Simultaneous inference of parental admixture proportions and admixture times from unphased local ancestry calls

Population genetic analyses of local ancestry tracts routinely assume that the ancestral admixture process is identical for both parents of an individual, an assumption that may be invalid when considering recent admixture. Here we present Parental Admixture Proportion Inference (PAPI), a Bayesian tool for inferring the admixture proportions and admixture times for each parent of a single admixed individual. PAPI analyzes unphased local ancestry tracts and has two components models: a binomial model that exploits the informativeness of homozygous ancestry regions to infer parental admixture proportions, and a hidden Markov model (HMM) that infers admixture times from tract lengths. Crucially, the HMM employs an approximation to the pedigree crossover dynamics that accounts for unobserved within-ancestry recombination, enabling inference of parental admixture times. We compared the accuracy of PAPI's admixture proportion estimates with those of ANCESTOR in simulated admixed individuals and found that PAPI outperforms ANCESTOR by an average of 46% in a representative set of simulation scenarios, with PAPI's estimates deviating from the ground truth by 0.047 on average. Moreover, PAPI's admixture time estimates were strongly correlated with the ground truth in these simulations (R = 0.76), but have an average downward bias of 1.01 generations that is partly attributable to inaccuracies in local ancestry inference. As an illustration of its utility, we ran PAPI on real African Americans from the PAGE study (N = 5,786) and found strong evidence of assortative mating by ancestry proportion: couples' ancestry proportions are closer to each other than expected by chance (P<10-6), and are highly correlated (R = 0.87). We anticipate that PAPI will be useful in studying the population dynamics of admixture and will also be of interest to individuals seeking to learn about their personal genealogies.

Abstract P075: Genetic European Ancestry And Incident Diabetes Mellitus In Black Individuals-Insights From The SPRINT Trial

Background: A metabolic paradox of lower triglyceride (TG) and higher high-density lipoprotein cholesterol (HDL-C) levels but a higher incidence of diabetes has been described in Blacks. We evaluated the association of genetic ancestry-related variants with the risk of incident diabetes in self-identified Black individuals in the Systolic Blood Pressure (BP) Intervention Trial (SPRINT). Methods: The genetic European ancestry proportions were estimated using 106 biallelic genotype markers in non-diabetic Black participants. Participants were stratified into tertiles (T1-T3) of European ancestry proportions. Multivariable-adjusted association of baseline metabolic syndrome indices (fasting plasma glucose [FPG], TG, HDL-C, body mass index [BMI], and BP) with the ancestry proportion was assessed. Multivariable-adjusted Cox regression was used to assess the risk of incident diabetes (FPG ≥126 mg/dL or self-reported diabetes treatment) across tertiles. Results: In 2,466 participants with median European ancestry 19% (13 - 27%), those in T1 were relatively younger, with lower Framingham risk score, and worse renal function (p<0.05 for all). At baseline, higher European ancestry proportion was associated with higher TG and lower HDL-C levels after controlling for clinical and demographic factors (p<0.05 for both). FPG, BMI, and BP were not significantly associated with ancestry proportion. Compared with T1, those in second (HR: 0.64 [95% CI: 0.45-0.90]) and third tertiles (HR: 0.61 [0.44-0.89]) had a lower risk of incident diabetes after controlling for covariates. Specifically, a 5% increment in European ancestry was associated with a 29% lower risk of incident diabetes (HR: 0.71 [0.55-0.93]). No interaction was observed between intensive BP control strategy and European ancestry proportion tertiles on incident diabetes. Conclusions: Genetic factors may account for racial differences in TG and HDL-C levels. The higher risk of incident diabetes in Blacks may similarly be genetically determined.

Modeling epistasis in mice and yeast using the proportion of two or more distinct genetic backgrounds: Evidence for “polygenic epistasis”

Background The majority of quantitative genetic models used to map complex traits assume that alleles have similar effects across all individuals. Significant evidence suggests, however, that epistatic interactions modulate the impact of many alleles. Nevertheless, identifying epistatic interactions remains computationally and statistically challenging. In this work, we address some of these challenges by developing a statistical test for polygenic epistasis that determines whether the effect of an allele is altered by the global genetic ancestry proportion from distinct progenitors. Results We applied our method to data from mice and yeast. For the mice, we observed 49 significant genotype-by-ancestry interaction associations across 14 phenotypes as well as over 1,400 Bonferroni-corrected genotype-by-ancestry interaction associations for mouse gene expression data. For the yeast, we observed 92 significant genotype-by-ancestry interactions across 38 phenotypes. Given this evidence of epistasis, we test for and observe evidence of rapid selection pressure on ancestry specific polymorphisms within one of the cohorts, consistent with epistatic selection. Conclusions Unlike our prior work in human populations, we observe widespread evidence of ancestry-modified SNP effects, perhaps reflecting the greater divergence present in crosses using mice and yeast.

Characterization of Ancestral Origin of Cystic Fibrosis of Patients with New Reported Mutations in CFTR

The incidence of cystic fibrosis (CF) and the frequency of the variants reported for CFTR depend on the population; furthermore, CF symptomatology is characterized by obstructive lung disease and pancreatic insufficiency among other symptoms, which are reliant on the individual's genotype. The Ecuadorian population is a mixture of Native Americans, Europeans, and Africans. That population admixture could be the reason for the new mutations reported in a previous study by Ruiz et al. (2019). A panel of 46 Ancestry Informative Markers was used to estimate the ancestral proportions of each available sample (12 samples in total). As a result, the Native American ancestry proportion was the most prevalent in almost all individuals, except for three patients from Guayaquil with the mutation [c.757G>A:p.Gly253Arg; c.1352G>T:p.Gly451Val] who had the highest European composition.

Characterization Of Ancestral Origin Of Cystic Fibrosis Of Patients With New Reported Mutations In CFTR

The incidence of Cystic fibrosis (CF) and the frequency of the variants for CFTR depend on the population; furthermore, CF symptomatology is characterized by obstructive lung disease, pancreatic insufficiency among others, reliant on the individual genotype. Ecuadorian population is a mixture of Native Americans, Europeans, and Africans. That population admixture could be the reason for the new mutations reported in a previous study by Ruiz et al. (2019). A panel of 46 Ancestry Informative Markers was used to estimate the ancestral proportions of each available sample (12 samples in total). As a result, the Native American ancestry proportion was the most prevalent in almost all individuals, except for three patients from Guayaquil with the mutation [c.757G>A:p.Gly253Arg; c.1352G>T:p.Gly451Val] who had the highest European composition.

Ancestry explains the blunted ventilatory response to sustained hypoxia and lower exercise ventilation of Quechua altitude natives

Andean high-altitude (HA) natives have a low (blunted) hypoxic ventilatory response (HVR), lower effective alveolar ventilation, and lower ventilation (VE) at rest and during exercise compared with acclimatized newcomers to HA. Despite blunted chemosensitivity and hypoventilation, Andeans maintain comparable arterial O2saturation (SaO2). This study was designed to evaluate the influence of ancestry on these trait differences. At sea level, we measured the HVR in both acute (HVR-A) and sustained (HVR-S) hypoxia in a sample of 32 male Peruvians of mainly Quechua and Spanish origins who were born and raised at sea level. We also measured resting and exercise VE after 10–12 h of exposure to altitude at 4,338 m. Native American ancestry proportion (NAAP) was assessed for each individual using a panel of 80 ancestry-informative molecular markers (AIMs). NAAP was inversely related to HVR-S after 10 min of isocapnic hypoxia ( r = −0.36, P = 0.04) but was not associated with HVR-A. In addition, NAAP was inversely related to exercise VE ( r = −0.50, P = 0.005) and ventilatory equivalent (VE/V̇o2, r = −0.51, P = 0.004) measured at 4,338 m. Thus Quechua ancestry may partly explain the well-known blunted HVR ( 10 , 35 , 36 , 57 , 62 ) at least to sustained hypoxia, and the relative exercise hypoventilation at altitude of Andeans compared with European controls. Lower HVR-S and exercise VE could reflect improved gas exchange and/or attenuated chemoreflex sensitivity with increasing NAAP. On the basis of these ancestry associations and on the fact that developmental effects were completely controlled by study design, we suggest both a genetic basis and an evolutionary origin for these traits in Quechua.