CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome.

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression.

Human pangenome analysis of sequences missing from the reference genome reveals their widespread evolutionary, phenotypic, and functional roles.

Nonreference sequences (NRSs) are DNA sequences present in global populations but absent in the current human reference genome. However, the extent and functional significance of NRSs in the human genomes and populations remains unclear. Here, we de novo assembled 539 genomes from five genetically divergent human populations using long-read sequencing technology, resulting in the identification of 5.1 million NRSs. These were merged into 45284 unique NRSs, with 29.7% being novel discoveries. Among these NRSs, 38.7% were common across the five populations, and 35.6% were population specific. The use of a graph-based pangenome approach allowed for the detection of 565 transcript expression quantitative trait loci on NRSs, with 426 of these being novel findings. Moreover, 26 NRS candidates displayed evidence of adaptive selection within human populations. Genes situated in close proximity to or intersecting with these candidates may be associated with metabolism and type 2 diabetes. Genome-wide association studies revealed 14 NRSs to be significantly associated with eight phenotypes. Additionally, 154 NRSs were found to be in strong linkage disequilibrium with 258 phenotype-associated SNPs in the GWAS catalogue. Our work expands the understanding of human NRSs and provides novel insights into their functions, facilitating evolutionary and biomedical researches.

Estimating the timing of multiple admixture events using 3-locus linkage disequilibrium.

Estimating admixture histories is crucial for understanding the genetic diversity we see in present-day populations. Allele frequency or phylogeny-based methods are excellent for inferring the existence of admixture or its proportions. However, to estimate admixture times, spatial information from admixed chromosomes of local ancestry or the decay of admixture linkage disequilibrium (ALD) is used. One popular method, implemented in the programs ALDER and ROLLOFF, uses two-locus ALD to infer the time of a single admixture event, but is only able to estimate the time of the most recent admixture event based on this summary statistic. To address this limitation, we derive analytical expressions for the expected ALD in a three-locus system and provide a new statistical method based on these results that is able to resolve more complicated admixture histories. Using simulations, we evaluate the performance of this method on a range of different admixture histories. As an example, we apply the method to the Colombian and Mexican samples from the 1000 Genomes project. The implementation of our method is available at https://github.com/Genomics-HSE/LaNeta.

Balancing openness with Indigenous data sovereignty: An opportunity to leave no one behind in the journey to sequence all of life.

The field of genomics has benefited greatly from its "openness" approach to data sharing. However, with the increasing volume of sequence information being created and stored and the growing number of international genomics efforts, the equity of openness is under question. The United Nations Convention of Biodiversity aims to develop and adopt a standard policy on access and benefit-sharing for sequence information across signatory parties. This standardization will have profound implications on genomics research, requiring a new definition of open data sharing. The redefinition of openness is not unwarranted, as its limitations have unintentionally introduced barriers of engagement to some, including Indigenous Peoples. This commentary provides an insight into the key challenges of openness faced by the researchers who aspire to protect and conserve global biodiversity, including Indigenous flora and fauna, and presents immediate, practical solutions that, if implemented, will equip the genomics community with both the diversity and inclusivity required to respectfully protect global biodiversity.

Multiple migrations to the Philippines during the last 50,000 years.

Island Southeast Asia has recently produced several surprises regarding human history, but the region's complex demography remains poorly understood. Here, we report ∼2.3 million genotypes from 1,028 individuals representing 115 indigenous Philippine populations and genome-sequence data from two ∼8,000-y-old individuals from Liangdao in the Taiwan Strait. We show that the Philippine islands were populated by at least five waves of human migration: initially by Northern and Southern Negritos (distantly related to Australian and Papuan groups), followed by Manobo, Sama, Papuan, and Cordilleran-related populations. The ancestors of Cordillerans diverged from indigenous peoples of Taiwan at least ∼8,000 y ago, prior to the arrival of paddy field rice agriculture in the Philippines ∼2,500 y ago, where some of their descendants remain to be the least admixed East Asian groups carrying an ancestry shared by all Austronesian-speaking populations. These observations contradict an exclusive "out-of-Taiwan" model of farming-language-people dispersal within the last four millennia for the Philippines and Island Southeast Asia. Sama-related ethnic groups of southwestern Philippines additionally experienced some minimal South Asian gene flow starting ∼1,000 y ago. Lastly, only a few lowlanders, accounting for <1% of all individuals, presented a low level of West Eurasian admixture, indicating a limited genetic legacy of Spanish colonization in the Philippines. Altogether, our findings reveal a multilayered history of the Philippines, which served as a crucial gateway for the movement of people that ultimately changed the genetic landscape of the Asia-Pacific region.

Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.

The natural history of tuberculosis (TB) is characterized by a large inter-individual outcome variability after exposure to Mycobacterium tuberculosis. Specifically, some highly exposed individuals remain resistant to M. tuberculosis infection, as inferred by tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). We performed a genome-wide association study of resistance to M. tuberculosis infection in an endemic region of Southern Vietnam. We enrolled household contacts (HHC) of pulmonary TB cases and compared subjects who were negative for both TST and IGRA (n = 185) with infected individuals (n = 353) who were either positive for both TST and IGRA or had a diagnosis of TB. We found a genome-wide significant locus on chromosome 10q26.2 with a cluster of variants associated with strong protection against M. tuberculosis infection (OR = 0.42, 95%CI 0.35-0.49, P = 3.71×10-8, for the genotyped variant rs17155120). The locus was replicated in a French multi-ethnic HHC cohort and a familial admixed cohort from a hyper-endemic area of South Africa, with an overall OR for rs17155120 estimated at 0.50 (95%CI 0.45-0.55, P = 1.26×10-9). The variants are located in intronic regions and upstream of C10orf90, a tumor suppressor gene which encodes an ubiquitin ligase activating the transcription factor p53. In silico analysis showed that the protective alleles were associated with a decreased expression in monocytes of the nearby gene ADAM12 which could lead to an enhanced response of Th17 lymphocytes. Our results reveal a novel locus controlling resistance to M. tuberculosis infection across different populations.

Population structure of indigenous inhabitants of Arabia.

Modern day Saudi Arabia occupies the majority of historical Arabia, which may have contributed to ancient waves of migration out of Africa. This ancient history has left a lasting imprint in the genetics of the region, including the diverse set of tribes that call Saudi Arabia their home. How these tribes relate to each other and to the world's major populations remains an unanswered question. In an attempt to improve our understanding of the population structure of Saudi Arabia, we conducted genomic profiling of 957 unrelated individuals who self-identify with 28 large tribes in Saudi Arabia. Consistent with the tradition of intra-tribal unions, the subjects showed strong clustering along tribal lines with the distance between clusters correlating with their geographical proximities in Arabia. However, these individuals form a unique cluster when compared to the world's major populations. The ancient origin of these tribal affiliations is supported by analyses that revealed little evidence of ancestral origin from within the 28 tribes. Our results disclose a granular map of population structure and have important implications for future genetic studies into Mendelian and common diseases in the region.

Equitable Expanded Carrier Screening Needs Indigenous Clinical and Population Genomic Data.

Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world. Consequently, inclusion of currently underrepresented Indigenous and other minority population groups in genomic research is essential to enable equitable outcomes in ECS and other areas of genomic medicine. Here, we discuss this issue in relation to the implementation of ECS in Australia, which is currently being evaluated as part of the national Government's Genomics Health Futures Mission. We argue that significant effort is required to build an evidence base and genomic reference data so that ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. These efforts are essential steps to achieving the Australian Government's objectives and its commitment "to leveraging the benefits of genomics in the health system for all Australians." They require culturally safe, community-led research and community involvement embedded within national health and medical genomics programs to ensure that new knowledge is integrated into medicine and health services in ways that address the specific and articulated cultural and health needs of Indigenous people. Until this occurs, people who do not have European ancestry are at risk of being, in relative terms, further disadvantaged.

Influence of Genetic Ancestry on Human Serum Proteome.

Disease risk varies significantly between ethnic groups, however, the clinical significance and implications of these observations are poorly understood. Investigating ethnic differences within the human proteome may shed light on the impact of ancestry on disease risk. We used admixture mapping to explore the impact of genetic ancestry on 237 cardiometabolic biomarkers in 2,216 Latin Americans within the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study. We developed a variance component model in order to determine the proportion of variance explained by inter-ancestry differences, and we applied it to the biomarker panel. Multivariable linear regression was used to identify and localize genetic loci affecting biomarker variability between ethnicities. Variance component analysis revealed that 5% of biomarkers were significantly impacted by genetic admixture (p < 0.05/237), including C-peptide, apolipoprotein-E, and intercellular adhesion molecule 1. We also identified 46 regional associations across 40 different biomarkers (p < 1.13 × 10-6). An independent analysis revealed that 34 of these 46 regions were associated at genome-wide significance (p < 5 × 10-8) with their respective biomarker in either Europeans or Latin populations. Additional analyses revealed that an admixture mapping signal associated with increased C-peptide levels was also associated with an increase in diabetes risk (odds ratio [OR] = 6.07 per SD, 95% confidence interval [CI] 1.44 to 25.56, p = 0.01) and surrogate measures of insulin resistance. Our results demonstrate the impact of ancestry on biomarker levels, suggesting that some of the observed differences in disease prevalence have a biological basis, and that reference intervals for those biomarkers should be tailored to ancestry. Specifically, our results point to a strong role of ancestry in insulin resistance and diabetes risk.

Evolved Mechanisms of Aerobic Performance and Hypoxia Resistance in High-Altitude Natives.

Comparative physiology studies of high-altitude species provide an exceptional opportunity to understand naturally evolved mechanisms of hypoxia resistance. Aerobic capacity (VO2max) is a critical performance trait under positive selection in some high-altitude taxa, and several high-altitude natives have evolved to resist the depressive effects of hypoxia on VO2max. This is associated with enhanced flux capacity through the O2 transport cascade and attenuation of the maladaptive responses to chronic hypoxia that can impair O2 transport. Some highlanders exhibit elevated rates of carbohydrate oxidation during exercise, taking advantage of its high ATP yield per mole of O2. Certain highland native animals have also evolved more oxidative muscles and can sustain high rates of lipid oxidation to support thermogenesis. The underlying mechanisms include regulatory adjustments of metabolic pathways and to gene expression networks. Therefore, the evolution of hypoxia resistance in high-altitude natives involves integrated functional changes in the pathways for O2 and substrate delivery and utilization by mitochondria.

Cardiovascular Pharmacogenomics: Does It Matter If You're Black or White?

Race and ancestry have long been associated with differential risk and outcomes to disease as well as responses to medications. These differences in drug response are multifactorial with some portion associated with genomic variation. The field of pharmacogenomics aims to predict drug response in patients prior to medication administration and to uncover the biological underpinnings of drug response. The field of human genetics has long recognized that genetic variation differs in frequency between ancestral populations, with some single nucleotide polymorphisms found solely in one population. Thus far, most pharmacogenomic studies have focused on individuals of European and East Asian ancestry, resulting in a substantial disparity in the clinical utility of genetic prediction for drug response in US minority populations. In this review, we discuss the genetic factors that underlie variability to drug response and known pharmacogenomic associations and how these differ between populations, with an emphasis on the current knowledge in cardiovascular pharmacogenomics.

Genomic Research Through an Indigenous Lens: Understanding the Expectations.

Indigenous scholars are leading initiatives to improve access to genetic and genomic research and health care based on their unique cultural contexts and within sovereign-based governance models created and accepted by their peoples. In the past, Indigenous peoples' engagement with genomicresearch was hampered by a lack of standardized guidelines and institutional partnerships, resulting in group harms. This article provides a comparative analysis of research guidelines from Canada, New Zealand, Australia, and the United States that pertain to Indigenous peoples. The goals of the analysis are to identify areas that need attention, support Indigenous-led governance, and promote the development of a model research policy framework for genomic research and health care that has international relevance for Indigenous peoples.

Inference of Population Structure from Time-Series Genotype Data.

Sequencing ancient DNA can offer direct probing of population history. Yet, such data are commonly analyzed with standard tools that assume DNA samples are all contemporary. We present DyStruct, a model and inference algorithm for inferring shared ancestry from temporally sampled genotype data. DyStruct explicitly incorporates temporal dynamics by modeling individuals as mixtures of unobserved populations whose allele frequencies drift over time. We develop an efficient inference algorithm for our model using stochastic variational inference. On simulated data, we show that DyStruct outperforms the current state of the art when individuals are sampled over time. Using a dataset of 296 modern and 80 ancient samples, we demonstrate DyStruct is able to capture a well-supported admixture event of steppe ancestry into modern Europe. We further apply DyStruct to a genome-wide dataset of 2,067 modern and 262 ancient samples used to study the origin of farming in the Near East. We show that DyStruct provides new insight into population history when compared with alternate approaches, within feasible run time.

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

Inferring Transmission Histories of Rare Alleles in Population-Scale Genealogies.

Learning the transmission history of alleles through a family or population plays an important role in evolutionary, demographic, and medical genetic studies. Most classical models of population genetics have attempted to do so under the assumption that the genealogy of a population is unavailable and that its idiosyncrasies can be described by a small number of parameters describing population size and mate choice dynamics. Large genetic samples have increased sensitivity to such modeling assumptions, and large-scale genealogical datasets become a useful tool to investigate realistic genealogies. However, analyses in such large datasets are often intractable using conventional methods. We present an efficient method to infer transmission paths of rare alleles through population-scale genealogies. Based on backward-time Monte Carlo simulations of genetic inheritance, we use an importance sampling scheme to dramatically speed up convergence. The approach can take advantage of available genotypes of subsets of individuals in the genealogy including haplotype structure as well as information about the mode of inheritance and general prevalence of a mutation or disease in the population. Using a high-quality genealogical dataset of more than three million married individuals in the Quebec founder population, we apply the method to reconstruct the transmission history of chronic atrial and intestinal dysrhythmia (CAID), a rare recessive disease. We identify the most likely early carriers of the mutation and geographically map the expected carrier rate in the present-day French-Canadian population of Quebec.

Genetic legacy of cultures indigenous to the Northeast Asian coast in mitochondrial genomes of nearly extinct maritime tribes.

BACKGROUND: We have described the diversity of complete mtDNA sequences from 'relic' groups of the Russian Far East, primarily the Nivkhi (who speak a language isolate with no clear relatedness to any others) and Oroki of Sakhalin, as well as the sedentary Koryak from Kamchatka and the Udegey of Primorye. Previous studies have shown that most of their traditional territory was dramatically reshaped by the expansion of Tungusic-speaking groups. RESULTS: Overall, 285 complete mitochondrial sequences were selected for phylogenetic analyses of published, revised and new mitogenomes. To highlight the likely role of Neolithic expansions in shaping the phylogeographical landscape of the Russian Far East, we focus on the major East Eurasian maternal lineages (Y1a, G1b, D4m2, D4e5, M7a2, and N9b) that are restricted to the coastal area. To obtain more insight into autochthonous populations, we removed from the phylogeographic analysis the G2a, G3a2, M8a1, M9a1, and C4b1 lineages, also found within our samples, likely resulting from admixture between the expanding proto-Tungus and the indigenous Paleoasiatic groups with whom they assimilated. Phylogenetic analysis reveals that unlike the relatively diverse lineage spectrum observed in the Amur estuary and northwestern Sakhalin, the present-day subpopulation on the northeastern coast of the island is relatively homogenous: a sole Y1a sublineage, conspicuous for its nodal mutation at m.16189 T > C!, includes different haplotypes. Sharing of the Y1a-m.16189 T > C! sublineages and haplotypes among the Nivkhi, Ulchi and sedentary Koryak is also evident. Aside from Y1a, the entire tree approach expands our understanding of the evolutionary history of haplogroups G1, D4m, N9b, and M7a2. Specifically, we identified the novel haplogroup N9b1 in Primorye, which implies a link between a component of the Udegey ancestry and the Hokkaido Jomon. CONCLUSIONS: Through a comprehensive dataset of mitochondrial genomes retained in autochthonous populations along the coast between Primorye and the Bering Strait, we considerably extended the sequence diversity of these populations to provide new features based on the number and timing of founding lineages. We emphasize the value of integrating genealogical information with genetic data for reconstructing the population history of indigenous groups dramatically impacted by twentieth century resettlement and social upheavals.

Genetic Admixture Analysis in the Population of Tacuarembó-Uruguay Using Alu Insertions.

Tacuarembó is a department located in northeastern Uruguay, whose population is the result of several migration waves from Europe and Near East, as well as Africans and Afro-descents mostly from Brazil; these waves settled with the territory's various Native ethnic groups (Charrúa, Minuán, and Guaraní). In the past, this population has been the focus of genetic studies showing this trihybrid origin, with greater contributions of Natives and Africans than in other Uruguayan regions. In this study we analyzed eight Alu insertions (A25, ACE, APOA1, B65, D1, F13B, PV92, TPA25) to provide valuable information for ancestrality and genetic differentiation and to compare with both previous studies on the Tacuarembó population and Alu frequencies in other Uruguayan populations. The European contribution to Alu and classical markers was almost equal to that of a previous study using 22 classical markers (63% vs. 65%), while African contribution was higher (30% vs. 15%), and Native American contribution shows an important difference in Alu: 7% versus 20%. We found no significant differences in genetic differentiation between Tacuarembó and Montevideo but significant differences between Tacuarembó and Basque descendants from Trinidad. Our results support previous findings obtained with classical markers that demonstrate the trihybrid composition of the Tacuarembó population, correlated with historical records. Thus, Alu insertions provide interesting information in light of the admixture process in the Uruguayan population.

Association between vitamin D deficiency and common variants of Vitamin D binding protein gene among Mexican Mestizo and indigenous postmenopausal women.

PURPOSE: Vitamin D deficiency (VDD) and polymorphisms in the group-specific component (GC) gene are known to be associated in different populations. However, the effects of such genetic variants may vary across different populations. Thus, the objective of this study was to estimate the association between Vitamin D-Binding Protein (VDBP) haplotypes and VDD in mestizo postmenopausal women and Mexican Amerindian ethnic groups. METHODS: This was a cross-sectional study of 726 postmenopausal Mexican women from the Health Workers Cohort Study (HWCS) and 166 postmenopausal women from the Metabolic Analysis in an Indigenous Sample (MAIS) cohort in Mexico. GC polymorphisms (rs7045 and rs4588) were analyzed by TaqMan probes. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured by Chemiluminescent Microparticle Immuno Assay. RESULTS: The prevalence of VDD serum 25(OH)D < 20 ng/mL was 43.7% in mestizo women and 44.6% in indigenous women. In HWCS, the single nucleotide polymorphisms (SNPs) rs7041 and rs4588 were associated with VDD. In addition, women from the HWCS, carrying the haplotypes GC2/2 and GC1f/2 had higher odds of VDD (OR = 2.83, 95% CI 1.14, 7.02; and OR = 2.30, 95% CI 1.40, 3.78, respectively) compared to women with haplotype 1f/1 s. These associations were not statistically significant in the MAIS cohort. CONCLUSIONS: Our results show genetic association of the analyzed SNPs and related haplotypes, on the GC gene, with VDD in mestizo Mexican postmenopausal women. Moreover, a high prevalence of VDD with high genetic variability within the country was observed. Our results support the need for national policies for preventing VDD.

Development of a small panel of SNPs to infer ancestry in Chileans that distinguishes Aymara and Mapuche components.

BACKGROUND: Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south. RESULTS: A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country's average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors. CONCLUSIONS: We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.