Sex differences in deleterious mutational effects in D. melanogaster: combining quantitative and population genetic insights

Fitness effects of deleterious mutations can differ between females and males due to: (i) sex differences in the strength of purifying selection; and (ii) sex differences in ploidy. Although sex differences in fitness effects have important broader implications (e.g., for the evolution of sex and lifespan), few studies have quantified their scope. Those that have belong to one of two distinct empirical traditions: (i) quantitative genetics, which focusses on multi-locus genetic variances in each sex, but is largely agnostic about their genetic basis; and (ii) molecular population genetics, which focusses on comparing autosomal and X-linked polymorphism, but is poorly suited for inferring contemporary sex differences. Here we combine both traditions to present a comprehensive analysis of female and male adult reproductive fitness among 202 outbred, laboratory-adapted, hemiclonal genomes of Drosophila melanogaster. While we find no clear evidence for sex differences in the strength of purifying selection, sex differences in ploidy generate multiple signals of enhanced purifying selection for X-linked loci. These signals are present in quantitative genetic metrics—i.e., a disproportionate contribution of the X to male (but not female) fitness variation—and population genetic metrics—i.e., steeper regressions of an allele’s average fitness effect on its frequency, and proportionally less nonsynonymous polymorphism on the X than autosomes. Fitting our data to models for both sets of metrics, we infer that deleterious alleles are partially recessive. Given the often-large gap between quantitative and population genetic estimates of evolutionary parameters, our study showcases the benefits of combining genomic and fitness data when estimating such parameters.

A Primer of Population Genetics and Genomics

A Primer of Population Genetics and Genomics, 4th edition, has been completely revised and updated to provide a concise but comprehensive introduction to the basic concepts of population genetics and genomics. Recent textbooks have tended to focus on such specialized topics as the coalescent, molecular evolution, human population genetics, or genomics. This primer bucks that trend by encouraging a broader familiarity with, and understanding of, population genetics and genomics as a whole. The overview ranges from mating systems through the causes of evolution, molecular population genetics, and the genomics of complex traits. Interwoven are discussions of ancient DNA, gene drive, landscape genetics, identifying risk factors for complex diseases, the genomics of adaptation and speciation, and other active areas of research. The principles are illuminated by numerous examples from a wide variety of animals, plants, microbes, and human populations. The approach also emphasizes learning by doing, which in this case means solving numerical or conceptual problems. The rationale behind this is that the use of concepts in problem-solving lead to deeper understanding and longer knowledge retention. This accessible, introductory textbook is aimed principally at students of various levels and abilities (from senior undergraduate to postgraduate) as well as practising scientists in the fields of population genetics, ecology, evolutionary biology, computational biology, bioinformatics, biostatistics, physics, and mathematics.

Molecular Population Genetics

Chapter 7 is an introduction to molecular population genetics that includes the principal concepts of nucleotide polymorphism and divergence, the site frequency spectrum, and tests of selection and their limitations. Highlighted are rates of nucleotide substitution in coding and noncoding DNA, nucleotide and amino acid divergence between species, corrections for multiple substitutions, and the molecular clock. Discussion of the folded and unfolded site frequency spectrum includes the strengths and limitations of Tajima’s D, Fay and Wu’s H, and other measures. The chapter also discusses an emerging consensus to resolve the celebrated selection–neutrality controversy. It also includes examination of demographic history through the use of ancient DNA with special emphasis on the surprising findings in regard to the ancestral makeup of contemporary human populations. Also discussed are the population dynamics of transposable elements in prokaryotes and eukaryotes.

Case studies in molecular population genetics

Collections of DNA from nature for many individuals and loci give us the raw material for studying evolution at the molecular level. Chapter 9, “Case studies in molecular population genetics: genotype to phenotype to selection,” dives into several case studies of exciting real-world organisms that demonstrate the application from A to Z of the concepts developed throughout the book. It includes summaries of the natural context for each organism, ranging from armoring in fish (Eda, Pitx1) and color crypsis in mice (Mc1r) to butterfly flight ability (Pgi) and toxin metabolism in Drosophila fruit flies (Cyp6g1, Adh), then walks through the molecular data, their visualization, and their analysis. Complications and caveats to real-world analysis are discussed for how to identify demographic and selective effects in empirical datasets. The approaches include both candidate gene studies and genome scans, and show how different molecular population genetic analyses work in concert with one another. These population genetic analyses also can dovetail with functional molecular genetic experiments and with genetic mapping using crosses or genome-wide association study analysis. Chapter 9 ends by introducing a summary of several advanced topics in molecular population genetics, including concepts and tests for selection on standing variation, the genomic scale of data computation and evolutionary modelling, and connections to human evolution.

Introduction

Chapter 1, “Introduction: What is molecular population genetics?,” presents the motivations, applications, and historical context for molecular population genetics as a subdiscipline within biology. It describes how changes to DNA are inextricably woven into thinking about evolution and how molecular population genetics can be used to transport our thinking backward and forward through time. Key classic theoretical ideas summarizing allele frequency change, probability of fixation, and the time to fixation are encapsulated in brief vignettes. Both fundamental and applied uses of molecular population genetic perspectives are summarized in this survey of the historical, conceptual, and empirical development of the branch of science that we call population genetics and its integration with DNA sequences.

A Primer of Molecular Population Genetics

The study of molecular population genetics seeks to understand the micro-evolutionary principles underlying DNA sequence variation and change. It addresses such questions as: Why do individuals differ as much as they do in their DNA sequences? What are the genomic signatures of adaptations? How often does natural selection dictate changes to DNA and accumulate as differences between species? How does the ebb and flow in the abundance of individuals over time get marked onto chromosomes to record genetic history? The concepts used to answer such questions also apply to analysis of personal genomics, genome-wide association studies, phylogenetics, landscape and conservation genetics, forensics, molecular anthropology, and selection scans. This Primer of Molecular Population Genetics introduces the bare essentials of the theory and practice of evolutionary analysis through the lens of DNA sequence change in populations. Intended as an introductory text for upper-level undergraduates and junior graduate students, this Primer also provides an accessible entryway for scientists from other areas of biology to appreciate the ideas and practice of molecular population genetics. With the revolutionary advances in genomic data acquisition, understanding molecular population genetics is now a fundamental requirement for today’s life scientists.

Changes in Quantitative Traits Over Time

Quantitative traits—be they morphological or physiological characters, aspects of behavior, or genome-level features such as the amount of RNA or protein expression for a specific gene—usually show considerable variation within and among populations. This chapter provides a historical overview of the study of such traits and their connections with traditional and molecular population genetics, applied breeding, and evolutionary theory.