- Background: Modern Latin American populations were formed via genetic admixture among ancestral source populations from Africa, the Americas and Europe. - We are interested in studying how combinations of genetic ancestry in admixed Latin American populations may impact genomic determinants of health and disease. - Results: We analyzed a total of 347 admixed Latin American genomes along with 1102 putative ancestral source genomes from Africans, Europeans, and Native Americans. - We characterized the genetic ancestry, relatedness, and admixture patterns for each of the admixed Latin American genomes, finding a spectrum of ancestry proportions within and between populations. - SNPs that exist in any given Latin American population at a higher frequency than expected based on the population ’ s genetic ancestry profile. - For this set of ancestry-enriched SNPs, we inspected their phenotypic impact on disease, metabolism, and the immune system. - All four of the Latin American populations show ancestry-enrichment for a number of shared pathways, yielding evidence of similar selection pressures on these populations during their evolution. - Genes from both the innate and adaptive immune system were found to be regulated by ancestry-enriched SNPs with population-specific regulatory effects.. - Conclusions: Ancestry-enriched SNPs in Latin American populations have a substantial effect on health- and disease- related phenotypes. - Latin American genomes can thus be considered to represent a recent innovation in human evolution. - In- deed, genomes from modern Latin American popula- tions are evolutionarily novel in the sense that they contain combinations of genetic variants (haplotypes) that never previously existed together on the same gen- etic background. - Our group is interested in trying to understand the implications of the recent advent of novel Latin American genomes, particularly as it relates. - in an effort to expand our view of the relationship between genetic ancestry, admixture and health in Latin American populations.. - ancestry-enriched SNPs. - To find such ancestry- enriched SNPs, we consider the proportional contribu- tions of ancestral source populations to admixed Latin American populations, together with SNP frequencies in the ancestral populations, to derive expected SNP frequencies for the Latin American populations. - These expected frequencies are compared to observed fre- quencies in order to identify statistically significant ancestry-enriched SNPs. - the connection between ancestry-enriched SNPs and health-related phenotypes is then explored via analysis of the functional annota- tions of the SNPs and their linked genes. - In particular, we interrogated the impact of ancestry-enriched SNPs on disease, metabolism and immune system pathways.. - among all four of the Latin American populations that we analyzed, raising the possibility of shared selective pressures among them.. - Whole genome sequences from four admixed Latin American populations – Colombia (n = 94), Mexico (n = 64), Peru (n = 85), and Puerto Rico (n = 104. - Genome sequences from the four Latin American populations were compared to whole genome sequences and whole genome genotypes of global reference popula- tions from African, European, and Native American con- tinental population groups to characterize their patterns of genetic ancestry and admixture (Fig. - (1) Genetic ancestry and admixture profiles were characterized for four Latin American populations. - (2) Expected SNP frequencies in the admixed Latin American populations are calculated based on their ancestry profiles. - (3) Ancestry-enriched SNPs are identified by comparing observed versus expected SNP allele frequencies in in the admixed Latin American populations. - (4) Ancestry-enriched SNPs are mapped to genes, which in turn are used for gene set enrichment in order to identify impacted health-related pathways and phenotypes. - ADMIXTURE [22] was run on individuals from both the global reference and admixed Latin American populations to infer their genome-wide ancestry profiles. - The ADMIXTURE results for the admixed Latin American populations were used to infer individuals’ per- cent ancestry contributions from each of these three con- tinental ancestry groups. - Detection of ancestry-enriched SNPs. - Ancestry-enriched SNPs were characterized as SNPs found in higher frequencies in admixed Latin American populations compared to what is expected based on (1) their frequencies in the ancestral source populations, and (2) the proportion of ancestry derived from each an- cestral source population. - For any given SNP, in any given Latin American population, the expected fre- quency of the SNP f(SNP) Exp can be calculated as:. - ð1Þ where f(SNP) Pop is the frequency of the SNP in a specific ancestral source population and P(Anc) Pop is the propor- tion of ancestry in the modern Latin American popula- tion derived from that same ancestral population.. - 0.05) were consid- ered to be ancestry-enriched in the Latin American population, i.e. - For ancestry-enriched SNPs, the individual ancestry components (Anc) that gave rise to the pattern of en- richment were also determined by jointly minimizing the frequency difference between the SNP in the Latin American population and a single ancestral source population while maximizing the distance between that single source population and the other two ancestral populations:. - =2− f SNP ð Þ Obs −f SNP ð Þ Pop1 ð 3 Þ where f(SNP) Popx is the frequency of the SNP in each of the ancestral source populations and f(SNP) Obs is the fre- quency of the ancestry-enriched SNP in the Latin American population.. - Ancestry-enriched SNPs were mapped to genes if they mapped within the NCBI RefSeq [24] gene models, i.e.. - Gene set enrichment analysis (GSEA) was performed for each Latin American popula- tion by adopting the MSigDB statistical framework to find functional gene sets that were enriched for genes with mapped ancestry-enriched SNPs. - To do this, genes that harbor ancestry-enriched SNPs were overlapped. - Relating genome ancestry and health in Latin America We developed and applied a single nucleotide polymorph- ism (SNP)-based approach to relate genome ancestry to genetic determinants of health in admixed Latin American populations (Fig. - First, patterns of genetic ancestry and admixture in Latin American populations were character- ized via comparison with reference genome sequences of putative ancestral source populations from Africa, the Americas and Europe (Table 1). - We then computed the ex- pected SNP frequencies in Latin American populations by taking into consideration the SNP frequencies in the ances- tral source populations along with the proportional contri- butions of each ancestral source population to the modern Latin American populations. - Comparisons of observed ver- sus expected SNP frequencies in admixed Latin American populations were used to identify what we refer to as. - ‘ancestry-enriched’ SNPs, which are SNPs found at anomal- ous frequencies in Latin American populations compared to what can be expected based on their ancestry profiles.. - Ancestry-enriched SNPs were mapped to genes, and then genes were used in gene set enrichment analysis to identify impacted health-related pathways and phenotypes.. - Genetic ancestry and admixture in four Latin American populations. - Genome sequences from four Latin American popula- tions – Colombia, Mexico, Peru, and Puerto Rico – were compared to whole genome sequences and whole gen- ome genotypes of global reference populations from Af- rican, European, and Native American continental population groups in order to characterize their patterns of genetic ancestry and admixture. - Each Latin American population has a distinct pattern of three-way continen- tal genetic admixture characterized by population-spe- cific proportions of African, European and Native American ancestry (Fig. - The 80% Na- tive American ancestry component for Peru is the single highest contribution of any ancestral population to an admixed Latin American population, and the 2% African ancestry fraction for this same population is the lowest.. - of ancestry to all four Latin American populations ana- lyzed here. - The continental ancestry proportions for each Latin American population were used as described in the following section to detect ancestry-enriched SNPs that exist in any given population at a higher fre- quency than expected based on its ancestry profile.. - Ancestry-enriched SNPs in Latin American populations Our approach to relating genetic ancestry to determi- nants of health and disease in modern Latin American populations relies on the detection of SNPs that are found at anomalously high frequencies in admixed populations compared to what is expected based on their frequencies in the ancestral source populations, i.e.. - We reasoned that such ancestry-enriched SNPs are likely to have an outsized ef- fect on health and disease in modern Latin American populations, perhaps related to an initial increase in population frequency via adaptive introgression.. - We developed and applied a quantitative method to iden- tify individual SNPs that are enriched in admixed Latin American populations with respect to ancestry from one of the three ancestral source populations: Africa, Europe, and the Americas. - To do so, the expected frequencies for each SNP were calculated using the frequency of the given SNP in each of the three ancestral source populations conditioned upon the proportion of each ancestral source population in the Latin American population of interest. - Observed SNP frequencies were compared to expected SNP frequencies to identify ancestry-enriched SNPs. - Statistically signifi- cant ancestry-enriched SNPs for each population were mapped to genes for subsequent analysis of their impact on health- and disease-related phenotypes. - Out of 156 total genes with mapped ancestry-enriched SNPs are shared among two or more populations compared to 54 (35%) that are population-specific. - There are 40 genes that bear ancestry-specific SNPs in all four Latin American popula- tions, which is by far the single largest component of shared versus unique genes. - This approach allowed us to identify the specific pathways and phenotypes that are most affected by ancestry-enriched SNPs. - The presence of significantly overrepresented pathways and/or pheno- types in two or more populations was taken to indicate a higher likelihood of genetic ancestry effects on health and disease in modern Latin American populations.. - A number of pathways and phenotypes have significantly overrepresented ancestry-enriched SNP genes in all four. - Immune system pathways with ancestry-enriched SNPs include the cytokine receptor interaction, T cell receptor signaling, and antigen processing and presentation pathways. - Diseases of note in- clude several pathologies that are known to be found in high prevalence in Latin American populations: type I diabetes,. - 2 Genetic ancestry and admixture in Latin American populations. - The ancestry contributions of putative ancestral source populations to four modern, admixed Latin American populations are shown. - a Triangle plots showing the relative ancestry contributions – African, European, Native American – to admixed individuals from four Latin American populations. - b PCA plot showing the genetic relationships among individuals from admixed Latin American populations compared to putative ancestral source populations. - c Admixture plots showing the fractions of African, Native American and European ancestry among admixed individuals from four Latin American populations. - d Violin plots showing distributions of ancestry fractions among individuals from four Latin American populations. - Lists of all pathways that show significant en- richment of genes with mapped ancestry-enriched SNPs, for each admixed Latin American population – along with infor- mation regarding the overlapping genes and pathway enrich- ment statistical significance (FDR q-values. - We focused on several notable examples of health- and disease-related pathways that were found to have signifi- cantly overrepresented ancestry-enriched SNP genes in all four Latin American populations (Fig. - For each of these pathways, and in each population studied, we performed additional meta-analyses of the sets of mapped ancestry- enriched SNPs in order to evaluate the pathway’ s overall an- cestry enrichment. - To do this, we searched for ancestry-enriched SNPs that have ancestry-specific or shared genotype-expression associations. - Using this approach, we found a number of cases of SNPs that show overrepresented African or European an- cestry in modern Latin American populations and are also associated with ancestry-specific gene regulation (Fig. - In particular, genes from both the innate and adaptive immune system were found to be regulated by ancestry-enriched SNPs that exert population-specific regulatory effects (Fig. - For example, African ancestry-enriched SNPs were found to exert African-specific regulatory control over genes for both immunoglobulin receptors (PVR and TYROBP) and. - 3 Ancestry-enriched SNPs in Latin American populations. - An overview of the distributions of ancestry-enriched SNPs within and between the four admixed Latin American populations are shown, giving an indication of the overall numbers of ancestry-enriched SNPs along with the extent to which they are shared or unique to specific populations. - a Cumulative distributions of ancestry-enrichment χ 2 values for all SNPs in the four Latin American populations. - In other words, Latin American genomes represent a very recent evolution- ary innovation in the long trajectory of human evolution and migration around the globe. - Accordingly, the develop- ment and application of genomic approaches to healthcare in Latin America will require a deep understanding of the genetic ancestry and admixture profiles of Latin American populations. - 4 Gene set enrichment analysis of ancestry-enriched SNP genes. - Functionally coherent gene sets and pathways that are overrepresented with respect to ancestry-enriched SNPs are shown, giving an indication of the kinds of health-related phenotypes that have been shaped by genetic ancestry in the four admixed Latin American populations. - a Heatmap showing significantly enriched functional gene sets (i.e., pathways and phenotypes) shared by two, three or all four Latin American populations. - b Network showing significantly enriched pathways and phenotypes shared by all four Latin American populations. - Nodes sizes represent the number of ancestry-enriched genes in each set. - Here, we have tried to address this issue by relating pat- terns of genetic ancestry and admixture to health and dis- ease determinants in Latin American genomes. - Our approach leverages in- formation on the genetic ancestry of the modern Latin American populations to discover SNP variants that exist in a given population at higher frequencies than expected, i.e. - We found that specific sets of ancestry-enriched genetic variants, from each of the three ancestral source populations, have been preferentially retained in modern Latin American populations based on a variety of roles that they play in health and fitness. - Gene set enrichment analysis uncovered a number of immunity, metabolism, and disease-related pathways that are significantly overrepresented with respect to genes that contain ancestry-enriched SNPs (Figs. - These results suggest that these particular pathways, and their related phenotypes, could underlie population-specific health disparities in the four admixed Latin American populations studied here. - 5 Pathways with ancestry-enriched SNP genes in functional categories of interest. - These results highlight examples of specific health-related functions and pathways that have been shaped by genetic ancestry in the four admixed Latin American populations. - Expression quantitative trait loci (eQTL) analysis revealed ancestry-enriched SNPs in modern Latin American. - These results give an indication of how ancestry-enriched SNPs can impact health-related phenotypes by virtue of their gene regulatory effects. - Given the di- versity of Latin American populations, and in particular their distinct ancestry profiles, we should expect to see distinct an- cestry enrichments for different countries in the region, such as Argentina, Chile, Brazil etc. - For each admixed Latin American population, all ancestry-enriched SNPs (q<. - The allele (reference or alternate) and enriched ancestry (African, European or Native American) are designated for each ancestry-enriched SNP. - Lists of pathways that show significant enrichment of genes with mapped ancestry-enriched SNPs for each admixed Latin American population. - For each KEGG pathway with significant enrichment of genes with mapped ancestry-enriched SNPs in at least one of the four populations, the overlapping genes and FDR q-values are given. - Geographic patterns of genome admixture in Latin American mestizos
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