Human genetic ancestry, health, and adaptation in Latin America

Abstract

Genetic admixture is the process that occurs when populations that were previously reproductively isolated, and consequently genetically diverged, come back together and exchange genes. Recent studies of modern and ancient genomes have underscored the frequency with which admixture has occurred during human evolution. Indeed, human evolution has been characterized by numerous iterations of physical isolation and genetic divergence followed by population convergence and admixture. Genetic admixture has profound implications for human evolution as it results in the creation of evolutionarily novel genomes that contain combinations of genetic variants (haplotypes) never seen before on the same genomic background. This dissertation explores the implications of large-scale genetic admixture in Latin America for human health, evolution (natural selection), and population structure (assortative mating). Latin America provides an ideal setting to explore the implications of admixture given the formation of modern populations via admixture among distinct African, European, and Native American population groups. Human health and evolution are explored through the lens of admixture, with an emphasis on the demographic processes that serve to combine distinct ancestry components within genomes. Population structure is considered with respect to assortative mating, which serves to limit the extent of genetic admixture within populations, thereby maintaining genetic diversity among distinct population groups even when they are co-located. In order to understand the implications of admixture for the formation of the New World, comparative genomic analyses were used to characterize patterns of genetic ancestry and admixture for individuals from four modern Latin American populations: Colombia, Mexico, Peru, and Puerto Rico. Comparative genomic analyses with ancestral source populations allowed for the characterization of genetic ancestry and admixture profiles for these four Latin American populations at both genome-wide (global) and variant/gene (local) levels. These data on genetic ancestry were integrated with a variety of functional genomic data sources in an effort to more fully understand the biological implications of admixture. Global patterns of ancestry for each population were used to parameterize the expected values of local ancestry, for both specific genetic variants and at the level of individual genes, and comparisons of observed versus expected ancestry levels were used to look for anomalous deviations of local ancestry, i.e. ancestry enrichment. Ancestry-enriched genetic variants were implicated in a number of health-related phenotypes, including immune system and disease response pathways, and a number of these variants were shown to exert their phenotypic effects via ancestry-specific gene regulation. Ancestry enrichment at the gene level was used to provide evidence for rapid adaptation to local environments via admixture-enabled selection, which occurs when admixture introduces novel genetic variants (haplotypes) to newly formed populations at intermediate frequencies. Admixture-enabled selection was observed for the major histocompatibility complex (MHC) locus of the adaptive immune system across multiple Latin American populations, and both the adaptive and innate immune systems were shown to evolve via polygenic admixture-enabled selection. Patterns of gene level ancestry were also used to search for evidence of population structure caused by assortative mating, whereby mate choice is influenced by phenotypic similarity. This analysis allowed us to characterize the genetic basis of phenotypic cues that influence patterns of assortative mating, including a number of anthropometric and neurological traits as well as the MHC locus. Considered together, these results underscore the outsized role that admixture has played in shaping the biology of modern Latin American populations. Global patterns of genetic ancestry and admixture are distinct to each population, and local ancestry can differ widely even for closely related individuals within a population. Local ancestry impacts a wide variety of health-related traits, provides the raw material for rapid, adaptive evolution, and informs the phenotypic cues that are used for mate choice and help to maintain population structure.