Abstract

Bigham, Abigail W., Melisa Kiyamu, Fabiola León-Verlarde, Esteban J. Parra, Maria Rivera-Ch, Mark D. Shriver, and Tom D. Brutsaert. Angiotensin-converting enzyme genotype and arterial oxygen saturation at high altitude in Peruvian Quechua. High Alt. Med. Biol. 9:167–178, 2008.—The I-allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with performance benefits at high altitude (HA). In n = 142 young males and females of largely Quechua origins in Peru, we evaluated 3 specific hypotheses with regard to the HA benefits of the I-allele: (1) the I-allele is associated with higher arterial oxygen saturation (\documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$${\rm Sa}_{\rm O_2}$$\end{document}) at HA, (2) the I-allele effect depends on the acclimatization state of the subjects, and (3) the putative I-allele effect on \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$${\rm Sa}_{\rm O_2}$$\end{document} is mediated by the isocapnic hypoxic ventilatory response (HVR, \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$$1 / {\rm min}^{- 1} / \%{\rm Sa}_{\rm O_2}{- 1}$$\end{document}). The subject participants comprised two different study groups including BLA subjects (born at low altitude) who were lifelong sea-level residents transiently exposed to hypobaric hypoxia (<24 h) and BHA subjects (born at HA) who were lifelong residents of HA. To control for the possibility of population stratification, Native American ancestry proportion (NAAP) was estimated as a covariate for each individual using a panel of 70 ancestry-informative molecular markers (AIMS). At HA, resting and exercise \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$${\rm Sa}_{\rm O_2}$$\end{document} was strongly associated with the ACE genotype, p = 0.008 with ∼4% of the total variance in \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$${\rm Sa}_{\rm O_2}$$\end{document} attributed to ACE genotype. Moreover, I/I individuals maintained ∼2.3 percentage point higher \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$${\rm Sa}_{\rm O_2}$$\end{document} compared to I/D and D/D. This I-allele effect was evident in both BLA and BHA groups, suggesting that acclimatization state has little influence on the phenotypic expression of the ACE gene. Finally, ACE genotype was not associated with the isocapnic HVR, although HVR had a strong independent effect on \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$${\rm Sa}_{\rm O_2}$$\end{document} (p = 0.001). This suggests that the I-allele effect on \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland,xspace}\usepackage{amsmath,amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$${\rm Sa}_{\rm O_2}$$\end{document} is not mediated by the peripheral control of breathing, but rather by some other central cardiopulmonary effect of the ACE gene on the renin–angiotensin–aldosterone system (RAAS).

Pro- versus anti-inflammatory cytokine balance is important for successful pregnancy. Chronic hypoxia alters cytokine levels and increases the frequency of fetal growth restriction (FGR). Multigenerational Andean (AND) versus shorter duration European (EUR) high-altitude (HA) residents are protected from altitude-associated FGR. To address whether ancestry group differences in cytokine levels were involved, we conducted serial studies in 56 low-altitude ([LA]; 400 m; n = 29 AND and n = 27 EUR) and 42 HA residents (3600-4100 m; n = 19 ANDs and n = 23 EURs). Pregnancy raised pro- (interleukin 1β [IL-1β]) and anti- (IL-10) inflammatory cytokines and HA lowered IL-6 and tumor necrosis factor-α (TNF-α) near term. There were no ancestry group differences in cytokine levels at any time, but HA reduced IL-1β in ANDs only near term. Higher IL-1β levels correlated with uterine artery (UA) blood flow at 20 weeks in ANDs at HA, suggesting that IL-1β may play a role in AND protection from altitude-associated reductions in fetal growth.

For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study “virtual genomes” of admixed individuals. We apply this approach to a cohort of 492 parent–offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations—Africa, Europe, and America—vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10–15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people.

Author Summary

Admixed individuals, such as African Americans and Latinos, arise from mating between individuals from different continents. Detailed knowledge about the ancestral origin of an admixed population not only provides insight regarding the history of the population itself, but also affords opportunities to study the evolutionary biology of the ancestral populations. Applying novel statistical methods, we analyzed the high-density genotype data of nearly 1,500 Mexican individuals from Mexico City, who are admixed among Indigenous Americans, Europeans, and Africans. The relative contributions from the three continental-level ancestral populations vary substantially between individuals. The European ancestors of these Mexican individuals genetically resemble Southern Europeans, such as the Spaniard and the Portuguese. The Indigenous American ancestry of the Mexicans in our study is largely attributed to the indigenous groups residing in the southwestern region of Mexico, although some individuals have inherited varying degrees of ancestry from the Mayans of the Yucatan Peninsula and other indigenous American populations. A search for signatures of selection, focusing on the parts of the genomes derived from an ancestral population (e.g. Indigenous American), identifies regions in which a genetic variant may have been favored by natural selection in that ancestral population.

Background

HIV susceptibility and pathogenicity exhibit both interindividual and intergroup variability. The etiology of intergroup variability is still poorly understood, and could be partly linked to genetic differences among racial/ethnic groups. These genetic differences may be traceable to different regimes of natural selection in the 60,000 years since the human radiation out of Africa. Here, we examine population differentiation and haplotype patterns at several loci identified through genome-wide association studies on HIV-1 control, as determined by viral-load setpoint, in European and African-American populations. We use genome-wide data from the Human Genome Diversity Project, consisting of 53 world-wide populations, to compare measures of FST and relative extended haplotype homozygosity (REHH) at these candidate loci to the rest of the respective chromosome.

Results

We find that the Europe-Middle East and Europe-South Asia pairwise FST in the most strongly associated region are elevated compared to most pairwise comparisons with the sub-Saharan African group, which exhibit very low FST. We also find genetic signatures of recent positive selection (higher REHH) at these associated regions among all groups except for sub-Saharan Africans and Native Americans. This pattern is consistent with one in which genetic differentiation, possibly due to diversifying/positive selection, occurred at these loci among Eurasians.

Conclusions

These findings are concordant with those from earlier studies suggesting recent evolutionary change at immunity-related genomic regions among Europeans, and shed light on the potential genetic and evolutionary origin of population differences in HIV-1 control.

Pro- versus anti-inflammatory cytokine balance is important for successful pregnancy. Chronic hypoxia alters cytokine levels and increases the frequency of fetal growth restriction (FGR). Multigenerational Andean (AND) versus shorter duration European (EUR) high-altitude (HA) residents are protected from altitude-associated FGR. To address whether ancestry group differences in cytokine levels were involved, we conducted serial studies in 56 low-altitude ([LA]; 400 m; n = 29 AND and n = 27 EUR) and 42 HA residents (3600-4100 m; n = 19 ANDs and n = 23 EURs). Pregnancy raised pro- (interleukin 1β [IL-1β]) and anti- (IL-10) inflammatory cytokines and HA lowered IL-6 and tumor necrosis factor-α (TNF-α) near term. There were no ancestry group differences in cytokine levels at any time, but HA reduced IL-1β in ANDs only near term. Higher IL-1β levels correlated with uterine artery (UA) blood flow at 20 weeks in ANDs at HA, suggesting that IL-1β may play a role in AND protection from altitude-associated reductions in fetal growth.

Objective

This prospective study was designed to determine whether variation in angiogenic (placental growth factor [PlGF]) and/or anti-angiogenic (soluble fms-like tyrosine kinase [sFlt-1]) factors contribute to the protective effect of highland ancestry (Andean) from altitude-associated reductions in fetal growth.

Study design

Plasma sFlt-1 and PlGF levels, uterine artery (UA) blood flow, and fetal biometry were determined in low-altitude (400 m; Andean n = 27, European n = 28) and high-altitude (3600 m; Andean n = 51, European n = 44) residents during pregnancy (20 and 36 weeks) and 4 months postpartum.

Results

High-altitude decreased sFlt-1 levels in both groups, Andeans had lower sFlt-1, comparable PlGF, lower sFlt-1/PlGF ratios, and higher UA blood flow throughout pregnancy relative to Europeans. Altitude decreased birth weight in Europeans but not Andeans. In high-altitude Europeans sFlt-1/PlGF and sFlt-1 levels were negatively associated with UA diameter and birth weight, respectively.

Conclusions

Lower sFlt-1 and sFlt-1/PLGF ratio may contribute to or result from variations in maternal vascular adaptation to pregnancy between Andean and Europeans at high altitude. Subsequently, these effects could potentially influence ancestry-associated differences in birth weight.

Variation in individual admixture proportions leads to heterogeneity within populations. Though novel methods and marker panels have been developed to quantify individual admixture, empirical data describing individual admixture distributions are limited. We investigated variation in individual admixture in four US populations [European American (EA), African American (AA) and Hispanics from Connecticut (EC) and California (WC)] assuming three-way intermixture among Europeans, Africans and Indigenous Americans. Admixture estimates were inferred using a panel of 36 microsatellites and 1 SNP, which have significant allele frequency differences between ancestral populations, and by using both a maximum likelihood (ML) based method and a Bayesian method implemented in the program STRUCTURE. Simulation studies showed that estimates obtained with this marker panel are within 96% of expected values. EAs had the lowest non-European admixture with both methods, but showed greater homogeneity with STRUCTURE than with ML. All other samples showed a high degree of variation in admixture estimates with both methods, were highly concordant and showed evidence of admixture stratification. With both methods, AA subjects had 16% European and <10% Indigenous American admixture on average. EC Hispanics had higher mean African admixture and the WC Hispanics higher mean Indigenous American admixture, possibly reflecting their different continental origins.

SUMMARY

Dramatic pigmentation changes have evolved within most vertebrate groups, including fish and humans. Here we use genetic crosses in sticklebacks to investigate the parallel origin of pigmentation changes in natural populations. High-resolution mapping and expression experiments show that light gills and light ventrums map to a divergent regulatory allele of the Kit ligand (Kitlg) gene. The divergent allele reduces expression in gill and skin tissue, and is shared by multiple derived freshwater populations with reduced pigmentation. In humans, Europeans and East Asians also share derived alleles at the KITLG locus. Strong signatures of selection map to regulatory regions surrounding the gene, and admixture mapping shows that the KITLG genomic region has a significant effect on human skin color. These experiments suggest that regulatory changes in Kitlg contribute to natural variation in vertebrate pigmentation, and that similar genetic mechanisms may underlie rapid evolutionary change in fish and humans.

High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor (HIF) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIF pathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF-targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude.

Ethnic disparity in preterm delivery between African Americans and European Americans has existed for decades, and is likely the consequence of multiple factors, including socioeconomic status, access to care, environment, and genetics. This review summarizes existing information on genetic variation and its association with preterm birth in African Americans. Candidate gene-based association studies, in which investigators have evaluated particular genes selected primarily because of their potential roles in the process of normal and pathological parturition, provide evidence that genetic contributions from both mother and fetus account for some of the disparity in preterm births. To date, most attention has been focused on genetic variation in pro- and anti-inflammatory cytokine genes and their respective receptors. These genes, particularly the pro-inflammatory cytokine genes and their receptors, are linked to matrix metabolism since these cytokines increase expression of matrix degrading metalloproteinases. However, the role that genetic variants that are different between populations play in preterm birth cannot yet be quantified. Future studies based on genome wide association or admixture mapping may reveal other genes that contribute to disparity in prematurity.

High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor (HIF) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIF pathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF-targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude.

Background

The α-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists.

Methods

The present study was conducted to prospectively investigate the relationship between the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 hypertensive coronary artery disease patients, who participated in the INternational VErapamil SR-trandolapril STudy (INVEST) and provided genomic DNA. The primary outcome was defined as first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification.

Results

In Blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.23–5.58; p = .012), with a similar trend in Whites and Hispanics, albeit a smaller magnitude of effect (adjusted HR 1.43, 0.86–2.39 in Hispanics; 1.24, 0.90–1.71 in Whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes.

Conclusions

In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status.

Objectives

We sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel β1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/trandolapril STudy (INVEST-GENES).

Background

KCNMB1 is involved in calcium sensitivity and hypertension. The association between variability in KCNMB1 and calcium antagonist response, however, has not been assessed.

Methods

Genetic samples were collected from 5979 patients in INVEST. Blood pressure response to verapamil SR and time to achieve blood pressure control was assessed in relation to Glu65Lys and Val110Leu genotypes. The primary outcome (all cause mortality, nonfatal myocardial infarction or nonfatal stroke) was compared between genotype groups, and interaction with verapamil SR therapy was assessed.

Results

Systolic blood pressure response to verapamil SR did not differ by KCNMB1 genotype. Lys65 variant carriers, however, achieved blood pressure control earlier than Glu65Glu individuals [1.47 (interquartile ratio 2.77) versus 2.83 (interquartile ratio 4.17) months, P = 0.01] and were less likely to require multiple drugs at the time of blood pressure control (adjusted odds ratio 0.43, 95% confidence interval 0.19–0.95). Leu110 variant carriers had a reduced risk of primary outcome (hazard ratio 0.68, 95% confidence interval 0.47–0.998). Subgroup analysis revealed this finding to be more pronounced in verapamil SR-assigned patients (hazard ratio 0.587, 95% confidence interval 0.33–1.04) compared with atenolol-assigned patients (hazard ratio 0.946, 95% confidence interval 0.56–1.59). No difference was seen in the occurrence of the primary outcome compared by codon 65 genotype.

Conclusions

Our findings suggest that KCNMB1 genotype influences responsiveness to verapamil SR and risk of adverse cardiovascular outcomes.

While the number of success stories for mapping genes associated with complex diseases using genome-wide association approaches is growing, there is still much work to be done in developing methods for such studies when the samples are collected from a population which may not be homogeneous. Here we report the first genome-wide association study to identify genes associated with asthma in an admixed population. We genotyped 96 Puerto Rican moderate to severe asthma cases and 88 controls as well as 109 samples representing Puerto Rico’s founding populations using the Affymetrix GeneChip Human Mapping 100K array sets. The data from samples representing Puerto Rico’s founding populations was used to identify ancestry informative markers for admixture mapping analyses. In addition, a genome-wide association analysis using logistic regression was performed on the data. Although neither admixture mapping nor regression analysis gave any significant association with asthma after correction for multiple testing, an overlap analysis using the top scoring SNPs from different methods suggested chromosomal regions 5q23.3 and 13q13.3 as potential regions harboring genes for asthma in Puerto Ricans. The validation analysis of these two regions in 284 Puerto Rican asthma trios gave significant association for the 5q23.3 region. Our results provide strong evidence that the previously linked 5q23 region is associated with asthma in Puerto Ricans. The detection of causative variants in this region will require fine mapping and functional validation.

Ethnicity can be a means by which people identify themselves and others. This type of identification mediates many kinds of social interactions and may reflect adaptations to a long history of group living in humans. Recent admixture in the US between groups from different continents, and the historically strong emphasis on phenotypic differences between members of these groups, presents an opportunity to examine the degree of concordance between estimates of group membership based on genetic markers and on visually-based estimates of facial features. We first measured the degree of Native American, European, African and East Asian genetic admixture in a sample of 14 self-identified Hispanic individuals, chosen to cover a broad range of Native American and European genetic admixture proportions. We showed frontal and side-view photographs of the 14 individuals to 241 subjects living in New Mexico, and asked them to estimate the degree of NA admixture for each individual. We assess the overall concordance for each observer based on an aggregated measure of the difference between the observer and the genetic estimates. We find that observers reach a significantly higher degree of concordance than expected by chance, and that the degree of concordance as well as the direction of the discrepancy in estimates differs based on the ethnicity of the observer, but not on the observers' age or sex. This study highlights the potentially high degree of discordance between physical appearance and genetic measures of ethnicity, as well as how perceptions of ethnic affiliation are context-specific. We compare our findings to those of previous studies and discuss their implications.

Pigmentation of the skin, hair, and eyes varies both within and between human populations. Identifying the genes and alleles underlying this variation has been the goal of many candidate gene and several genome-wide association studies (GWAS). Most GWAS for pigmentary traits to date have been based on subjective phenotypes using categorical scales. But skin, hair, and eye pigmentation vary continuously. Here, we seek to characterize quantitative variation in these traits objectively and accurately and to determine their genetic basis. Objective and quantitative measures of skin, hair, and eye color were made using reflectance or digital spectroscopy in Europeans from Ireland, Poland, Italy, and Portugal. A GWAS was conducted for the three quantitative pigmentation phenotypes in 176 women across 313,763 SNP loci, and replication of the most significant associations was attempted in a sample of 294 European men and women from the same countries. We find that the pigmentation phenotypes are highly stratified along axes of European genetic differentiation. The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation. All three quantitative phenotypes are correlated with each other. In our two-stage association study, we reproduce the association of rs1667394 at the OCA2/HERC2 locus with eye color but we do not identify new genetic determinants of skin and hair pigmentation supporting the lack of major genes affecting skin and hair color variation within Europe and suggesting that not only careful phenotyping but also larger cohorts are required to understand the genetic architecture of these complex quantitative traits. Interestingly, we also see that in each of these four populations, men are more lightly pigmented in the unexposed skin of the inner arm than women, a fact that is underappreciated and may vary across the world.

The genetic basis of acute lung injury (ALI) is poorly understood. The myosin light chain kinase (MYLK) gene encodes the nonmuscle myosin light chain kinase isoform, a multifunctional protein involved in the inflammatory response (apoptosis, vascular permeability, leukocyte diapedesis). To examine MYLK as a novel candidate gene in sepsis-associated ALI, we sequenced exons, exon–intron boundaries, and 2 kb of 5′ UTR of the MYLK, which revealed 51 single-nucleotide polymorphisms (SNPs). Potential association of 28 MYLK SNPs with sepsis-associated ALI were evaluated in a case-control sample of 288 European American subjects (EAs) with sepsis alone, subjects with sepsis-associated ALI, or healthy control subjects, and a sample population of 158 African American subjects (AAs) with sepsis and ALI. Significant single locus associations in EAs were observed between four MYLK SNPs and the sepsis phenotype (P < 0.001), with an additional SNP associated with the ALI phenotype (P = 0.03). A significant association of a single SNP (identical to the SNP identified in EAs) was observed in AAs with sepsis (P = 0.002) and with ALI (P = 0.01). Three sepsis risk-conferring haplotypes in EAs were defined downstream of start codon of smooth muscle MYLK isoform, a region containing putative regulatory elements (P < 0.001). In contrast, multiple haplotypic analyses revealed an ALI-specific, risk-conferring haplotype at 5′ of the MYLK gene in both European and African Americans and an additional 3′ region haplotype only in African Americans. These data strongly implicate MYLK genetic variants to confer increased risk of sepsis and sepsis-associated ALI.

An 11-year-old boy presented in an outpatient clinic with a vocal habit that occurred during reading and conversation. A brief reading assessment was conducted to determine an effective intervention to decrease the habit. A modified version of the word error-correction procedure resulted in positive changes and was implemented by his mother during home reading practices. Significant decreases in the rate of vocal habit were observed during home reading probes, generalization probes, and follow-up.

Understanding the distribution of human genetic variation is an important foundation for research into the genetics of common diseases. Some of the alleles that modify common disease risk are themselves likely to be common and, thus, amenable to identification using gene-association methods. A problem with this approach is that the large sample sizes required for sufficient statistical power to detect alleles with moderate effect make gene-association studies susceptible to false-positive findings as the result of population stratification [1,2]. Such type I errors can be eliminated by using either family-based association tests or methods that sufficiently adjust for population stratification [3-5]. These methods require the availability of genetic markers that can detect and, thus, control for sources of genetic stratification among populations. In an effort to investigate population stratification and identify appropriate marker panels, we have analysed 11,555 single nucleotide polymorphisms in 203 individuals from 12 diverse human populations. Individuals in each population cluster to the exclusion of individuals from other populations using two clustering methods. Higher-order branching and clustering of the populations are consistent with the geographic origins of populations and with previously published genetic analyses. These data provide a valuable resource for the definition of marker panels to detect and control for population stratification in population-based gene identification studies. Using three US resident populations (European-American, African-American and Puerto Rican), we demonstrate how such studies can proceed, quantifying proportional ancestry levels and detecting significant admixture structure in each of these populations.

Understanding the nature of evolutionary relationships among persons and populations is important for the efficient application of genome science to biomedical research. We have analysed 8,525 autosomal single nucleotide polymorphisms (SNPs) in 84 individuals from four populations: African-American, European-American, Chinese and Japanese. Individual relationships were reconstructed using the allele sharing distance and the neighbour-joining tree making method. Trees show clear clustering according to population, with the root branching from the African-American clade. The African-American cluster is much less star-like than European-American and East Asian clusters, primarily because of admixture. Furthermore, on the East Asian branch, all ten Chinese individuals cluster together and all ten Japanese individuals cluster together. Using positional information, we demonstrate strong correlations between inter-marker distance and both locus-specific FST (the proportion of total variation due to differentiation) levels and branch lengths. Chromosomal maps of the distribution of locus-specific branch lengths were constructed by combining these data with other published SNP markers (total of 33,704 SNPs). These maps clearly illustrate a non-uniform distribution of human genetic substructure, an instructional and useful paradigm for education and research.

Admixture is an important evolutionary force that can and should be used in efforts to apply genomic data and technology to the study of complex disease genetics. Admixture linkage disequilibrium (ALD) is created by the process of admixture and, in recently admixed populations, extends for substantial distances (of the order of 10 to 20 cM). The amount of ALD generated depends on the level of admixture, ancestry information content of markers and the admixture dynamics of the population, and thus influences admixture mapping (AM). The authors discuss different models of admixture and how these can have an impact on the success of AM studies. Selection of markers is important, since markers informative for parental population ancestry are required and these are uncommon. Rarely does the process of admixture result in a population that is uniform for individual admixture levels, but instead there is substantial population stratification. This stratification can be understood as variation in individual admixtures and can be both a source of statistical power for ancestry-phenotype correlation studies as well as a confounder in causing false-positives in gene association studies. Methods to detect and control for stratification in case/control and AM studies are reviewed, along with recent studies showing individual ancestry-phenotype correlations. Using skin pigmentation as a model phenotype, implications of AM in complex disease gene mapping studies are discussed. Finally, the article discusses some limitations of this approach that should be considered when designing an effective AM study.

Identifying regions of the human genome that have been targets of natural selection will provide important insights into human evolutionary history and may facilitate the identification of complex disease genes. Although the signature that natural selection imparts on DNA sequence variation is difficult to disentangle from the effects of neutral processes such as population demographic history, selective and demographic forces can be distinguished by analyzing multiple loci dispersed throughout the genome. We studied the molecular evolution of 132 genes by comprehensively resequencing them in 24 African-Americans and 23 European-Americans. We developed a rigorous computational approach for taking into account multiple hypothesis tests and demographic history and found that while many apparent selective events can instead be explained by demography, there is also strong evidence for positive or balancing selection at eight genes in the European-American population, but none in the African-American population. Our results suggest that the migration of modern humans out of Africa into new environments was accompanied by genetic adaptations to emergent selective forces. In addition, a region containing four contiguous genes on Chromosome 7 showed striking evidence of a recent selective sweep in European-Americans. More generally, our results have important implications for mapping genes underlying complex human diseases.

An analysis of 132 human genes suggests that the migration of modern humans out of Africa into new environments was accompanied by genetic adaptations to emergent selective forces

Background

Many allergic conditions occur more frequently in African-American patients when compared with white patients; however it is not known whether this represents genetic predisposition or disparate environmental exposures.

Objective

To assess the relationship of self-reported race and genetic ancestry to allergic sensitization.

Methods

We included 601 women enrolled in a population-based cohort study whose self-reported race was African-American or white. Genetic ancestry was estimated using markers that differentiate West African and European ancestry. We assessed the relationship between allergic sensitization (defined as ≥1 allergen-specific IgE result) and both self-reported race and genetic ancestry. Regression models adjusted for socio-demographic variables, environmental exposures, and location of residence.

Results

The average proportion of West African ancestry in African-American participants was 0.69, whereas the mean proportion of European ancestry in white participants was 0.79. Self-reported African-American race was associated with allergic sensitization when compared with those who reported being white (adjusted odds ratio [aOR] 2.19; 95% confidence interval [CI] 1.22 – 3.93) even after adjusting for other variables. Genetic ancestry was not significantly associated with allergic sensitization after accounting for location of residence (aOR 2.09 for urban vs. suburban residence, 95% CI 1.32 −3.31).

Conclusion

Self-reported race and location of residence appeared to be more important predictors of allergic sensitization when compared with genetic ancestry, suggesting that the disparity in allergic sensitization by race may be primarily due to environmental factors rather than genetic differences.

Clinical Implications

These data suggest that efforts to eliminate disparities in allergic sensitization should focus on contributing environmental factors.

High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.

Author Summary

High-altitude hypoxia is caused by decreased barometric pressure at high altitude, and results in severe physiological stress to the human body. Three human populations have resided at high altitude for millennia including Andeans on the Andean Altiplano, Tibetans on the Himalayan plateau, and Ethiopian highlanders on the Semian Plateau. Each of these populations exhibits a unique suite of physiological changes to the decreased oxygen available at altitude. However, we are just beginning to understand the genetic changes responsible for the observed physiology. The aim of the current study was to identify gene regions that may be involved in adaptation to high altitude in both Andeans and Tibetans. Genomic regions showing evidence of recent positive selection were identified in these two high-altitude human groups separately. We found compelling evidence of positive selection in HIF pathway genes, in the globin cluster located on chromosome 11, and in several chromosomal regions for Andeans and Tibetans. Our results suggest that key HIF regulatory and targeted genes are responsible for adaptation to altitude and implicate several distinct chromosomal regions. The candidate genes and gene regions identified in Andeans and Tibetans are largely distinct from one another. However, one HIF pathway gene, EGLN1, shows evidence of directional selection in both high-altitude populations.