scholarly journals The promise of disease gene discovery in South Asia

2016 ◽  
Author(s):  
Nathan Nakatsuka ◽  
Priya Moorjani ◽  
Niraj Rai ◽  
Biswanath Sarkar ◽  
Arti Tandon ◽  
...  
Keyword(s):  
South Asia ◽  
Disease Burden ◽  
South Asians ◽  
Large Population ◽  
Disease Genes ◽  
Ashkenazi Jews ◽  
Disease Gene Discovery ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Founder Events

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population, but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identify 81 unique groups, of which 14 have estimated census sizes of more than a million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identify multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an under-appreciated opportunity for reducing disease burden among South Asians through the discovery of and testing for recessive disease genes.

scholarly journals The Genomic Formation of South and Central Asia

2018 ◽  
Author(s):  
Vagheesh M. Narasimhan ◽  
Nick Patterson ◽  
Priya Moorjani ◽  
Iosif Lazaridis ◽  
Mark Lipson ◽  
...  
Keyword(s):  
South Asia ◽  
Bronze Age ◽  
South Asian ◽  
Ancient Dna ◽  
South Asians ◽  
Asian Populations ◽  
European Languages ◽  
Genome Wide ◽  
Steppe Communities ◽  
Genome Wide Data

AbstractThe genetic formation of Central and South Asian populations has been unclear because of an absence of ancient DNA. To address this gap, we generated genome-wide data from 362 ancient individuals, including the first from eastern Iran, Turan (Uzbekistan, Turkmenistan, and Tajikistan), Bronze Age Kazakhstan, and South Asia. Our data reveal a complex set of genetic sources that ultimately combined to form the ancestry of South Asians today. We document a southward spread of genetic ancestry from the Eurasian Steppe, correlating with the archaeologically known expansion of pastoralist sites from the Steppe to Turan in the Middle Bronze Age (2300-1500 BCE). These Steppe communities mixed genetically with peoples of the Bactria Margiana Archaeological Complex (BMAC) whom they encountered in Turan (primarily descendants of earlier agriculturalists of Iran), but there is no evidence that the main BMAC population contributed genetically to later South Asians. Instead, Steppe communities integrated farther south throughout the 2nd millennium BCE, and we show that they mixed with a more southern population that we document at multiple sites as outlier individuals exhibiting a distinctive mixture of ancestry related to Iranian agriculturalists and South Asian hunter-gathers. We call this group Indus Periphery because they were found at sites in cultural contact with the Indus Valley Civilization (IVC) and along its northern fringe, and also because they were genetically similar to post-IVC groups in the Swat Valley of Pakistan. By co-analyzing ancient DNA and genomic data from diverse present-day South Asians, we show that Indus Periphery-related people are the single most important source of ancestry in South Asia—consistent with the idea that the Indus Periphery individuals are providing us with the first direct look at the ancestry of peoples of the IVC—and we develop a model for the formation of present-day South Asians in terms of the temporally and geographically proximate sources of Indus Periphery-related, Steppe, and local South Asian hunter-gatherer-related ancestry. Our results show how ancestry from the Steppe genetically linked Europe and South Asia in the Bronze Age, and identifies the populations that almost certainly were responsible for spreading Indo-European languages across much of Eurasia.One Sentence SummaryGenome wide ancient DNA from 357 individuals from Central and South Asia sheds new light on the spread of Indo-European languages and parallels between the genetic history of two sub-continents, Europe and South Asia.

scholarly journals No Evidence from Genome-Wide Data of a Khazar Origin for the Ashkenazi Jews

Human Biology ◽  
2013 ◽  
Vol 85 (6) ◽  
pp. 859-900 ◽  
Author(s):  
Doron M. Behar ◽  
Mait Metspalu ◽  
Yael Baran ◽  
Naama M. Kopelman ◽  
Bayazit Yunusbayev ◽  
...  
Keyword(s):  
Ashkenazi Jews ◽  
Genome Wide ◽  
Genome Wide Data

scholarly journals Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery

2018 ◽  
Author(s):  
Xinchen Wang ◽  
David B. Goldstein
Keyword(s):  
Complex Disease ◽  
Genome Wide Association Study ◽  
Regulatory Elements ◽  
Disease Genes ◽  
Transcriptional Regulatory Elements ◽  
Regulatory Domains ◽  
Disease Gene Discovery ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Transcriptional Regulatory

AbstractNon-coding transcriptional regulatory elements are critical for controlling the spatiotemporal expression of genes. Here, we demonstrate that the number of bases in enhancers linked to a gene reflects its disease pathogenicity. Moreover, genes with redundant enhancer domains are depleted of cis-acting genetic variants that disrupt gene expression, and are buffered against the effects of disruptive non-coding mutations. Our results demonstrate that dosage-sensitive genes have evolved robustness to the disruptive effects of genetic variation by expanding their regulatory domains. This resolves a puzzle in the genetic literature about why disease genes are depleted of cis-eQTLs, suggesting that eQTL information may implicate the wrong genes at genome-wide association study loci, and establishes a framework for identifying non-coding regulatory variation with phenotypic consequences.

scholarly journals The genetic legacy of continental scale admixture in Indian Austroasiatic speakers

2018 ◽  
Author(s):  
Kai Tätte ◽  
Luca Pagani ◽  
Ajai K. Pathak ◽  
Sulev Kõks ◽  
Binh Ho Duy ◽  
...  
Keyword(s):  
South Asians ◽  
Asian Population ◽  
South Asian Population ◽  
Southeast Asians ◽  
Continental Scale ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Different Populations ◽  
Source Populations ◽  
Austroasiatic Languages

AbstractSurrounded by speakers of Indo-European, Dravidian and Tibeto-Burman languages, around 11 million Munda (a branch of Austroasiatic language family) speakers live in the densely populated and genetically diverse South Asia. Their genetic makeup holds components characteristic of South Asians as well as Southeast Asians. The admixture time between these components has been previously estimated on the basis of archaeology, linguistics and uniparental markers. Using genome-wide genotype data of 102 Munda speakers and contextual data from South and Southeast Asia, we retrieved admixture dates between 2000 – 3800 years ago for different populations of Munda. The best modern proxies for the source populations for the admixture with proportions 0.78/0.22 are Lao people from Laos and Dravidian speakers from Kerala in India, while the South Asian population(s), with whom the incoming Southeast Asians intermixed, had a smaller proportion of West Eurasian component than contemporary proxies. Somewhat surprisingly Malaysian Peninsular tribes rather than the geographically closer Austroasiatic languages speakers like Vietnamese and Cambodians show highest sharing of IBD segments with the Munda. In addition, we affirmed that the grouping of the Munda speakers into North and South Munda based on linguistics is in concordance with genome-wide data.

Suicide and Psychosis: Results From a Population-Based Cohort of Suicide Death (N = 4380)

2021 ◽  
Author(s):  
Anna R Docherty ◽  
Amanda V Bakian ◽  
Emily DiBlasi ◽  
Andrey A Shabalin ◽  
Danli Chen ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Large Population ◽  
Population Based ◽  
Suicide Death ◽  
Genetics Research ◽  
Affective Symptoms ◽  
Genome Wide ◽  
Increased Risk ◽  
Genetic Risks ◽  
Genome Wide Data

Abstract Approximately 5% of individuals with schizophrenia die from suicide. However, suicide in psychosis is still poorly characterized, partly due to a lack of adequate population-based clinical or genetic data on suicide death. The Utah Suicide Genetics Research Study (USGRS) provides a large population-based cohort of suicide deaths with medical record and genome-wide data (N = 4380). Examination of this cohort identified medical and genetic risks associated with type of suicide death and investigated the relative contributions of psychotic and affective symptoms to method of suicide. Key differences in method of suicide (common vs. atypical methods) were tested in relation to lifetime psychosis and genome-wide genetic risk for schizophrenia, major depressive disorder, and neuroticism. Consistent with previous studies, psychosis-spectrum disorders were observed to be common in suicide (15% of the cohort). Individuals with psychosis more frequently died from atypical methods, with rates of atypical suicide increasing across the schizophrenia spectrum. Genetic risk for schizophrenia was also associated with atypical suicide, regardless of clinical diagnosis, though this association weakened when filtering individuals with schizophrenia from the analysis. Follow-up examination indicated that high rates of atypical suicide observed in schizophrenia are not likely accounted for by restricted access to firearms. Overall, better accounting for the increased risk of atypical suicide methods in psychosis could lead to improved prevention strategies in a large portion of the suicide risk population.

No Evidence from Genome-wide Data of a Khazar Origin fo the Ashkenazi Jews

Human Biology ◽  
2013 ◽  
Vol 85 (6) ◽  
pp. 859
Author(s):  
Doron M. Behar ◽  
Mait Metspalu ◽  
Yael Baran ◽  
Naama M. Kopelman ◽  
Bayazit Yunusbayev ◽  
...  
Keyword(s):  
Ashkenazi Jews ◽  
Genome Wide ◽  
Genome Wide Data

scholarly journals Within-island diversification in a passerine bird

2020 ◽  
Vol 287 (1923) ◽  
pp. 20192999 ◽  
Author(s):  
Maëva Gabrielli ◽  
Benoit Nabholz ◽  
Thibault Leroy ◽  
Borja Milá ◽  
Christophe Thébaud
Keyword(s):  
Phylogenetic Analyses ◽  
Large Population ◽  
Population Sample ◽  
Passerine Bird ◽  
Population History ◽  
Hybrid Zones ◽  
Genome Wide ◽  
Genome Wide Data ◽  
History Of

The presence of congeneric taxa on the same island suggests the possibility of in situ divergence, but can also result from multiple colonizations of previously diverged lineages. Here, using genome-wide data from a large population sample, we test the hypothesis that intra-island divergence explains the occurrence of four geographical forms meeting at hybrid zones in the Reunion grey white-eye ( Zosterops borbonicus ), a species complex endemic to the small volcanic island of Reunion. Using population genomic and phylogenetic analyses, we reconstructed the population history of the different forms. We confirmed the monophyly of the complex and found that one of the lowland forms is paraphyletic and basal relative to others, a pattern highly consistent with in situ divergence. Our results suggest initial colonization of the island through the lowlands, followed by expansion into the highlands, which led to the evolution of a distinct geographical form, genetically and ecologically different from the lowland ones. Lowland forms seem to have experienced periods of geographical isolation, but they diverged from one another by sexual selection rather than niche change. Overall, low dispersal capabilities in this island bird combined with both geographical and ecological opportunities seem to explain how divergence occurred at such a small spatial scale.

scholarly journals Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

2015 ◽  
Vol 113 (1) ◽  
pp. 152-157 ◽  
Author(s):  
Clare D. Marsden ◽  
Diego Ortega-Del Vecchyo ◽  
Dennis P. O’Brien ◽  
Jeremy F. Taylor ◽  
Oscar Ramirez ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Amino Acid ◽  
Artificial Selection ◽  
Selective Breeding ◽  
Large Population ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Selective Sweeps ◽  
Gray Wolves ◽  
Genome Wide

Population bottlenecks, inbreeding, and artificial selection can all, in principle, influence levels of deleterious genetic variation. However, the relative importance of each of these effects on genome-wide patterns of deleterious variation remains controversial. Domestic and wild canids offer a powerful system to address the role of these factors in influencing deleterious variation because their history is dominated by known bottlenecks and intense artificial selection. Here, we assess genome-wide patterns of deleterious variation in 90 whole-genome sequences from breed dogs, village dogs, and gray wolves. We find that the ratio of amino acid changing heterozygosity to silent heterozygosity is higher in dogs than in wolves and, on average, dogs have 2–3% higher genetic load than gray wolves. Multiple lines of evidence indicate this pattern is driven by less efficient natural selection due to bottlenecks associated with domestication and breed formation, rather than recent inbreeding. Further, we find regions of the genome implicated in selective sweeps are enriched for amino acid changing variants and Mendelian disease genes. To our knowledge, these results provide the first quantitative estimates of the increased burden of deleterious variants directly associated with domestication and have important implications for selective breeding programs and the conservation of rare and endangered species. Specifically, they highlight the costs associated with selective breeding and question the practice favoring the breeding of individuals that best fit breed standards. Our results also suggest that maintaining a large population size, rather than just avoiding inbreeding, is a critical factor for preventing the accumulation of deleterious variants.

scholarly journals Childhood socio-economic conditions and risk of cardiovascular disease: results from a pooled sample of 14 011 adults from India

2020 ◽  
pp. jech-2020-214016
Author(s):  
Poppy Alice Carson Mallinson ◽  
Judith Lieber ◽  
Santhi Bhogadi ◽  
Sanjay Kinra
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Cardiovascular Disease ◽  
South Asia ◽  
South Asians ◽  
Large Population ◽  
Economic Conditions ◽  
Linear Regression Models ◽  
Premature Cardiovascular Disease ◽  
Increased Risk

BackgroundSouth Asians are at an increased risk of premature cardiovascular disease, but the reasons for this are unclear. Poor socio-economic conditions in childhood are associated with an increased risk of cardiovascular disease in many high-income countries and may be particularly relevant to South Asia, where socio-economic deprivation is more prevalent and severe. However, evidence from South Asia is limited.MethodsWe pooled data from two large population-based studies in India to provide a geographically representative and adequately powered sample of Indian adults. We used multilevel linear regression models to assess associations between standard of living index (SLI) in childhood (measured by recalled household assets at age 10–12 years) and major cardiovascular risk factors including adiposity, blood pressure, and fasting blood lipids, glucose and insulin.ResultsData on 14 011 adults (median age 39 years, 56% men) were analysed. SLI in childhood was inversely associated with systolic and diastolic blood pressure, independent of socio-economic conditions in adulthood, with beta coefficients (95% CIs) of −0.70 mmHg (−1.17 to −0.23) and −0.56 mmHg (−0.91 to −0.22), respectively, per SD increase in SLI in childhood. There was no strong evidence for an association between SLI in childhood and other risk factors of cardiovascular disease.ConclusionsPoor socio-economic conditions in childhood may contribute to the increased risk of premature cardiovascular disease among South Asians by raising their blood pressure. Elucidating the mechanisms and improving socio-economic conditions for children in South Asia could provide major reductions in the burden of cardiovascular disease.

scholarly journals Reconstructing the history of founder events using genome-wide patterns of allele sharing across individuals

2020 ◽  
Author(s):  
Rémi Tournebize ◽  
Gillian Chu ◽  
Priya Moorjani
Keyword(s):  
Disease Risk ◽  
Sequence Data ◽  
South Asians ◽  
Critical Role ◽  
Allele Sharing ◽  
Ashkenazi Jews ◽  
Island Populations ◽  
Locus Method ◽  
History Of ◽  
Founder Events

AbstractFounder events play a critical role in shaping genetic diversity, impacting the fitness of a species and disease risk in humans. Yet our understanding of the prevalence and distribution of founder events in humans and other species remains incomplete, as most existing methods for characterizing founder events require large sample sizes or phased genomes. To learn about the frequency and evolutionary history of founder events, we introduce ASCEND (Allele Sharing Correlation for the Estimation of Non-equilibrium Demography), a flexible two-locus method to infer the age and strength of founder events. This method uses the correlation in allele sharing across the genome between pairs of individuals to recover signatures of past bottlenecks. By performing coalescent simulations, we show that ASCEND can reliably estimate the parameters of founder events under a range of demographic scenarios, with genotype or sequence data. We apply ASCEND to ~5,000 worldwide human samples (~3,500 present-day and ~1,500 ancient individuals), and ~1,000 domesticated dog samples. In both species, we find pervasive evidence of founder events in the recent past. In humans, over half of the populations surveyed in our study had evidence for a founder events in the past 10,000 years, associated with geographic isolation, modes of sustenance, and historical invasions and epidemics. We document that island populations have historically maintained lower population sizes than continental groups, ancient hunter-gatherers had stronger founder events than Neolithic Farmers or Steppe Pastoralists, and periods of epidemics such as smallpox were accompanied by major population crashes. Many present-day groups--including Central & South Americans, Oceanians and South Asians--have experienced founder events stronger than estimated in Ashkenazi Jews who have high rates of recessive diseases due to their history of founder events. In dogs, we uncovered extreme founder events in most groups, more than ten times stronger than the median strength of founder events in humans. These founder events occurred during the last 25 generations and are likely related to the establishment of dog breeds during Victorian times. Our results highlight a widespread history of founder events in humans and dogs, and provide insights about the demographic and cultural processes underlying these events.

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