Africa is the source of all modern humans, but characterization of genetic variation and of relationships among populations across the continent has been enigmatic. We studied 121 African populations, four African American populations, and 60 non-African populations for patterns of variation at 1327 nuclear microsatellite and insertion/deletion markers. We identified 14 ancestral population clusters in Africa that correlate with self-described ethnicity and shared cultural and/or linguistic properties. We observed high levels of mixed ancestry in most populations, reflecting historical migration events across the continent. Our data also provide evidence for shared ancestry among geographically diverse hunter-gatherer populations (Khoesan speakers and Pygmies). The ancestry of African Americans is predominantly from Niger-Kordofanian (approximately 71%), European (approximately 13%), and other African (approximately 8%) populations, although admixture levels varied considerably among individuals. This study helps tease apart the complex evolutionary history of Africans and African Americans, aiding both anthropological and genetic epidemiologic studies.

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The Genetic Structure and History of Africans and African Americans

The vast majority of genome-wide association studies (GWASs) are performed in Europeans, and their transferability to other populations is dependent on many factors (e.g., linkage disequilibrium, allele frequencies, genetic architecture). As medical genomics studies become increasingly large and diverse, gaining insights into population history and consequently the transferability of disease risk measurement is critical. Here, we disentangle recent population history in the widely used 1000 Genomes Project reference panel, with an emphasis on populations underrepresented in medical studies. To examine the transferability of single-ancestry GWASs, we used published summary statistics to calculate polygenic risk scores for eight well-studied phenotypes. We identify directional inconsistencies in all scores; for example, height is predicted to decrease with genetic distance from Europeans, despite robust anthropological evidence that West Africans are as tall as Europeans on average. To gain deeper quantitative insights into GWAS transferability, we developed a complex trait coalescent-based simulation framework considering effects of polygenicity, causal allele frequency divergence, and heritability. As expected, correlations between true and inferred risk are typically highest in the population from which summary statistics were derived. We demonstrate that scores inferred from European GWASs are biased by genetic drift in other populations even when choosing the same causal variants and that biases in any direction are possible and unpredictable. This work cautions that summarizing findings from large-scale GWASs may have limited portability to other populations using standard approaches and highlights the need for generalized risk prediction methods and the inclusion of more diverse individuals in medical genomics.

Human Demographic History Impacts Genetic Risk Prediction across Diverse Populations

Summary: Evolution of RNA viruses occurs through disequilibria of collections of closely related mutant spectra or mutant clouds termed viral quasispecies. Here we review the origin of the quasispecies concept and some biological implications of quasispecies dynamics. Two main aspects are addressed: (i) mutant clouds as reservoirs of phenotypic variants for virus adaptability and (ii) the internal interactions that are established within mutant spectra that render a virus ensemble the unit of selection. The understanding of viruses as quasispecies has led to new antiviral designs, such as lethal mutagenesis, whose aim is to drive viruses toward low fitness values with limited chances of fitness recovery. The impact of quasispecies for three salient human pathogens, human immunodeficiency virus and the hepatitis B and C viruses, is reviewed, with emphasis on antiviral treatment strategies. Finally, extensions of quasispecies to nonviral systems are briefly mentioned to emphasize the broad applicability of quasispecies theory.

Viral Quasispecies Evolution

Over the past 500 years, North America has been the site of ongoing mixing of Native Americans, European settlers, and Africans (brought largely by the trans-Atlantic slave trade), shaping the early history of what became the United States. We studied the genetic ancestry of 5,269 self-described African Americans, 8,663 Latinos, and 148,789 European Americans who are 23andMe customers and show that the legacy of these historical interactions is visible in the genetic ancestry of present-day Americans. We document pervasive mixed ancestry and asymmetrical male and female ancestry contributions in all groups studied. We show that regional ancestry differences reflect historical events, such as early Spanish colonization, waves of immigration from many regions of Europe, and forced relocation of Native Americans within the US. This study sheds light on the fine-scale differences in ancestry within and across the United States and informs our understanding of the relationship between racial and ethnic identities and genetic ancestry.

/pdf/the-genetic-ancestry-of-african-americans-latinos-and-58n0oid9zc.pdf

The Genetic Ancestry of African Americans, Latinos, and European Americans across the United States

Quantifying patterns of population structure in Africans and African Americans illuminates the history of human populations and is critical for undertaking medical genomic studies on a global scale. To obtain a fine-scale genome-wide perspective of ancestry, we analyze Affymetrix GeneChip 500K genotype data from African Americans (n = 365) and individuals with ancestry from West Africa (n = 203 from 12 populations) and Europe (n = 400 from 42 countries). We find that population structure within the West African sample reflects primarily language and secondarily geographical distance, echoing the Bantu expansion. Among African Americans, analysis of genomic admixture by a principal component-based approach indicates that the median proportion of European ancestry is 18.5% (25th–75th percentiles: 11.6–27.7%), with very large variation among individuals. In the African-American sample as a whole, few autosomal regions showed exceptionally high or low mean African ancestry, but the X chromosome showed elevated levels of African ancestry, consistent with a sex-biased pattern of gene flow with an excess of European male and African female ancestry. We also find that genomic profiles of individual African Americans afford personalized ancestry reconstructions differentiating ancient vs. recent European and African ancestry. Finally, patterns of genetic similarity among inferred African segments of African-American genomes and genomes of contemporary African populations included in this study suggest African ancestry is most similar to non-Bantu Niger-Kordofanian-speaking populations, consistent with historical documents of the African Diaspora and trans-Atlantic slave trade.

https://www.pnas.org/content/pnas/early/2009/12/10/0909559107.full.pdf

Genome-wide patterns of population structure and admixture in West Africans and African Americans

The differential relative contribution of males and females from Africa and Europe to individual African American genomes is relevant to mapping genes utilizing admixture analysis. The assessment of ancestral population contributions to the four types of genomic DNA (autosomes, X and Y chromosomes, and mitochondrial) with their differing modes of inheritance is most easily addressed in males. A thorough evaluation of 93 African American males for 2,018 autosomal single nucleotide polymorphic (SNP) markers, 121 X chromosome SNPs, 10 Y chromosome haplogroups specified by SNPs, and six haplogroup defining mtDNA SNPs is presented. A distinct lack of correlation observed between the X chromosome and the autosomal admixture fractions supports separate treatment of these chromosomes in admixture-based gene mapping applications. The European genetic contributions were highest (and African lowest) for the Y chromosome (28.46%), followed by the autosomes (19.99%), then the X chromosome (12.11%), and the mtDNA (8.51%). The relative order of admixture fractions in the genomic compartments validates previous studies that suggested sex-biased gene flow with elevated European male and African female contributions. There is a threefold higher European male contribution compared with European females (Y chromosome vs. mtDNA) to the genomes of African American individuals meaning that admixture-based gene discovery will have the most power for the autosomes and will be more limited for X chromosome analysis.

Elevated male European and female African contributions to the genomes of African American individuals.

Human cyclophilin A, or CypA, encoded by the gene peptidyl prolyl isomerase A (PPIA), is incorporated into the HIV type 1 (HIV-1) virion and promotes HIV-1 infectivity by facilitating virus uncoating. We examined the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the PPIA gene on HIV-1 infection and disease progression in five HIV-1 longitudinal history cohorts. Kaplan-Meier survival statistics and Cox proportional hazards model were used to assess time to AIDS outcomes. Among eight SNPs tested, two promoter SNPs (SNP3 and SNP4) in perfect linkage disequilibrium were associated with more rapid CD4+ T-cell loss (relative hazard = 3.7, p = 0.003) in African Americans. Among European Americans, these alleles were also associated with a significant trend to more rapid progression to AIDS in a multi-point categorical analysis (p = 0.005). Both SNPs showed differential nuclear protein-binding efficiencies in a gel shift assay. In addition, one SNP (SNP5) located in the 5′ UTR previously shown to be associated with higher ex vivo HIV-1 replication was found to be more frequent in HIV-1-positive individuals than in those highly exposed uninfected individuals. These results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV-1 pathogenesis.

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Regulatory polymorphisms in the cyclophilin A gene, PPIA, accelerate progression to AIDS

/pdf/regulatory-polymorphisms-in-the-cyclophilin-a-gene-ppia-16b04amw2l.pdf

Holli Hutcheson-Dilks

Papers

Elevated male European and female African contributions to the genomes of African American individuals.

Regulatory polymorphisms in the cyclophilin A gene, PPIA, accelerate progression to AIDS

Regulatory Polymorphisms in the Cyclophilin A Gene, PPIA, Accelerate Progression to AIDS