Fine-scale genetic structure and population-specific functional variants in the indigenous tribal populations of India

India harbors one of the most complex demographic and genetic landscapes globally, comprising more than 4600 endogamous ethnolinguistic groups shaped by multiple waves of migration, prolonged isolation, and deep social stratification. Odisha, an eastern state of India, is home to 62 indigenous tribal groups, including 13 Particularly Vulnerable Tribal Groups (PVTGs), many of which remain genetically understudied. These populations provide a unique opportunity to explore fine-scale population structure and population-specific functional variation in underrepresented South Asian populations. We generated high-coverage whole-exome sequencing (WES) of 13 tribal groups (n = 515) from Odisha, collectively termed OdiTribe. We identified 625,596 single-nucleotide variants (SNVs), of which 42.51% were rare, and 5.54% (n=34,667) were novel. Population genetic analyses revealed clear substructure within the OdiTribe, along with strong population-specific genetic drift in the Juang tribe. The Juang and Bonda tribes exhibited significant shared genetic drift with the Nicobarese, as indicated by outgroup F3 statistics, suggesting shared ancestral connections. Approximately 43% of the individuals showed elevated inbreeding coefficients (>= 0.0156), and 14.2% carried ROH segments > 8 Mb, indicative of recent consanguinity. Functional annotation uncovered population-specific pathogenic variants in HBB, HBD, BTD and BRCA2 genes, as well as multiple high-confidence homozygous loss-of-function (HC-LoF) variants across the dataset. Our study provides exome-wide insights into genetic diversity, endogamy and population-specific functional variants among endogamous indigenous tribal populations, underscoring the importance of including isolated and underrepresented groups in population and medical genetics research.印度拥有全球最为复杂的人口学与遗传学景观之一，境内分布着超4600个因多轮移民浪潮、长期隔离与森严社会分层而形成的内婚制族语群体。作为印度东部的邦，奥里萨邦境内拥有62个本土部落群体，其中包含13个特定脆弱部落群体（Particularly Vulnerable Tribal Groups，PVTGs），多数群体的遗传学研究仍处于匮乏状态。此类群体为探究代表性不足的南亚人群的精细群体结构与群体特异性功能变异提供了独特契机。本研究对奥里萨邦的13个部落群体（共515名受试者）开展了高覆盖度全外显子组测序（whole-exome sequencing，WES），该队列被统一命名为OdiTribe。本次研究共鉴定出625596个单核苷酸变异（single-nucleotide variants，SNVs），其中42.51%为稀有变异，5.54%（共计34667个）为新发变异。群体遗传学分析显示，OdiTribe队列内部存在明确的亚结构，其中Juang部落呈现出显著的群体特异性遗传漂变。外群F3统计量结果显示，Juang部落与Bonda部落均与尼科巴人（Nicobarese）存在显著的共享遗传漂变，提示二者拥有共同的祖先关联。约43%的受试者表现出升高的近交系数（≥0.0156），14.2%的受试者携带长度超过8Mb的纯合子区域（Runs of Homozygosity，ROH）片段，提示存在近期近亲婚配现象。功能注释分析揭示了HBB、HBD、BTD与BRCA2基因中存在群体特异性致病变异，同时在本数据集中共发现多个高可信度纯合功能丧失（high-confidence homozygous loss-of-function，HC-LoF）变异。本研究为内婚制本土部落群体的遗传多样性、内婚现象与群体特异性功能变异提供了全外显子组层面的解析，同时强调了将隔离且代表性不足的群体纳入群体遗传学与医学遗传学研究的重要性。