Recent shifts in the genomic ancestry of Mexican Americans may alter the genetic architecture of biomedical traits.

People in the Americas represent a diverse continuum of populations with varying degrees of admixture among African, European, and Amerindigenous ancestries. In the United States, populations with non-European ancestry remain understudied, and thus little is known about the genetic architecture of phenotypic variation in these populations. Using genotype data from the Hispanic Community Health Study/Study of Latinos, we find that Amerindigenous ancestry increased by an average of ~20% spanning 1940s-1990s in Mexican Americans. These patterns result from complex interactions between several population and cultural factors which shaped patterns of genetic variation and influenced the genetic architecture of complex traits in Mexican Americans. We show for height how polygenic risk scores based on summary statistics from a European-based genome-wide association study perform poorly in Mexican Americans. Our findings reveal temporal changes in population structure within Hispanics/Latinos that may influence biomedical traits, demonstrating a need to improve our understanding of admixed populations.

A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma.

Short-acting ß2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African-American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10-8). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

Ebola virus, but not Marburg virus, replicates efficiently and without required adaptation in snake cells.

Ebola virus (EBOV) disease is a viral hemorrhagic fever with a high case-fatality rate in humans. This disease is caused by four members of the filoviral genus Ebolavirus, including EBOV. The natural hosts reservoirs of ebolaviruses remain to be identified. Glycoprotein 2 of reptarenaviruses, known to infect only boa constrictors and pythons, is similar in sequence and structure to ebolaviral glycoprotein 2, suggesting that EBOV may be able to infect reptilian cells. Therefore, we serially passaged EBOV and a distantly related filovirus, Marburg virus (MARV), in boa constrictor JK cells and characterized viral infection/replication and mutational frequency by confocal imaging and sequencing. We observed that EBOV efficiently infected and replicated in JK cells, but MARV did not. In contrast to most cell lines, EBOV-infected JK cells did not result in an obvious cytopathic effect. Surprisingly, genomic characterization of serial-passaged EBOV in JK cells revealed that genomic adaptation was not required for infection. Deep sequencing coverage (>10,000×) demonstrated the existence of only a single nonsynonymous variant (EBOV glycoprotein precursor pre-GP T544I) of unknown significance within the viral population that exhibited a shift in frequency of at least 10 per cent over six serial passages. In summary, we present the first reptilian cell line that replicates a filovirus at high titers, and for the first time demonstrate a filovirus genus-specific restriction to MARV in a cell line. Our data suggest the possibility that there may be differences between the natural host spectra of ebolaviruses and marburgviruses.

The Effects of Migration and Assortative Mating on Admixture Linkage Disequilibrium.

Statistical models in medical and population genetics typically assume that individuals assort randomly in a population. While this simplifies model complexity, it contradicts an increasing body of evidence of nonrandom mating in human populations. Specifically, it has been shown that assortative mating is significantly affected by genomic ancestry. In this work, we examine the effects of ancestry-assortative mating on the linkage disequilibrium between local ancestry tracks of individuals in an admixed population. To accomplish this, we develop an extension to the Wright-Fisher model that allows for ancestry-based assortative mating. We show that ancestry-assortment perturbs the distribution of local ancestry linkage disequilibrium (LAD) and the variance of ancestry in a population as a function of the number of generations since admixture. This assortment effect can induce errors in demographic inference of admixed populations when methods assume random mating. We derive closed form formulae for LAD under an assortative-mating model with and without migration. We observe that LAD depends on the correlation of global ancestry of couples in each generation, the migration rate of each of the ancestral populations, the initial proportions of ancestral populations, and the number of generations since admixture. We also present the first direct evidence of ancestry-assortment in African Americans and examine LAD in simulated and real admixed population data of African Americans. We find that demographic inference under the assumption of random mating significantly underestimates the number of generations since admixture, and that accounting for assortative mating using the patterns of LAD results in estimates that more closely agrees with the historical narrative.

Stress and Bronchodilator Response in Children with Asthma.

RATIONALE: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR). OBJECTIVES: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma. METHODS: This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids. MEASUREMENTS AND MAIN RESULTS: High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the ß2-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety). CONCLUSIONS: High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children.