Introduction: phenotypes and genetic variation
Phenotypes are composites of the observable traits of organisms and living individuals that originate from the expression of the instructions recorded in the organism's DNA under the influence of environmental factors. Researchers working in such disparate fields as livestock selection, medical genetics, behavioral economics, or evolutionary biology need to understand the genetic basis of phenotypes. For instance, plant breeders aim to predict traits such as crop response to fertilizers (Hospital, 2009); clinical geneticists intend to trace genetic mutations that result in diseases – abnormal phenotypes characterized by pathology (Sullivan et al., 2012); behavioral economists try to understand the genetic underpinnings of human behavioral variation (Navarro, 2009); and evolutionary biologists try to detect the molecular signature of natural selection in genes related to adaptive traits, such as lactase persistence (Hurst, 2009).
Despite its outstanding scientific and economic interest, studying the genetics of phenotypes is not devoid of complexities. Most traits, such as human height, tend to present continuous variation across individuals. This is because they are controlled by large numbers of genes and each causal variant explains but a tiny fraction of the overall phenotypic variation. In this regard, genome-wide association studies (GWAS) have arisen as one of the most powerful tools to unravel the alleles that underlie individual phenotypic variation. This chapter reviews the bases of the study of the genetics of polygenic traits and provides a brief historical account of the developments in the field until the current wave of GWAS.
The study of the genetic architecture of phenotypes
Forces shaping human genetic variation
Many different tools of statistical genomics, including GWAS, have been designed with the aim of mapping phenotype diversity to the underlying causal genetic factors that vary across individuals. The two main forces increasing genetic diversity in human genomes are mutation and recombination. Additional forces, such as genetic drift and natural selection, govern the fate of extant genetic variation in populations. Together, all of them shape the degree of phenotypic variability present across humans.
Two major classes of genetic variation can be distinguished in our genomes according to their size: point mutations, and structural variation (Frazer et al., 2009). Point mutations are substitutions of a single base and are known as single nucleotide polymorphisms (SNPs).