2005, Current Biology.

[42]  Matthew Hartfield,et al.  Current hypotheses for the evolution of sex and recombination. , 2012, Integrative zoology.

[43]  J. D. Fry THE GENOMIC LOCATION OF SEXUALLY ANTAGONISTIC VARIATION: SOME CAUTIONARY COMMENTS , 2009, Evolution; international journal of organic evolution.

[44]  R. Lenski,et al.  The fate of competing beneficial mutations in an asexual population , 2004, Genetica.

[45]  M Slatkin,et al.  Fisher's fundamental theorem of natural selection. , 1992, Trends in ecology & evolution.

[46]  G. Arnqvist,et al.  INTRALOCUS SEXUAL CONFLICT AND ENVIRONMENTAL STRESS , 2014, Evolution; international journal of organic evolution.

[47]  D. J. Merrell Limits on heterozygous advantage as an explanation of polymorphism. , 1969, The Journal of heredity.

[48]  A. Clark,et al.  The Resolution of Sexual Antagonism by Gene Duplication , 2011, Genetics.

[49]  Troy Day,et al.  A Biologist's Guide to Mathematical Modeling in Ecology and Evolution , 2007 .

[50]  W. Rice SEX CHROMOSOMES AND THE EVOLUTION OF SEXUAL DIMORPHISM , 1984, Evolution; international journal of organic evolution.

[51]  C. Pál,et al.  Does the recombination rate affect the efficiency of purifying selection? The yeast genome provides a partial answer. , 2001, Molecular biology and evolution.

[52]  Thomas Lenormand,et al.  Distributions of epistasis in microbes fit predictions from a fitness landscape model , 2007, Nature Genetics.

[53]  T. Lenormand The evolution of sex dimorphism in recombination. , 2003, Genetics.

[54]  M. Kirkpatrick,et al.  Y Fuse? Sex Chromosome Fusions in Fishes and Reptiles , 2015, PLoS genetics.

[55]  Arlin Stoltzfus,et al.  Modeling Evolution Using the Probability of Fixation: History and Implications , 2014, The Quarterly Review of Biology.

[56]  George C. Williams,et al.  PLEIOTROPY, NATURAL SELECTION, AND THE EVOLUTION OF SENESCENCE , 1957, Science of Aging Knowledge Environment.

[57]  H. Om,et al.  Does Diploidy Increase the Rate of Adaptation ? , 2022 .

[58]  S. Otto,et al.  Evolution of sex: Resolving the paradox of sex and recombination , 2002, Nature Reviews Genetics.

[59]  M. Jennions,et al.  EXPERIMENTAL EVIDENCE FOR MULTIVARIATE STABILIZING SEXUAL SELECTION , 2005, Evolution; international journal of organic evolution.

[60]  Nicholas H. Barton,et al.  The Relative Rates of Evolution of Sex Chromosomes and Autosomes , 1987, The American Naturalist.

[61]  Gideon S. Bradburd,et al.  Finding the Genomic Basis of Local Adaptation: Pitfalls, Practical Solutions, and Future Directions , 2016, The American Naturalist.

[62]  Olivier Tenaillon,et al.  Quantifying Organismal Complexity using a Population Genetic Approach , 2007, PloS one.

[63]  Brian Charlesworth,et al.  The Effects of Deleterious Mutations on Evolution at Linked Sites , 2012, Genetics.

[64]  Richard A. Watson,et al.  PERSPECTIVE:SIGN EPISTASIS AND GENETIC CONSTRAINT ON EVOLUTIONARY TRAJECTORIES , 2005 .

[65]  B. Charlesworth,et al.  Evolution on the X chromosome: unusual patterns and processes , 2006, Nature Reviews Genetics.

[66]  P. Rydén,et al.  The shared genome is a pervasive constraint on the evolution of sex-biased gene expression. , 2013, Molecular biology and evolution.

[67]  A. Clark,et al.  SEX LINKAGE, SEX‐SPECIFIC SELECTION, AND THE ROLE OF RECOMBINATION IN THE EVOLUTION OF SEXUALLY DIMORPHIC GENE EXPRESSION , 2010, Evolution; international journal of organic evolution.

[68]  G. Wagner,et al.  The pleiotropic structure of the genotype–phenotype map: the evolvability of complex organisms , 2011, Nature Reviews Genetics.

[69]  A. Clark,et al.  Evolutionary inevitability of sexual antagonism , 2014, Proceedings of the Royal Society B: Biological Sciences.

[70]  L. Cook The Genetical Theory of Natural Selection — A Complete Variorum Edition , 2000, Heredity.

[71]  G. Price Fisher's ‘fundamental theorem’ made clear , 1972, Annals of human genetics.

[72]  H. Ellegren,et al.  Genome-wide association mapping in a wild avian population identifies a link between genetic and phenotypic variation in a life-history trait , 2015, Proceedings of the Royal Society B: Biological Sciences.

[73]  C. Zeyl,et al.  An Evolutionary Advantage of Haploidy in Large Yeast Populations , 2003, Science.

[74]  W. G. Hill,et al.  The effect of linkage on limits to artificial selection. , 1966, Genetical research.

[75]  M. Nowak,et al.  Stochastic Tunnels in Evolutionary Dynamics , 2004, Genetics.

[76]  Jianzhi Zhang,et al.  Genomic patterns of pleiotropy and the evolution of complexity , 2010, Proceedings of the National Academy of Sciences.

[77]  F. B. Christiansen Hard and Soft Selection in a Subdivided Population , 1975, The American Naturalist.

[78]  Richard Gomulkiewicz,et al.  Demographic and Genetic Constraints on Evolution , 2009, The American Naturalist.

[79]  M. Feldman,et al.  Evolutionary traction: the cost of adaptation and the evolution of sex , 2005, Journal of evolutionary biology.

[80]  A. Betancourt,et al.  Linkage limits the power of natural selection in Drosophila , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[81]  S. Otto,et al.  Haploids adapt faster than diploids across a range of environments , 2011, Journal of evolutionary biology.

[82]  O. Tenaillon,et al.  The Utility of Fisher's Geometric Model in Evolutionary Genetics. , 2014, Annual review of ecology, evolution, and systematics.

[83]  D. Houle,et al.  Measuring and comparing evolvability and constraint in multivariate characters , 2008, Journal of evolutionary biology.

[84]  D. Houle,et al.  PROPERTIES OF SPONTANEOUS MUTATIONAL VARIANCE AND COVARIANCE FOR WING SIZE AND SHAPE IN DROSOPHILA MELANOGASTER , 2013, Evolution; international journal of organic evolution.

[85]  W J Ewens,et al.  An interpretation and proof of the Fundamental Theorem of Natural Selection. , 1989, Theoretical population biology.

[86]  A. Robertson,et al.  The genetic control of sex ratio , 1966 .

[87]  P. Phillips Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems , 2008, Nature Reviews Genetics.

[88]  J. Peck A ruby in the rubbish: beneficial mutations, deleterious mutations and the evolution of sex. , 1994, Genetics.

[89]  D. Haig,et al.  FITNESS VARIATION DUE TO SEXUAL ANTAGONISM AND LINKAGE DISEQUILIBRIUM , 2010, Evolution; international journal of organic evolution.

[90]  Tyler N. Starr,et al.  Epistasis in protein evolution , 2016, Protein science : a publication of the Protein Society.

[91]  N. Barton,et al.  PERSPECTIVE: A CRITIQUE OF SEWALL WRIGHT'S SHIFTING BALANCE THEORY OF EVOLUTION , 1997, Evolution; international journal of organic evolution.

[92]  B. Charlesworth,et al.  The relations between recombination rate and patterns of molecular variation and evolution in Drosophila. , 2014, Annual review of genetics.

[93]  Daniel B. Weissman,et al.  The Rate of Fitness-Valley Crossing in Sexual Populations , 2010, Genetics.

[94]  R. Lande Risk of population extinction from fixation of deleterious and reverse mutations , 2004, Genetica.

[95]  T. Nagylaki Selection in dioecious populations , 1979, Annals of human genetics.

[96]  M. Kirkpatrick Patterns of quantitative genetic variation in multiple dimensions , 2009, Genetica.

[97]  R. Punnett,et al.  The Genetical Theory of Natural Selection , 1930, Nature.

[98]  Crispin Y Jordan,et al.  Accumulation of Deleterious Mutations Near Sexually Antagonistic Genes , 2016, G3: Genes, Genomes, Genetics.

[99]  P. D. de Bakker,et al.  Negative selection in humans and fruit flies involves synergistic epistasis , 2016, Science.

[100]  W. G. Hill,et al.  On the Pleiotropic Structure of the Genotype–Phenotype Map and the Evolvability of Complex Organisms , 2012, Genetics.

[101]  E. Dempster Maintenance of genetic heterogeneity. , 1955, Cold Spring Harbor symposia on quantitative biology.

[102]  D. Coltman,et al.  SEX‐SPECIFIC GENETIC VARIANCE AND THE EVOLUTION OF SEXUAL DIMORPHISM: A SYSTEMATIC REVIEW OF CROSS‐SEX GENETIC CORRELATIONS , 2010, Evolution; international journal of organic evolution.

[103]  M. Kimura,et al.  An introduction to population genetics theory , 1971 .

[104]  S. Otto,et al.  Loss-of-heterozygosity facilitates passage through Haldane’s sieve for Saccharomyces cerevisiae undergoing adaptation , 2014, Nature Communications.

[105]  Michael J. Wade,et al.  The Evolutionary Origin And Elaboration Of Sociality In The Aculeate Hymenoptera: Maternal Effects, Sib‐social Effects, And Heterochrony , 2005, The Quarterly Review of Biology.

[106]  J. Felsenstein The theoretical population genetics of variable selection and migration. , 1976, Annual review of genetics.

[107]  P. Pye-Smith The Descent of Man, and Selection in Relation to Sex , 1871, Nature.

[108]  A. Carter,et al.  Evolution of functionally conserved enhancers can be accelerated in large populations: a population–genetic model , 2002, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[109]  B. Charlesworth,et al.  Population genetics from 1966 to 2016 , 2016, Heredity.

[110]  R. Meisel,et al.  The faster-X effect: integrating theory and data. , 2013, Trends in genetics : TIG.

[111]  Lilach Hadany,et al.  The probability of improvement in Fisher's geometric model: a probabilistic approach. , 2015, Theoretical population biology.

[112]  M. Kirkpatrick,et al.  Signatures of Sex-Antagonistic Selection on Recombining Sex Chromosomes , 2014, Genetics.

[113]  B. Charlesworth Causes of natural variation in fitness: Evidence from studies of Drosophila populations , 2015, Proceedings of the National Academy of Sciences.

[114]  Nicholas C. Wu,et al.  A Comprehensive Biophysical Description of Pairwise Epistasis throughout an Entire Protein Domain , 2014, Current Biology.

[115]  H. A. Orr,et al.  The genetic theory of adaptation: a brief history , 2005, Nature Reviews Genetics.

[116]  B. Charlesworth,et al.  A Model for the Evolution of Dioecy and Gynodioecy , 1978, The American Naturalist.

[117]  J. Haigh The accumulation of deleterious genes in a population--Muller's Ratchet. , 1978, Theoretical population biology.

[118]  H. A. Orr,et al.  The distribution of fitness effects among beneficial mutations in Fisher's geometric model of adaptation. , 2006, Journal of theoretical biology.

[119]  Kevin R. Thornton,et al.  Retroposed new genes out of the X in Drosophila. , 2002, Genome research.

[120]  Mandy J. Haldane,et al.  A Mathematical Theory of Natural and Artificial Selection, Part V: Selection and Mutation , 1927, Mathematical Proceedings of the Cambridge Philosophical Society.

[121]  B. Charlesworth,et al.  Sex differences in fitness and selection for centric fusions between sex-chromosomes and autosomes. , 1980, Genetical research.

[122]  H. Hoekstra,et al.  Molecular spandrels: tests of adaptation at the genetic level , 2011, Nature Reviews Genetics.

[123]  B. Walsh,et al.  Abundant Genetic Variation + Strong Selection = Multivariate Genetic Constraints: A Geometric View of Adaptation , 2009 .

[124]  A. Clark,et al.  Impact of genetic architecture on the relative rates of X versus autosomal adaptive substitution. , 2012, Molecular biology and evolution.

[125]  N. Barton,et al.  A general model for the evolution of recombination. , 1995, Genetical research.

[126]  E. Mayr Adaptation and selection , 1981 .

[127]  A. Clark,et al.  A General Population Genetic Framework for Antagonistic Selection That Accounts for Demography and Recurrent Mutation , 2012, Genetics.

[128]  Katrina McGuigan,et al.  The distribution of genetic variance across phenotypic space and the response to selection , 2015, Molecular ecology.

[129]  H. Girardey,et al.  Trajectories , 2009, Handbook of Critical Agrarian Studies.

[130]  B. Charlesworth,et al.  Elements of Evolutionary Genetics , 2010 .

[131]  M. Blows A tale of two matrices: multivariate approaches in evolutionary biology , 2007, Journal of evolutionary biology.

[132]  Robert L. Unckless,et al.  Population Extinction and the Genetics of Adaptation , 2008, The American Naturalist.

[133]  Stephen F. Chenoweth,et al.  The Nature and Extent of Mutational Pleiotropy in Gene Expression of Male Drosophila serrata , 2014, Genetics.

[134]  R. Lande QUANTITATIVE GENETIC ANALYSIS OF MULTIVARIATE EVOLUTION, APPLIED TO BRAIN:BODY SIZE ALLOMETRY , 1979, Evolution; international journal of organic evolution.

[135]  W. Rice THE ACCUMULATION OF SEXUALLY ANTAGONISTIC GENES AS A SELECTIVE AGENT PROMOTING THE EVOLUTION OF REDUCED RECOMBINATION BETWEEN PRIMITIVE SEX CHROMOSOMES , 1987, Evolution; international journal of organic evolution.

[136]  Philipp W. Messer,et al.  Heterozygote advantage as a natural consequence of adaptation in diploids , 2011, Proceedings of the National Academy of Sciences.

[137]  B. Charlesworth,et al.  Reduced Effectiveness of Selection Caused by a Lack of Recombination , 2009, Current Biology.

[138]  Nova Scotia ANTAGONISTIC PLEIOTROPY, DOMINANCE, AND GENETIC VARIATION* , 1982 .

[139]  M. Long,et al.  Recombination yet inefficient selection along the Drosophila melanogaster subgroup's fourth chromosome. , 2010, Molecular biology and evolution.

[140]  Turner J.R.G. Butterfly mimicry: the genetical evolution of an adaptation. , 1977 .

[141]  R. Brooks,et al.  Experimental Evidence That Sexual Conflict Influences the Opportunity, Form and Intensity of Sexual Selection , 2008, Evolution; international journal of organic evolution.

[142]  B. Charlesworth Evolutionary Rates in Partially Self-Fertilizing Species , 1992, The American Naturalist.

[143]  T. Ohta,et al.  Theoretical aspects of population genetics. , 1972, Monographs in population biology.

[144]  J. B. S. Haldane,et al.  A mathematical theory of natural and artificial selection—I , 1927, Mathematical Proceedings of the Cambridge Philosophical Society.

[145]  Luis-Miguel Chevin GENETIC CONSTRAINTS ON ADAPTATION TO A CHANGING ENVIRONMENT , 2013, Evolution; international journal of organic evolution.

[146]  S. Otto,et al.  RECOMBINATION AND HITCHHIKING OF DELETERIOUS ALLELES , 2011, Evolution; international journal of organic evolution.

[147]  J. Parsch,et al.  X Chromosome Inactivation during Drosophila Spermatogenesis , 2007, PLoS biology.

[148]  G. Martin Fisher’s Geometrical Model Emerges as a Property of Complex Integrated Phenotypic Networks , 2014, Genetics.

[149]  D. Hartl,et al.  Compensatory nearly neutral mutations: selection without adaptation. , 1996, Journal of theoretical biology.

[150]  A. Owen A genetical system admitting of two distinct stable equilibria under natural selection , 1953, Heredity.

[151]  B. Blossey,et al.  Evolution of Increased Competitive Ability in Invasive Nonindigenous Plants: A Hypothesis , 1995 .

[152]  Colin Olito Consequences of genetic linkage for the maintenance of sexually antagonistic polymorphism in hermaphrodites , 2017, Evolution; international journal of organic evolution.

[153]  J. Felsenstein The evolutionary advantage of recombination. , 1974, Genetics.

[154]  Art Poon,et al.  COMPENSATING FOR OUR LOAD OF MUTATIONS: FREEZING THE MELTDOWN OF SMALL POPULATIONS , 2000, Evolution; international journal of organic evolution.

[155]  M. Hall,et al.  Genetic correlations and sex‐specific adaptation in changing environments , 2016, Evolution; international journal of organic evolution.

[156]  H. A. Orr,et al.  An adaptive hypothesis for the evolution of the Y chromosome. , 1998, Genetics.

[157]  Annalise B. Paaby,et al.  The many faces of pleiotropy. , 2013, Trends in Genetics.

[158]  M. Kimura,et al.  Evolution in Sexual and Asexual Populations , 1965, The American Naturalist.

[159]  Ching Chun Li,et al.  The Stability of an Equilibrium and the Average Fitness of a Population , 1955, The American Naturalist.

[160]  Christopher R. Jones,et al.  Sex increases the efficacy of natural selection in experimental yeast populations , 2005, Nature.

[161]  S. Wright,et al.  The shifting balance theory and macroevolution. , 1982, Annual review of genetics.

[162]  B. Charlesworth,et al.  Theoretical genetics of Batesian mimicry II. Evolution of supergenes. , 1975, Journal of theoretical biology.

[163]  J. M. Smith What Determines the Rate of Evolution? , 1976, The American Naturalist.

[164]  Ary A. Hoffmann,et al.  A reassessment of genetic limits to evolutionary change , 2005 .

[165]  S. Chenoweth,et al.  Intralocus sexual conflict. , 2009, Trends in ecology & evolution.

[166]  N. Barton,et al.  The frequency of shifts between alternative equilibria. , 1987, Journal of theoretical biology.

[167]  H. A. Orr,et al.  THE POPULATION GENETICS OF ADAPTATION: THE DISTRIBUTION OF FACTORS FIXED DURING ADAPTIVE EVOLUTION , 1998, Evolution; international journal of organic evolution.

[168]  R. Lande,et al.  GENOTYPE‐ENVIRONMENT INTERACTION AND THE EVOLUTION OF PHENOTYPIC PLASTICITY , 1985, Evolution; international journal of organic evolution.

[169]  P. Feldman Evolution of sex , 1975, Nature.

[170]  T. Lenormand,et al.  The fitness effect of mutations across environments: Fisher's geometrical model with multiple optima , 2015, Evolution; international journal of organic evolution.

[171]  T. Johnson,et al.  The effect of deleterious alleles on adaptation in asexual populations. , 2002, Genetics.

[172]  A. Pomiankowski,et al.  Can paternal leakage maintain sexually antagonistic polymorphism in the cytoplasm? , 2015, Journal of evolutionary biology.

[173]  F. M. Stewart,et al.  Regions of stable equilibria for models of differential selection in the two sexes under random mating. , 1977, Genetics.

[174]  Michael M. Desai,et al.  Sex Speeds Adaptation by Altering the Dynamics of Molecular Evolution , 2016, Nature.

[175]  J. Thoday Population Genetics , 1956, Nature.

[176]  S. Lien,et al.  Sex-dependent dominance at a single locus maintains variation in age at maturity in salmon , 2015, Nature.

[177]  G. Coop,et al.  No effect of recombination on the efficacy of natural selection in primates. , 2008, Genome research.

[178]  M. Blows,et al.  SEXUAL CONFLICT AND THE MAINTENANCE OF MULTIVARIATE GENETIC VARIATION , 2010, Evolution; international journal of organic evolution.

[179]  J. Abbott,et al.  Intralocus Tactical Conflict and the Evolution of Alternative Reproductive Tactics , 2013 .

[180]  M. Kirkpatrick How and Why Chromosome Inversions Evolve , 2010, PLoS biology.

[181]  E. Ortlund,et al.  Crystal Structure of an Ancient Protein: Evolution by Conformational Epistasis , 2007, Science.

[182]  M. Kirkpatrick,et al.  Sex-Specific Selection and Sex-Biased Gene Expression in Humans and Flies , 2016, PLoS genetics.

[183]  T. Lenormand,et al.  Fitness Landscapes: An Alternative Theory for the Dominance of Mutation , 2011, Genetics.

[184]  H. A. Orr,et al.  The population genetics of beneficial mutations , 2010, Philosophical Transactions of the Royal Society B: Biological Sciences.

[185]  H. A. Orr,et al.  ADAPTATION AND THE COST OF COMPLEXITY , 2000, Evolution; international journal of organic evolution.

[186]  D. Queller Fundamental Theorems of Evolution , 2017, The American Naturalist.

[187]  S. Glémin,et al.  MATING SYSTEM, HALDANE'S SIEVE, AND THE DOMESTICATION PROCESS , 2012, Evolution; international journal of organic evolution.

[188]  R. Lande,et al.  SEXUAL DIMORPHISM, SEXUAL SELECTION, AND ADAPTATION IN POLYGENIC CHARACTERS , 1980, Evolution; international journal of organic evolution.