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

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

How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we found that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (ka) and after no more than an 8000-year isolation period in Beringia. After their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 ka, one that is now dispersed across North and South America and the other restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative "Paleoamerican" relict populations, including the historical Mexican Pericues and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.

/pdf/genomic-evidence-for-the-pleistocene-and-recent-population-2ekb1axezr.pdf

Genomic evidence for the Pleistocene and recent population history of Native Americans

"The Genetic Ancestry of African Americans, Latinos, and European Americans Across the United States" data files

Searching for genetic variants with unusual differentiation between subpopulations is an established approach for identifying signals of natural selection. However, existing methods generally require discrete subpopulations. We introduce a method that infers selection using principal components (PCs) by identifying variants whose differentiation along top PCs is significantly greater than the null distribution of genetic drift. To enable the application of this method to large datasets, we developed the FastPCA software, which employs recent advances in random matrix theory to accurately approximate top PCs while reducing time and memory cost from quadratic to linear in the number of individuals, a computational improvement of many orders of magnitude. We apply FastPCA to a cohort of 54,734 European Americans, identifying 5 distinct subpopulations spanning the top 4 PCs. Using the PC-based test for natural selection, we replicate previously known selected loci and identify three new genome-wide significant signals of selection, including selection in Europeans at ADH1B. The coding variant rs1229984∗T has previously been associated to a decreased risk of alcoholism and shown to be under selection in East Asians; we show that it is a rare example of independent evolution on two continents. We also detect selection signals at IGFBP3 and IGH, which have also previously been associated to human disease.

Fast Principal-Component Analysis Reveals Convergent Evolution of ADH1B in Europe and East Asia

Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.

The genetics of Mexico recapitulates Native American substructure and affects biomedical traits

This paper describes for the first time, the genetic distances among Amerindian populations and Mexican mestizos as well by using the polymorphisms of the HLA-B gene, since this locus is the most polymorphic of the Major Histocompatibility Complex (MHC) region. We obtained the allelic frequencies of 10 Amerindians populations reported in the literature for HLA-B gene. We also included the frequencies of Mexican mestizos (n = 102), Asiatic of north (n = 380), Euro-Americans (n = 287) and Afro-Americans (n = 396) of USA, kurds (n = 101), Koreans (n = 29), Mandenka of Senegal (n = 68), and Malayos of South of Asia (n = 94), data was obtained from MHC Anthropology database. Variations in the HLA system in Amerindians showed a particular trend, characterized by a considerable number of new alleles as detected by high resolution DNA typing. These peculiarities tend to engage the most important factors in biological history from Amerindians. In mestizos, the variation was characterized by the distribution of the frequencies in a major number of alleles, which confirms the high degree of diversity contributed by the ancestral populations to the Mexican mestizos.

/pdf/variacion-del-hla-b-en-poblaciones-mexicanas-2bjmjknk0o.pdf

Variación del HLA-B en poblaciones mexicanas

https://www.imidsmexico.com/files/imids_22_2_1_005-013.pdf

Julio Granados-Arriola

Papers

The genetics of Mexico recapitulates Native American substructure and affects biomedical traits

Variación del HLA-B en poblaciones mexicanas

Inmunonutrición en enfermedades autoinmunitarias