Complex Traits in Natural Populations

This chapter could as well be titled “Population Genomics,” although many aspects of population genomics are integrated throughout the other chapters. It includes estimates of mutational variance and standing variance, phenotypic evolution under directional selection as measured by the linear selection gradient, and phenotypic evolution under stabilizing selection. It explores the strengths and limitations of genome-wide association studies of quantitative trait loci (QTLs) and expression (eQTLs) to detect genetic influencing complex traits in natural populations and genetic risk factors for complex diseases such as heart disease or diabetes. The number of genes affecting complex traits is considered, as well as evidence bearing on the issue of whether complex diseases are primarily affected by a very large number of genes, almost all of small effect, and how this bears on direct-to-consumer and over-the-counter genetic testing. The population genomics of adaptation is considered, including drug resistance, domestication, and local selection versus gene flow. The chapter concludes with the population genomics of speciation as illustrated by reinforcement of mating barriers, the reproducibility of phenotypic and genetic changes, and the accumulation of genetic incompatibilities.

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.

Mutation, Gene Conversion, and Migration

Chapter 4 focuses on forward and reverse mutation, gene duplication and functional divergence, gene conversion, and equilibrium heterozygosity. It includes an introduction to the coalescent as well as the Wright–Fisher and Moran models of random genetic drift, measures of nucleotide polymorphism and diversity, and how these may be estimated from sequence data. Biased gene conversion is discussed in regard to its effects on homogeneity of nucleotide sequence across the genome. Several distinct types of effective population number are compared and contrasted including the inbreeding, variance, and coalescent effective numbers. Various models of migration are also examined including one-way migration, the island model, and stepping-stone models.

Inbreeding and Population Structure

Inbreeding and its consequences are the main subject of Chapter 3, beginning with the concepts of identity by descent versus identity by state, the inbreeding coefficient F, genotype frequencies with inbreeding, and calculation of the inbreeding coefficient from pedigrees. Inbreeding and heterosis are discussed along with the effects of inbreeding in humans and other organisms, regular systems of mating (selfing and partial selfing, sib mating), and the utility of recombinant inbred lines. The chapter emphasizes the intimate connection between inbreeding and hierarchical population structure as measured by the F-statistics.

Population Genetics of Complex Traits

Chapter 8’s focus is on the genetic architecture of complex traits determined jointly by multiple genes and environmental factors. Sometimes called quantitative genetics, the basic concepts include components of genetic and environmental variance, genotype-by-environment interaction, genotype-by-environment association, correlation between relatives, and broad-sense and narrow-sense heritability. It distinguishes between physiological and statistical epistasis, and it shows why the former can be large while the latter may be negligible. Various types of artificial selection are considered, and individual truncation selection is examined in detail, culminating in the famous prediction equation R = h 2 S. Special topics include genomic selection, correlated response, selection limits, and the heritability of liability of threshold traits.

Organization of Genetic Variation

Chapter 2 deals with the manner in which genetic variation is organized in random-mating populations, including such basics as the Hardy–Weinberg principle, multiple alleles and DNA typing, and X-linkage. These are basic, elementary concepts that set the stage for later chapters. It also includes detailed examination of two-locus linkage disequilibrium (LD), measures of LD, and the levels of LD observed in natural populations. The chi-square test for goodness of fit is discussed, together with its interpretation, along with the basics of hypothesis testing including type I error (false positive), type II error (false negative), power, and the need to correct for multiple comparisons. Also discussed are LD due to population admixture and Wahlund’s principle.

Random Genetic Drift in Small Populations

Chapter 6 deals with the consequences of random genetic drift in finite populations and includes details of the diffusion approximations and their solutions as well as conditional diffusion processes. It includes probabilities of fixation and conditional times to fixation for neutral and nonneutral alleles. Various scenarios of mutation, migration, and selection are examined with regard to the stationary distributions of allele frequency. The Ewens sampling formula and its importance is discussed, as well as its implications for the distribution of the number of alleles in samples. An analysis of allozyme polymorphisms supports the hypothesis that most amino acid polymorphisms in natural populations are slightly deleterious.

Natural Selection in Large Populations

This chapter includes selection in haploid and diploid organisms, hard and soft selective sweeps, background selection, and the probability of ultimate survival of a new favorable mutation in a large population. It considers overdominance and heterozygote inferiority in detail as well as different types of equilibria and the fundamental theorem of natural selection. Various types of balancing selection are examined including mutation–selection balance, migration–selection balance, meiotic drive and gametic selection, and the theory of CRISPR-mediated gene drive to control natural populations. It closes with a discussion of other modes of selection and their implications.