Publications by authors named "Abigail W Bigham"

41 Publications

Genome-Wide DNA Methylation Changes Associated With High-Altitude Acclimatization During an Everest Base Camp Trek.

Front Physiol 2021 28;12:660906. Epub 2021 Jun 28.

Department of Anthropology, University of California, Los Angeles, Los Angeles, CA, United States.

The individual physiological response to high-altitude hypoxia involves both genetic and non-genetic factors, including epigenetic modifications. Epigenetic changes in hypoxia factor pathway (HIF) genes are associated with high-altitude acclimatization. However, genome-wide epigenetic changes that are associated with short-term hypoxia exposure remain largely unknown. We collected a series of DNA samples from 15 participants of European ancestry trekking to Everest Base Camp to identify DNA methylation changes associated with incremental altitude ascent. We determined genome-wide DNA methylation levels using the Illumina MethylationEPIC chip comparing two altitudes: baseline 1,400 m (day 0) and elevation 4,240 m (day 7). The results of our epigenome-wide association study revealed 2,873 significant differentially methylated positions (DMPs) and 361 significant differentially methylated regions (DMRs), including significant positions and regions in hypoxia inducible factor (HIF) and the renin-angiotensin system (RAS) pathways. Our pathway enrichment analysis identified 95 significant pathways including regulation of glycolytic process (GO:0006110), regulation of hematopoietic stem cell differentiation (GO:1902036), and regulation of angiogenesis (GO:0045765). Lastly, we identified an association between the gene insertion/deletion (I/D) polymorphism and oxygen saturation, as well as average methylation. These findings shed light on the genes and pathways experiencing the most epigenetic change associated with short-term exposure to hypoxia.
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http://dx.doi.org/10.3389/fphys.2021.660906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273439PMC
June 2021

Blood lead levels in Peruvian adults are associated with proximity to mining and DNA methylation.

Environ Int 2021 Oct 30;155:106587. Epub 2021 Apr 30.

Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA; Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.

Background: Inorganic lead (Pb) is common in the environment, and is toxic to neurological, renal, and cardiovascular systems. Pb exposure influences the epigenome with documented effects on DNA methylation (DNAm). We assessed the impact of low levels of Pb exposure on DNAm among non-miner individuals from two locations in Peru: Lima, the capital, and Cerro de Pasco, a highland mining town, to study the effects of Pb exposure on physiological outcomes and DNAm.

Methods: Pb levels were measured in whole blood (n = 305). Blood leukocyte DNAm was determined for 90 DNA samples using the Illumina MethylationEPIC chip. An epigenome-wide association study was performed to assess the relationship between Pb and DNAm.

Results: Individuals from Cerro de Pasco had higher Pb than individuals from Lima (p-value = 2.00E-16). Males had higher Pb than females (p-value = 2.36E-04). Pb was positively associated with hemoglobin (p-value = 8.60E-04). In Cerro de Pasco, blood Pb decreased with the distance from the mine (p-value = 0.04), and association with soil Pb was approaching significance (p-value = 0.08). We identified differentially methylated positions (DMPs) associated with genes SOX18, ZMIZ1, and KDM1A linked to neurological function. We also found 45 differentially methylated regions (DMRs), seven of which were associated with genes involved in metal ion binding and nine to neurological function and development.

Conclusions: Our results demonstrate that even low levels of Pb can have a significant impact on the body including changes to DNAm. We report associations between Pb and hemoglobin, Pb and distance from mining, and between blood and soil Pb. We also report associations between loci- and region-specific DNAm and Pb.
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http://dx.doi.org/10.1016/j.envint.2021.106587DOI Listing
October 2021

High-altitude deer mouse hypoxia-inducible factor-2α shows defective interaction with CREB-binding protein.

J Biol Chem 2021 Jan-Jun;296:100461. Epub 2021 Feb 25.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Numerous mammalian species have adapted to the chronic hypoxia of high altitude. Recent genomic studies have identified evidence for natural selection of genes and associated genetic changes in these species. A major gap in our knowledge is an understanding of the functional significance, if any, of these changes. Deer mice (Peromyscus maniculatus) live at both low and high altitudes in North America, providing an opportunity to identify functionally important genetic changes. High-altitude deer mice show evidence of natural selection on the Epas1 gene, which encodes for hypoxia-inducible factor-2α (Hif-2α), a central transcription factor of the hypoxia-inducible factor pathway. An SNP encoding for a T755M change in the Hif-2α protein is highly enriched in high-altitude deer mice, but its functional significance is unknown. Here, using coimmunoprecipitation and transcriptional activity assays, we show that the T755M mutation produces a defect in the interaction of Hif-2α with the transcriptional coactivator CREB-binding protein. This results in a loss of function because of decreased transcriptional activity. Intriguingly, the effect of this mutation depends on the amino acid context. Interchanges between methionine and threonine at the corresponding position in house mouse (Mus musculus) Hif-2α are without effects on CREB-binding protein binding. Furthermore, transfer of a set of deer mouse-specific Hif-2α amino acids to house mouse Hif-2α is sufficient to confer sensitivity of house mouse Hif-2α to the T755M substitution. These findings provide insight into high-altitude adaptation in deer mice and evolution at the Epas1 locus.
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http://dx.doi.org/10.1016/j.jbc.2021.100461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024697PMC
February 2021

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.

Genome Biol Evol 2021 Feb;13(2)

Department of Anthropology, University of California, Los Angeles.

High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.
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http://dx.doi.org/10.1093/gbe/evaa239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859850PMC
February 2021

Identifying adaptive alleles in the human genome: from selection mapping to functional validation.

Hum Genet 2021 Feb 29;140(2):241-276. Epub 2020 Jul 29.

Department of Anthropology, University of California Los Angeles, 341 Haines Hall, Los Angeles, CA, 90095, USA.

The suite of phenotypic diversity across geographically distributed human populations is the outcome of genetic drift, gene flow, and natural selection throughout human evolution. Human genetic variation underlying local biological adaptations to selective pressures is incompletely characterized. With the emergence of population genetics modeling of large-scale genomic data derived from diverse populations, scientists are able to map signatures of natural selection in the genome in a process known as selection mapping. Inferred selection signals further can be used to identify candidate functional alleles that underlie putative adaptive phenotypes. Phenotypic association, fine mapping, and functional experiments facilitate the identification of candidate adaptive alleles. Functional investigation of candidate adaptive variation using novel techniques in molecular biology is slowly beginning to unravel how selection signals translate to changes in biology that underlie the phenotypic spectrum of our species. In addition to informing evolutionary hypotheses of adaptation, the discovery and functional annotation of adaptive alleles also may be of clinical significance. While selection mapping efforts in non-European populations are growing, there remains a stark under-representation of diverse human populations in current public genomic databases, of both clinical and non-clinical cohorts. This lack of inclusion limits the study of human biological variation. Identifying and functionally validating candidate adaptive alleles in more global populations is necessary for understanding basic human biology and human disease.
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http://dx.doi.org/10.1007/s00439-020-02206-7DOI Listing
February 2021

Tibetan , an allele with loss-of-function properties.

Proc Natl Acad Sci U S A 2020 06 15;117(22):12230-12238. Epub 2020 May 15.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway, and The product of the former induces the degradation of the product of the latter. Key issues regarding Tibetan are whether it is a gain-of-function or loss-of-function allele, and how it might contribute to high-altitude adaptation. Tibetan PHD2 possesses two amino acid changes, D4E and C127S. We previously showed that in vitro, Tibetan PHD2 is defective in its interaction with p23, a cochaperone of the HSP90 pathway, and we proposed that Tibetan is a loss-of-function allele. Here, we report that additional PHD2 mutations at or near Asp-4 or Cys-127 impair interaction with p23 in vitro. We find that mice with the Tibetan allele display augmented hypoxic ventilatory response, supporting this loss-of-function proposal. This is phenocopied by mice with a mutation in that abrogates the PHD2:p23 interaction. haploinsufficiency, but not the Tibetan allele, ameliorates hypoxia-induced increases in right ventricular systolic pressure. The Tibetan allele is not associated with hemoglobin levels in mice. We propose that Tibetans possess genetic alterations that both activate and inhibit selective outputs of the HIF pathway to facilitate successful adaptation to the chronic hypoxia of high altitude.
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http://dx.doi.org/10.1073/pnas.1920546117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275716PMC
June 2020

DNA Methylation Changes Are Associated With an Incremental Ascent to High Altitude.

Front Genet 2019 29;10:1062. Epub 2019 Oct 29.

Department of Exercise Science, Syracuse University, Syracuse, NY, United States.

Genetic and nongenetic factors are involved in the individual ability to physiologically acclimatize to high-altitude hypoxia through processes that include increased heart rate and ventilation. High-altitude acclimatization is thought to have a genetic component, yet it is unclear if other factors, such as epigenetic gene regulation, are involved in acclimatization to high-altitude hypoxia in nonacclimatized individuals. We collected saliva samples from a group of healthy adults of European ancestry (n = 21) in Kathmandu (1,400 m; baseline) and three altitudes during a trek to the Everest Base Camp: Namche (3,440 m; day 3), Pheriche (4,240 m; day 7), and Gorak Shep (5,160 m; day 10). We used quantitative bisulfite pyrosequencing to determine changes in DNA methylation, a well-studied epigenetic marker, in LINE-1, , , , and . We found significantly lower DNA methylation between baseline (1,400 m) and high altitudes in LINE-1, (at 4,240 m only), and . We found increased methylation in (at 4,240 m only) and . We also found positive associations between methylation and systolic blood pressure and methylation and hemoglobin. Our results show that incremental exposure to hypoxia can affect the epigenome. Changes to the epigenome, in turn, could underlie the process of altitude acclimatization.
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http://dx.doi.org/10.3389/fgene.2019.01062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828981PMC
October 2019

Association of gene with high aerobic capacity of Peruvian Quechua at high altitude.

Proc Natl Acad Sci U S A 2019 11 11;116(48):24006-24011. Epub 2019 Nov 11.

Department of Anthropology, University of Michigan, Ann Arbor, MI 48109-1107.

Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VOmax) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated gene () as a candidate gene. The encoded protein, EGLN1/PHD2, is an O sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 SNPs associated with higher VOmax (L⋅min and mL⋅min⋅kg) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VOmax) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VOmax genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min⋅kg vs. CC = 30.5 mL⋅min⋅kg). To guard against spurious association, we controlled for population stratification. Findings were replicated for SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at in Andeans, and support the hypothesis that natural selection has increased the frequency of an causal variant that enhances O delivery or use during exercise at altitude in Peruvian Quechua.
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http://dx.doi.org/10.1073/pnas.1906171116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883775PMC
November 2019

Severe Dengue Prognosis Using Human Genome Data and Machine Learning.

IEEE Trans Biomed Eng 2019 10 4;66(10):2861-2868. Epub 2019 Feb 4.

Dengue has become one of the most important worldwide arthropod-borne diseases. Dengue phenotypes are based on laboratorial and clinical exams, which are known to be inaccurate.

Objective: We present a machine learning approach for the prediction of dengue fever severity based solely on human genome data.

Methods: One hundred and two Brazilian dengue patients and controls were genotyped for 322 innate immunity single nucleotide polymorphisms (SNPs). Our model uses a support vector machine algorithm to find the optimal loci classification subset and then an artificial neural network (ANN) is used to classify patients into dengue fever or severe dengue.

Results: The ANN trained on 13 key immune SNPs selected under dominant or recessive models produced median values of accuracy greater than 86%, and sensitivity and specificity over 98% and 51%, respectively.

Conclusion: The proposed classification method, using only genome markers, can be used to identify individuals at high risk for developing the severe dengue phenotype even in uninfected conditions.

Significance: Our results suggest that the genetic context is a key element in phenotype definition in dengue. The methodology proposed here is extendable to other Mendelian based and genetically influenced diseases.
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http://dx.doi.org/10.1109/TBME.2019.2897285DOI Listing
October 2019

LINE-1 and EPAS1 DNA methylation associations with high-altitude exposure.

Epigenetics 2019 01 9;14(1):1-15. Epub 2019 Jan 9.

a Department of Anthropology , University of Michigan , Ann Arbor , MI , USA.

Recent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1 and LINE-1 repetitive element among 572 Quechua individuals from high- (4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1 DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1 methylation. The number of years lived at high altitude was negatively associated with EPAS1 methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1 rs2236225, TYMS rs502396, FOLH1 rs202676, GLDC rs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1 and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation.
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http://dx.doi.org/10.1080/15592294.2018.1561117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380404PMC
January 2019

Complex signatures of natural selection at GYPA.

Hum Genet 2018 Feb 23;137(2):151-160. Epub 2018 Jan 23.

Departments of Pediatrics and Genome Sciences, The University of Washington, Seattle, WA, USA.

The human MN blood group antigens are isoforms of glycophorin A (GPA) encoded by the gene, GYPA, and are the most abundant erythrocyte sialoglycoproteins. The distribution of MN antigens has been widely studied in human populations yet the evolutionary and/or demographic factors affecting population variation remain elusive. While the primary function of GPA is yet to be discovered, it serves as the major binding site for the 175-kD erythrocyte-binding antigen (EB-175) of the malarial parasite, Plasmodium falciparum, a major selective pressure in recent human history. More specifically, exon two of GYPA encodes the receptor-binding ligand to which P. falciparum binds. Accordingly, there has been keen interest in understanding what impact, if any, natural selection has had on the distribution of variation in GYPA and exon two in particular. To this end, we resequenced GYPA in individuals sampled from both P. falciparum endemic (sub-Saharan Africa and South India) and non-endemic (Europe and East Asia) regions of the world. Observed patterns of variation suggest that GYPA has been subject to balancing selection in populations living in malaria endemic areas and in Europeans, but no such evidence was found in samples from East Asia, Oceania, and the Americas. These results are consistent with malaria acting as a selective pressure on GYPA, but also suggest that another selective force has resulted in a similar pattern of variation in Europeans. Accordingly, GYPA has perhaps a more complex evolutionary history, wherein on a global scale, spatially varying selective pressures have governed its natural history.
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http://dx.doi.org/10.1007/s00439-018-1866-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223178PMC
February 2018

The Genetic Anthropologist's Contribution to Understanding Race and Racial Health Disparities.

Hum Biol 2015 10;87(4):291-293

2 Department of Anthropology, University of California San Diego, La Jolla, California.

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http://dx.doi.org/10.13110/humanbiology.87.4.0291DOI Listing
October 2015

Genetics of human origin and evolution: high-altitude adaptations.

Authors:
Abigail W Bigham

Curr Opin Genet Dev 2016 Dec 6;41:8-13. Epub 2016 Aug 6.

Department of Anthropology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

High altitude, defined as elevations lying above 2500m sea level, challenges human survival and reproduction. This environment provides a natural experimental design wherein specific populations, Andeans, Ethiopians, and Tibetans, have lived in a chronic hypoxia state for millennia. These human groups have overcome the low ambient oxygen tension of high elevation via unique physiologic and genetic adaptations. Genomic studies have identified several genes that underlie high-altitude adaptive phenotypes, many of which are central components of the Hypoxia Inducible Factor (HIF) pathway. Further study of mechanisms governing the adaptive changes responsible for high-altitude adaptation will contribute to our understanding of the molecular basis of evolutionary change and assist in the functional annotation of the human genome.
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http://dx.doi.org/10.1016/j.gde.2016.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161537PMC
December 2016

Toll-like receptor gene variants and bacterial vaginosis among HIV-1 infected and uninfected African women.

Genes Immun 2015 Jul-Aug;16(5):362-365. Epub 2015 Apr 30.

Department of Global Health & Medicine, University of Washington 325 Ninth Ave, Seattle, WA 98104.

Bacterial vaginosis (BV) is a common vaginal syndrome associated with altered microflora that increases the risk of preterm delivery and acquisition of sexually transmitted diseases. The cause of BV is unknown although toll-like receptors (TLRs), that are central to innate immune responses, may be important. We evaluated associations between TLR SNPs and BV among HIV-1 infected and uninfected African women. Logistic regression was used to assess associations between SNPs (N=99) in TLRs 2-4, 7-9 and BV (as classified by Nugent's criteria). Among HIV-1 uninfected women, TLR7 rs5743737 and TLR7 rs1634323 were associated with a decreased risk of BV, whereas TLR7 rs179012 was associated with an increased risk. TLR2 SNP rs3804099 was associated with a decreased risk of BV among HIV-1 infected women. Our findings indicate that there may be differences in TLR association with BV among HIV-1 infected and HIV-1 uninfected women.
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http://dx.doi.org/10.1038/gene.2015.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523061PMC
May 2016

Estimates of continental ancestry vary widely among individuals with the same mtDNA haplogroup.

Am J Hum Genet 2015 Feb 22;96(2):183-93. Epub 2015 Jan 22.

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address:

The association between a geographical region and an mtDNA haplogroup(s) has provided the basis for using mtDNA haplogroups to infer an individual's place of origin and genetic ancestry. Although it is well known that ancestry inferences using mtDNA haplogroups and those using genome-wide markers are frequently discrepant, little empirical information exists on the magnitude and scope of such discrepancies between multiple mtDNA haplogroups and worldwide populations. We compared genetic-ancestry inferences made by mtDNA-haplogroup membership to those made by autosomal SNPs in ∼940 samples of the Human Genome Diversity Panel and recently admixed populations from the 1000 Genomes Project. Continental-ancestry proportions often varied widely among individuals sharing the same mtDNA haplogroup. For only half of mtDNA haplogroups did the highest average continental-ancestry proportion match the highest continental-ancestry proportion of a majority of individuals with that haplogroup. Prediction of an individual's mtDNA haplogroup from his or her continental-ancestry proportions was often incorrect. Collectively, these results indicate that for most individuals in the worldwide populations sampled, mtDNA-haplogroup membership provides limited information about either continental ancestry or continental region of origin.
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http://dx.doi.org/10.1016/j.ajhg.2014.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320259PMC
February 2015

Human high-altitude adaptation: forward genetics meets the HIF pathway.

Genes Dev 2014 Oct;28(20):2189-204

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxia-inducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2α, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia.
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http://dx.doi.org/10.1101/gad.250167.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201282PMC
October 2014

Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude.

Physiol Genomics 2014 Sep 15;46(18):687-97. Epub 2014 Jul 15.

Departments of Anthropology and Health/Behavioral Sciences, University of Colorado Denver, Denver, Colorado; Department of Obstetrics and Gynecology, University of Colorado Denver, Aurora, Colorado.

Low birth weight and intrauterine growth restriction (IUGR) increase the risk of mortality and morbidity during the perinatal period as well as in adulthood. Environmental and genetic factors contribute to IUGR, but the influence of maternal genetic variation on birth weight is largely unknown. We implemented a gene-by-environment study wherein we utilized the growth restrictive effects of high altitude. Multigenerational high-altitude residents (Andeans) are protected from altitude-associated IUGR compared with recent migrants (Europeans). Using a combined cohort of low- and high-altitude European and Andean women, we tested 63 single nucleotide polymorphisms (SNPs) from 16 natural selection-nominated candidate gene regions for associations with infant birth weight. We identified significant SNP associations with birth weight near coding regions for two genes involved in oxygen sensing and vascular control, PRKAA1 and EDNRA, respectively. Next, we identified a significant association for the PRKAA1 SNP with an intermediate phenotype, uterine artery diameter, which has been shown to be related to Andean protection from altitude-associated reductions in fetal growth. To explore potential functional relationships for the effect of maternal SNP genotype on birth weight, we evaluated the relationship between maternal PRKAA1 SNP genotype and gene expression patterns in general and, in particular, of key pathways involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of IUGR. Our observations suggest that maternal genetic variation within genes that regulate oxygen sensing, metabolic homeostasis, and vascular control influence fetal growth and birth weight outcomes and hence Andean adaptation to high altitude.
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http://dx.doi.org/10.1152/physiolgenomics.00063.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166715PMC
September 2014

Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing.

J Biol Chem 2014 May 7;289(21):14656-65. Epub 2014 Apr 7.

From the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and

The Tibetan population has adapted to the chronic hypoxia of high altitude. Tibetans bear a genetic signature in the prolyl hydroxylase domain protein 2 (PHD2/EGLN1) gene, which encodes for the central oxygen sensor of the hypoxia-inducible factor (HIF) pathway. Recent studies have focused attention on two nonsynonymous coding region substitutions, D4E and C127S, both of which are markedly enriched in the Tibetan population. These amino acids reside in a region of PHD2 that harbors a zinc finger, which we have previously discovered binds to a Pro-Xaa-Leu-Glu (PXLE) motif in the HSP90 cochaperone p23, thereby recruiting PHD2 to the HSP90 pathway to facilitate HIF-α hydroxylation. We herein report that the Tibetan PHD2 haplotype (D4E/C127S) strikingly diminishes the interaction of PHD2 with p23, resulting in impaired PHD2 down-regulation of the HIF pathway. The defective binding to p23 depends on both the D4E and C127S substitutions. We also identify a PXLE motif in HSP90 itself that can mediate binding to PHD2 but find that this interaction is maintained with the D4E/C127S PHD2 haplotype. We propose that the Tibetan PHD2 variant is a loss of function (hypomorphic) allele, leading to augmented HIF activation to facilitate adaptation to high altitude.
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http://dx.doi.org/10.1074/jbc.M113.541227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031521PMC
May 2014

Variants in host viral replication cycle genes are associated with heterosexual HIV-1 acquisition in Africans.

J Acquir Immune Defic Syndr 2014 Jun;66(2):127-34

*Department of Anthropology, University of Michigan, Ann Arbor, MI; Departments of †Global Health; ‡Epidemiology; §Medicine, University of Washington, Seattle, WA; ‖Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa; ¶Department of Medicine, University of Manitoba, Winnipeg, Canada; #Department of Obstetrics and Gynaecology, University of Nairobi, Nairobi, Kenya; Departments of **Pediatrics; ††Genome Sciences; ‡‡Laboratory Medicine, University of Washington, Seattle, WA; and §§Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Objective: We evaluated genetic variants in 51 candidate genes encoding proteins that interact with HIV-1 during the virus life cycle for association with HIV-1 outcomes in an African cohort.

Methods: Using a nested case-control study within a cohort of heterosexual HIV-1-serodiscordant couples, we genotyped 475 haplotype-tagging single-nucleotide polymorphisms (tagSNPs) and 18 SNPs previously associated with HIV-1 transmission and/or progression (candidate SNPs) in 51 host genes. We used logistic and Cox proportional hazard regression with adjustment for sex, age, and population stratification to detect SNP associations with HIV-1 acquisition, plasma HIV-1 set point, and a composite measure of HIV-1 disease progression. Significant thresholds for tagSNP, but not candidate SNP, associations were subjected to Bonferroni correction for multiple testing.

Results: We evaluated 491 HIV-1-infected and 335 HIV-1-uninfected individuals for 493 SNPs, 459 of which passed quality control filters. Candidate SNP PPIA rs8177826 and tagSNP SMARCB1 rs6003904 were significantly associated with HIV-1 acquisition risk (odds ratio = 0.14, P = 0.03, and odds ratio = 2.11, Pcorr = 0.01, respectively). Furthermore, the TT genotype for CCR5 rs1799988 was associated with a mean 0.2 log10 copies per milliliter lower plasma HIV-1 RNA set point (P = 0.04). We also identified significant associations with HIV-1 disease progression for variants in FUT2 and MBL2.

Conclusions: Using a targeted gene approach, we identified variants in host genes whose protein products interact with HIV-1 during the virus replication cycle and were associated with HIV-1 outcomes in this African cohort.
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http://dx.doi.org/10.1097/QAI.0000000000000113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025588PMC
June 2014

Toll-like receptor polymorphism associations with HIV-1 outcomes among sub-Saharan Africans.

J Infect Dis 2014 May 10;209(10):1623-7. Epub 2013 Dec 10.

Department of Global Health.

Objective: We evaluated Toll-like receptors (TLRs) single nucleotide polymorphisms (SNPs) for associations with HIV-1 acquisition, set-point and disease progression in African couples.

Methods: Seven candidate and 116 haplotype-tagging SNPs (tagSNPs) were genotyped in 504 HIV-1 infected cases, and 343 seronegative controls.

Results: TLR9 1635A/G was associated with reduced HIV-1 acquisition among HIV-seronegative controls with high but not low HIV-1 exposure (odds ratio [OR] = 0.7; P = .03 and OR = 0.9, P = .5, respectively). TLR7 rs179012 and TLR2 597C/T reduced set-point; the latter modified by time since HIV-1 acquisition. TLR8 1A/G reduced disease progression.

Conclusions: TLR SNPs impact HIV-1 outcomes with epidemiologic factors modifying these relationships.
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http://dx.doi.org/10.1093/infdis/jit807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997584PMC
May 2014

Toll-like receptor variants are associated with infant HIV-1 acquisition and peak plasma HIV-1 RNA level.

AIDS 2013 Sep;27(15):2431-9

aInstitute for Public Health Genetics bDepartment of Epidemiology cDepartment of Medicine dDepartment of Biostatistics eDepartment of Global Health fDepartment of Pediatrics gDepartment of Genome Sciences, University of Washington, Seattle, Washington hDepartment of Anthropology, University of Michigan, Ann Arbor, Michigan iVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA jDepartment of Paediatrics, University of Nairobi, Nairobi, Kenya.

Objective: We evaluated the association of single nucleotide polymorphisms (SNPs) in TLRs with infant HIV-1 acquisition and viral control.

Design: Infant HIV-1 outcomes were assessed in a Kenyan perinatal HIV-1 cohort.

Methods: Infants were genotyped for six candidate and 118 haplotype-tagging polymorphisms in TLRs 2, 3, 4, 7, 8, and 9, MYD88 and TIRAP. Cox proportional hazards and linear regression were performed to assess associations with time to HIV-1 acquisition, time to infant mortality, and peak viral load.

Results: Among 368 infants, 56 (15%) acquired HIV-1 by month 1 and 17 (4.6%) between 1 and 12 months. Infants with the TLR9 1635A (rs352140) variant were more likely to acquire HIV-1 by 1 month [hazard ratio = 1.81, 95% confidence interval (CI) = 1.05-3.14, P = 0.033] and by 12 months (hazard ratio = 1.62, CI = 1.01-2.60, P = 0.044) in dominant models adjusted for maternal plasma HIV-1 RNA level and genetic ancestry. Among 56 infants infected at 1 month of age or less, at least one copy of the TLR9 1635A allele was associated with a 0.58 log₁₀ copies/ml lower peak viral load (P = 0.002). Female infants with at least one copy of the TLR8 1G (rs3764880) variant had a 0.78 log₁₀ copies/ml higher peak viral load (P = 0.0009) and having at least one copy of the C allele for a haplotype tagging TLR7 variant (rs1634319) was associated with a 0.80 log₁₀ copies/ml higher peak viral load in female infants (P = 0.0003).

Conclusion: In this African perinatal cohort, we found several TLR polymorphisms associated with HIV-1 acquisition and progression. Defining mechanisms for these TLR associations may inform HIV-1 prevention strategies that leverage innate responses.
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http://dx.doi.org/10.1097/QAD.0b013e3283629117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124859PMC
September 2013

Andean and Tibetan patterns of adaptation to high altitude.

Am J Hum Biol 2013 Mar-Apr;25(2):190-7. Epub 2013 Jan 24.

Department of Anthropology, University of Michigan, Ann Arbor, Michigan.

Objectives: High-altitude hypoxia, or decreased oxygen levels caused by low barometric pressure, challenges the ability of humans to live and reproduce. Despite these challenges, human populations have lived on the Andean Altiplano and the Tibetan Plateau for millennia and exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. We and others have identified natural selection candidate genes and gene regions for these adaptations using dense genome scan data. One gene previously known to be important in cellular oxygen sensing, egl nine homolog 1 (EGLN1), shows evidence of positive selection in both Tibetans and Andeans. Interestingly, the pattern of variation for this gene differs between the two populations. Continued research among Tibetan populations has identified statistical associations between hemoglobin concentration and single nucleotide polymorphism (SNP) genotype at EGLN1 and a second gene, endothelial PAS domain protein 1 (EPAS1).

Methods: To measure for the effects of EGLN1 and EPAS1 altitude genotypes on hemoglobin concentration among Andean highlanders, we performed a multiple linear regression analysis of 10 candidate SNPs in or near these two genes.

Results: Our analysis did not identify significant associations between EPAS1 or EGLN1 SNP genotypes and hemoglobin concentration in Andeans.

Conclusions: These results contribute to our understanding of the unique set of adaptations developed in different highland groups to the hypoxia of high altitude. Overall, the results provide key insights into the patterns of genetic adaptation to high altitude in Andean and Tibetan populations.
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http://dx.doi.org/10.1002/ajhb.22358DOI Listing
May 2014

Evolution and functional impact of rare coding variation from deep sequencing of human exomes.

Science 2012 Jul 17;337(6090):64-9. Epub 2012 May 17.

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.

As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111× in 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carried were predicted to affect protein function of ~313 genes per genome, and ~95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits.
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http://dx.doi.org/10.1126/science.1219240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708544PMC
July 2012

OPRM1 and EGFR contribute to skin pigmentation differences between Indigenous Americans and Europeans.

Hum Genet 2012 Jul 24;131(7):1073-80. Epub 2011 Dec 24.

Department of Anthropology, Pennsylvania State University, University Park, PA 16802, USA.

Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments. Previous studies have identified several genes involved in skin pigmentation differences among African, Asian, and European populations. However, none have examined skin pigmentation variation among Indigenous American populations, creating a critical gap in our understanding of skin pigmentation variation. This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans. Analysis was performed on two samples of Indigenous Americans genotyped on genome-wide SNP arrays. Using four tests for natural selection--locus-specific branch length (LSBL), ratio of heterozygosities (lnRH), Tajima's D difference, and extended haplotype homozygosity (EHH)--we identified 14 selection-nominated candidate genes (SNCGs). SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground-level ultraviolet radiation. In addition to SLC24A5 and SLC45A2, genes previously associated with European/non-European differences in skin pigmentation, OPRM1 and EGFR were associated with variation in skin pigmentation in New World populations for the first time.
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http://dx.doi.org/10.1007/s00439-011-1135-1DOI Listing
July 2012

Potential role for elevated maternal enzymatic antioxidant status in Andean protection against altitude-associated SGA.

J Matern Fetal Neonatal Med 2012 Aug 30;25(8):1233-40. Epub 2011 Nov 30.

Department of Emergency Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045-0508, USA.

Oxidative stress has been implicated in the uteroplacental ischemia characteristic of preeclampsia and small-for-gestational-age (SGA) birth, both of which are more common at high (>2500 m) vs low altitude. Since Andeans are protected relative to Europeans from the altitude-associated rise in SGA, we asked whether alterations in maternal antioxidant status or oxidative stress contributed to their protection. Enzymatic antioxidant (erythrocyte catalase and superoxide dismutase [SOD]) activity and a plasma marker of lipid peroxidation (8-iso-PGF2α) were measured during pregnancy and in the non-pregnant state in Andean or European residents of low (400 m) or high altitude (3600-4100 m). Pregnancy and altitude increased catalase and/or SOD activity to a greater extent in Andeans than Europeans. 8-iso-PGF2α levels were independent of altitude and pregnancy. SOD was lower in mothers of SGA infants at weeks 20 and 36. Our findings are consistent with the possibility that elevated enzymatic antioxidant activity contributes to Andean protection against altitude-associated SGA.
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http://dx.doi.org/10.3109/14767058.2011.636102DOI Listing
August 2012

Exome sequencing as a tool for Mendelian disease gene discovery.

Nat Rev Genet 2011 Sep 27;12(11):745-55. Epub 2011 Sep 27.

Department of Pediatrics, University of Washington, Health Sciences Building RR349, 1959 NE Pacific Street, Seattle, Washington 98195-6320, USA.

Exome sequencing - the targeted sequencing of the subset of the human genome that is protein coding - is a powerful and cost-effective new tool for dissecting the genetic basis of diseases and traits that have proved to be intractable to conventional gene-discovery strategies. Over the past 2 years, experimental and analytical approaches relating to exome sequencing have established a rich framework for discovering the genes underlying unsolved Mendelian disorders. Additionally, exome sequencing is being adapted to explore the extent to which rare alleles explain the heritability of complex diseases and health-related traits. These advances also set the stage for applying exome and whole-genome sequencing to facilitate clinical diagnosis and personalized disease-risk profiling.
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http://dx.doi.org/10.1038/nrg3031DOI Listing
September 2011

Host genetic risk factors for West Nile virus infection and disease progression.

PLoS One 2011 15;6(9):e24745. Epub 2011 Sep 15.

Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.

West Nile virus (WNV), a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p = 0.035) and MX1, (OR 0.19, p = 0.014) were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p = 0.003) was associated with increased risk for West Nile encephalitis and paralysis (WNE/P). Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024745PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174177PMC
February 2012

Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome.

Am J Med Genet A 2011 Jul 10;155A(7):1511-6. Epub 2011 Jun 10.

Department of Pediatrics, University of Washington, Seattle, 98195, USA.

Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.
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http://dx.doi.org/10.1002/ajmg.a.34074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121928PMC
July 2011

High-end arteriolar resistance limits uterine artery blood flow and restricts fetal growth in preeclampsia and gestational hypertension at high altitude.

Am J Physiol Regul Integr Comp Physiol 2011 May 16;300(5):R1221-9. Epub 2011 Feb 16.

Altitude Research Center, University of Colorado-Denver, 12469 East 17th Place, Aurora, CO 80045, USA.

The reduction in infant birth weight and increased frequency of preeclampsia (PE) in high-altitude residents have been attributed to greater placental hypoxia, smaller uterine artery (UA) diameter, and lower UA blood flow (Q(UA)). This cross-sectional case-control study determined UA, common iliac (CI), and external iliac (EI) arterial blood flow in Andeans residing at 3,600-4,100 m, who were either nonpregnant (NP, n = 23), or experiencing normotensive pregnancies (NORM; n = 155), preeclampsia (PE, n = 20), or gestational hypertension (GH, n = 12). Pregnancy enlarged UA diameter to ~0.62 cm in all groups, but indices of end-arteriolar vascular resistance were higher in PE or GH than in NORM. Q(UA) was lower in early-onset (≤34 wk) PE or GH than in NORM, but was normal in late-onset (>34 wk) illness. Left Q(UA) was consistently greater than right in NORM, but the pattern reversed in PE. Although Q(CI) and Q(EI) were higher in PE and GH than NORM, the fraction of Q(CI) distributed to the UA was reduced 2- to 3-fold. Women with early-onset PE delivered preterm, and 43% had stillborn small for gestational age (SGA) babies. Those with GH and late-onset PE delivered at term but had higher frequencies of SGA babies (GH=50%, PE=46% vs. NORM=15%, both P < 0.01). Birth weight was strongly associated with reduced Q(UA) (R(2) = 0.80, P < 0.01), as were disease severity and adverse fetal outcomes. We concluded that high end-arteriolar resistance, not smaller UA diameter, limited Q(UA) and restricted fetal growth in PE and GH. These are, to our knowledge, the first quantitative measurements of Q(UA) and pelvic blood flow in early- vs. late-onset PE in high-altitude residents.
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http://dx.doi.org/10.1152/ajpregu.91046.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094033PMC
May 2011
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