Population structure and relatedness estimates in a Mexican sample.

Population stratification (PS) is a confounding factor in genome-wide association studies (GWASs) and also an interesting process itself. Latin American populations have mixed genetic ancestry, which may account for PS. We have analyzed the relatedness, by means of the identity-by-descent (IBD) estimations, in a sample of 1805 individuals and 1.006.703 autosomal mutations from a case-control study of colorectal cancer in Mexico. When using the recommended protocol for quality control assessment, 402 should have been removed due to relatedness. Our purpose was to analyze this value in the context of an admixed population. For that aim, we reanalyzed the sample using two software designed for admixed populations, obtaining estimates of 110 and 70 related individuals to remove. The results showed that the first estimation of relatedness was an effect of the higher Native American contribution in part of the data samples, being a confounding factor for IBD estimations. We conclude in the importance of considering PS and genetic ancestry in order to avoid spurious results, not only in GWAS but also in relatedness analysis.

A view of the maternal inheritance of Espírito Santo populations: The contrast between the admixed and Pomeranian descent groups.

In addition to its valuable utility in forensic investigations, mitochondrial DNA (mtDNA) analysis is a reliable tool to uncover the origins of admixed populations, such as Brazilians. The state of Espírito Santo (ES), similar to other coastal Brazilian states, has a population shaped by 3 main ancestral roots: Amerindian, African and European. Among the latter, the Pomeranian descendants stand out due to the preservation of the traditional aspects of their culture, especially the Pomeranian language. Despite the genetic data already available, there is no mtDNA database that adequately reflects the diversity, the geographic distribution, and the origins of the maternal lineages from ES. To increase the knowledge of maternal ancestry and to investigate the population's genetic stratification, a total of 291 samples were collected in the 4 macroregions (Metropolitan, South, Central and North) of ES and in the Pomeranian communities. Complete control region data were produced for the general (N=214) and Pomeranian (N=77) groups. Regarding the general population, the high values of haplotype diversity (H=99.9%) and pairwise differences (MNPD=16.9) found are in agreement with those reported for other populations in the southeast region of the country. Regarding maternal inheritance, the ES populations stood out due to the predominance of European haplogroups (49.5%), although the North macroregion had a higher African ancestry (47.1%). Among the Pomeranians, the lowest MNPD value (11.2) and the high percentage of shared haplotypes (15%) were indicative of founder events. The FST analysis showed that the Pomeranians (98.7% of European lineages) are genetically isolated from the other admixed populations in Brazil. This study demonstrated that the ES state contains singularities regarding the intrapopulational and interpopulational diversity of mtDNA. Even after 5 centuries of interethnic admixture, the present-day population of Espírito Santo harbors genetic marks that trace back to the historical aspects of its formation.

A panel of 32 AIMs suitable for population stratification correction and global ancestry estimation in Mexican mestizos.

BACKGROUND: Association studies are useful to unravel the genetic basis of common human diseases. However, the presence of undetected population structure can lead to both false positive results and failures to detect genuine associations. Even when most of the approaches to deal with population stratification require genome-wide data, the use of a well-selected panel of ancestry informative markers (AIMs) may appropriately correct for population stratification. Few panels of AIMs have been developed for Latino populations and most contain a high number of markers (> 100 AIMs). For some association studies such as candidate gene approaches, it may be unfeasible to genotype a numerous set of markers to avoid false positive results. In such cases, methods that use fewer AIMs may be appropriate. RESULTS: We validated an accurate and cost-effective panel of AIMs, for use in population stratification correction of association studies and global ancestry estimation in Mexicans, as well as in populations having large proportions of both European and Native American ancestries. Based on genome-wide data from 1953 Mexican individuals, we performed a PCA and SNP weights were calculated to select subsets of unlinked AIMs within percentiles 0.10 and 0.90, ensuring that all chromosomes were represented. Correlations between PC1 calculated using genome-wide data versus each subset of AIMs (16, 32, 48 and 64) were r2 = 0.923, 0.959, 0.972 and 0.978, respectively. When evaluating PCs performance as population stratification adjustment covariates, no correlation was found between P values obtained from uncorrected and genome-wide corrected association analyses (r2 = 0.141), highlighting that population stratification correction is compulsory for association analyses in admixed populations. In contrast, high correlations were found when adjusting for both PC1 and PC2 for either subset of AIMs (r2 > 0.900). After multiple validations, including an independent sample, we selected a minimal panel of 32 AIMs, which are highly informative of the major ancestral components of Mexican mestizos, namely European and Native American ancestries. Finally, the correlation between the global ancestry proportions calculated using genome-wide data and our panel of 32 AIMs was r2 = 0.972. CONCLUSIONS: Our panel of 32 AIMs accurately estimated global ancestry and corrected for population stratification in association studies in Mexican individuals.

The geographic mosaic of Ecuadorian Y-chromosome ancestry.

Ecuadorians originated from a complex mixture of Native American indigenous people with Europeans and Africans. We analyzed Y-chromosome STRs (Y-STRs) in a sample of 415 Ecuadorians (145 using the AmpFlSTR® Yfiler™ system [Life Technologies, USA] and 270 using the PowerPlex®Y23 system [Promega Corp., USA]; hereafter Yfiler and PPY23, respectively) representing three main ecological continental regions of the country, namely Amazon rainforest, Andes, and Pacific coast. Diversity values are high in the three regions, and the PPY23 exhibits higher discrimination power than the Yfiler set. While summary statistics, AMOVA, and RST distances show low to moderate levels of population stratification, inferred ancestry derived from Y-STRs reveal clear patterns of geographic variation. The major ancestry in Ecuadorian males is European (61%), followed by an important Native American component (34%); whereas the African ancestry (5%) is mainly concentrated in the Northwest corner of the country. We conclude that classical procedures for measuring population stratification do not have the desirable sensitivity. Statistical inference of ancestry from Y-STRS is a satisfactory alternative for revealing patterns of spatial variation that would pass unnoticed when using popular statistical summary indices.

Properties of global- and local-ancestry adjustments in genetic association tests in admixed populations.

Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry-adjusted and -unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real-world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the genotype parameters of adjusted and unadjusted models all provide tests for LD between the marker and trait locus, but in different contexts. The local ancestry adjusted model tests for LD in the ancestral populations, while tests using the unadjusted and the global ancestry adjusted models depend on LD in the admixed population(s), which may be enriched due to different ancestral allele frequencies. Practically, this implies that global-ancestry adjustment should be used for screening, but local-ancestry adjustment may better inform fine mapping and provide better effect estimates at trait loci.

Population stratification effect on cancer susceptibility in an admixed population from Brazilian Amazon.

BACKGROUND/AIM: Many efforts have been made to identify candidate genes involved in cancer susceptibility. The present study aimed to investigate the association between Arg194Trp (XRCC1), Ala222Val (MTHFR) and Arg521Lys (EGFR) polymorphisms (SNPs) and their susceptibility to gastric and breast carcinoma cancer in patients from Brazilian Amazon, controlling population structure interference. MATERIALS AND METHODS: The SNPs were genotyped by TaqMan® SNP Genotyping Assays. Ancestry was estimated by analysis of a panel with 48 ancestry informative markers. RESULTS: Logistic regression analysis showed an inverse association with a 10% increase in African and European ancestry and cancer risk (odds ratio (OR)=1.919 and 0.676, respectively). In a preliminary Chi-square analysis a positive association between Arg521Lys (EGFR) polymorphism and carcinoma susceptibility was found (p=0.037); however, when two different methodologies to control population structure bias were utilized, this association was lost (p=0.064 and p=0.256). CONCLUSION: Genetic ancestry influence gastric and breast cancer risk and highlight the importance of population structure inference in association studies in highly admixed populations, such as those from Brazilian Amazon.

Male lineage strata of Brazilian population disclosed by the simultaneous analysis of STRs and SNPs.

Brazil has a large territory divided in five geographical regions harboring highly diverse populations that resulted from different degrees and modes of admixture between Native Americans, Europeans and Africans. In this study, a sample of 605 unrelated males was genotyped for 17 Y-STRs and 46 Y-SNPs aiming a deep characterization of the male gene pool of Rio de Janeiro and its comparison with other Brazilian populations. High values of Y-STR haplotype diversity (0.9999±0.0001) and Y-SNP haplogroup diversity (0.7589±0.0171) were observed. Population comparisons at both haplotype and haplogroup levels showed significant differences between Brazilian South Eastern and Northern populations that can be explained by differences in the proportion of African and Native American Y chromosomes. Statistical significant differences between admixed urban samples from the five regions of Brazil were not previously detected at haplotype level based on smaller size samples from South East, which emphasizes the importance of sample size to detected population stratification for an accurate interpretation of profile matches in kinship and forensic casework. Although not having an intra-population discrimination power as high as the Y-STRs, the Y-SNPs are more powerful to disclose differences in admixed populations. In this study, the combined analysis of these two types of markers proved to be a good strategy to predict population sub-structure, which should be taken into account when delineating forensic database strategies for Y chromosome haplotypes.

Genomic variation and population structure detected by single nucleotide polymorphism arrays in Corriedale, Merino and Creole sheep.

THE AIM OF THIS STUDY WAS TO INVESTIGATE THE GENETIC DIVERSITY WITHIN AND AMONG THREE BREEDS OF SHEEP: Corriedale, Merino and Creole. Sheep from the three breeds (Merino n = 110, Corriedale n = 108 and Creole n = 10) were genotyped using the Illumina Ovine SNP50 beadchip(®). Genetic diversity was evaluated by comparing the minor allele frequency (MAF) among breeds. Population structure and genetic differentiation were assessed using STRUCTURE software, principal component analysis (PCA) and fixation index (FST). Fixed markers (MAF = 0) that were different among breeds were identified as specific breed markers. Using a subset of 18,181 single nucleotide polymorphisms (SNPs), PCA and STUCTURE analysis were able to explain population stratification within breeds. Merino and Corriedale divergent lines showed high levels of polymorphism (89.4% and 86% of polymorphic SNPs, respectively) and moderate genetic differentiation (FST = 0.08) between them. In contrast, Creole had only 69% polymorphic SNPs and showed greater genetic differentiation from the other two breeds (FST = 0.17 for both breeds). Hence, a subset of molecular markers present in the OvineSNP50 is informative enough for breed assignment and population structure analysis of commercial and Creole breeds.

The effect of genetic admixture in an association study: genetic polymorphisms and chromosome aberrations in a Colombian population exposed to organic solvents.

The human population is heterogeneous in genetic susceptibility, chromosomal instability and disease risk; all factors which depend on inherited genetic constitution and acquired nongenetic environmental and occupational factors. Recently, special attention has been directed to the identification of sources of potential bias in population studies of gene-environment interactions including genetic admixture. The aim of this study was to evaluate the effect of genetic admixture in the association of genetic polymorphisms and chromosome aberrations (CA) in a population exposed to organic solvents. We assessed genetic admixture via 34 genetic ancestry informative markers (AIMs) in 398 Colombian individuals. We report a statistically significant difference of higher CA frequency in individuals' below-average European component, and in individuals' above-average Native American component after adjusting for covariates. In addition, the confounding risk ratio values are ≥10% than the adjusted risk ratio, suggesting that population stratification is a confounding factor in this gene-environment association study. Furthermore, after adjusting for individual admixture proportions and covariates, the results demonstrate that glutathione-S-transferase M1 (GSTM1)-null is associated with CA frequency increase. These results suggest that gene-environment association studies that involve recently admixed populations should take into consideration population stratification as a confounding factor and suggest GSTM1-null as a genetic marker associated with CA frequency increase.