The majority of studies of genetic association with disease have been performed in Europeans. This European bias has important implications for risk prediction of diseases across global populations. ...In this commentary, we justify the need to study more diverse populations using both empirical examples and theoretical reasoning.
The majority of studies of genetic association with disease have been performed in Europeans. This European bias has important implications for risk prediction of diseases across global populations. In this commentary, we justify the need to study more diverse populations using both empirical examples and theoretical reasoning.
Whole genome sequencing and SNP genotyping arrays can paint strikingly different pictures of demographic history and natural selection. This is because genotyping arrays contain biased sets of ...pre‐ascertained SNPs. In this short review, we use comparisons between high‐coverage whole genome sequences of African hunter‐gatherers and data from genotyping arrays to highlight how SNP ascertainment bias distorts population genetic inferences. Sample sizes and the populations in which SNPs are discovered affect the characteristics of observed variants. We find that SNPs on genotyping arrays tend to be older and present in multiple populations. In addition, genotyping arrays cause allele frequency distributions to be shifted towards intermediate frequency alleles, and estimates of linkage disequilibrium are modified. Since population genetic analyses depend on allele frequencies, it is imperative that researchers are aware of the effects of SNP ascertainment bias. With this in mind, we describe multiple ways to correct for SNP ascertainment bias.
The specific genetic variants that are analyzed can have important implications for studies of population genetics. Using data from African hunter‐gatherers, we demonstrate how high‐coverage whole genome sequences and ascertained SNPs on genotyping arrays yield different results.
To reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different ...hunter-gatherer populations at >60× coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic introgression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height.
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► 13.4 million variants identified in African hunter-gatherers, many of which are novel ► Evidence of archaic admixture found in the genomes of African hunter-gatherers ► Selection scans implicate loci involved in taste perception, metabolism, and immunity ► Genetic associations with height are found for Pygmy variants located on chromosome 3
Whole-genome sequencing of Africans from different hunter-gatherer groups uncovers millions of variants that had not been previously documented. The findings expand our understanding of human diversity and evolution and indicate which genes harbor signatures of positive selection in these hunter-gatherer populations.
The spread of modern humans across the globe has led to genetic adaptations to diverse local environments. Recent developments in genomic technologies, statistical analyses, and expanded sampled ...populations have led to improved identification and fine-mapping of genetic variants associated with adaptations to regional living conditions and dietary practices. Ongoing efforts in sequencing genomes of indigenous populations, accompanied by the growing availability of "-omics" and ancient DNA data, promises a new era in our understanding of recent human evolution and the origins of variable traits and disease risks.
Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk ...or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB.
Comparative studies of ethnically diverse human populations, particularly in Africa, are important for reconstructing human evolutionary history and for understanding the genetic basis of phenotypic ...adaptation and complex disease. African populations are characterized by greater levels of genetic diversity, extensive population substructure, and less linkage disequilibrium (LD) among loci compared to non-African populations. Africans also possess a number of genetic adaptations that have evolved in response to diverse climates and diets, as well as exposure to infectious disease. This review summarizes patterns and the evolutionary origins of genetic diversity present in African populations, as well as their implications for the mapping of complex traits, including disease susceptibility.
Gene conversion results in the nonreciprocal transfer of genetic information between two recombining sequences, and there is evidence that this process is biased toward G and C alleles. However, the ...strength of GC-biased gene conversion (gBGC) in human populations and its effects on hereditary disease have yet to be assessed on a genomic scale. Using high-coverage whole-genome sequences of African hunter-gatherers, agricultural populations, and primate outgroups, we quantified the effects of GC-biased gene conversion on population genomic data sets. We find that genetic distances (FST and population branch statistics) are modified by gBGC. In addition, the site frequency spectrum is left-shifted when ancestral alleles are favored by gBGC and right-shifted when derived alleles are favored by gBGC. Allele frequency shifts due to gBGC mimic the effects of natural selection. As expected, these effects are strongest in high-recombination regions of the human genome. By comparing the relative rates of fixation of unbiased and biased sites, the strength of gene conversion was estimated to be on the order of Nb ≈ 0.05 to 0.09. We also find that derived alleles favored by gBGC are much more likely to be homozygous than derived alleles at unbiased SNPs (+42.2% to 62.8%). This results in a curse of the converted, whereby gBGC causes substantial increases in hereditary disease risks. Taken together, our findings reveal that GC-biased gene conversion has important population genetic and public health implications.
Population Genomics of Human Adaptation Lachance, Joseph; Tishkoff, Sarah A.
Annual review of ecology, evolution, and systematics,
01/2013, Letnik:
44, Številka:
1
Journal Article
Recenzirano
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Recent advances in genotyping technologies have facilitated genome-wide scans for natural selection. Detecting targets of natural selection sheds light on human evolution and it can help identify ...genetic variants that influence normal human phenotypic variation as well as disease susceptibility. Here we focus on studies of natural selection in modern humans who originated ~200,000 years ago in Africa and migrated across the globe ~50,000-100,000 years ago. Movement into new environments, as well as changes in culture and technology, including plant and animal domestication, resulted in local adaptation to diverse environments. We summarize statistical approaches for detecting targets of natural selection and for distinguishing the effects of demographic history from natural selection. On a genome-wide scale, immune-related genes are major targets of positive selection. Genes associated with reproduction and fertility also are fast evolving. Additional examples of recent human adaptation include genes associated with lactase persistence, eccrine glands, and response to hypoxia. Lastly, we emphasize the need to supplement scans of selection with functional studies to demonstrate the physiologic impact of candidate loci.
Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of ...short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan.
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