Endogamy and high prevalence of deleterious mutations in India: evidence from strong founder events

Pratheusa Machha; Amirtha Gopalan; Yamini Elangovan; Sarath Chandra Mouli Veeravalli; Divya Tej Sowpati; Kumarasamy Thangaraj

doi:10.1016/j.jgg.2025.02.001

Volume 52 Issue 4

Apr. 2025

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Endogamy and high prevalence of deleterious mutations in India: evidence from strong founder events

doi: 10.1016/j.jgg.2025.02.001

a. CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana 500007, India;
b. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India;
c. Department of Rheumatology and Clinical Immunology, Krishna Institute of Medical Sciences, Secunderabad, Telangana 500003, India;
d. Department of Rheumatology and Clinical Immunology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana 500082, India;
e. Department of Biotechnology, Bharathidasan University, Tiruchirapalli, Tamil Nadu 620024, India;
f. Tata Institute for Genetics and Society, Bengaluru 560065, India

Funds:

and CSIR Bhatnagar Fellowship, from Council of Scientific and Industrial Research (CSIR), Ministry of Science and Technology, Government of India.

PM was supported by the DBT JRF-SRF research fellowship. KT was supported the J C Bose Fellowship from Science and Engineering Research Board (SERB), Department of Science and Technology, Government of India (JCB/2019/000027)

Received Date: 2024-09-02
Accepted Date: 2025-02-06
Rev Recd Date: 2025-02-02

Available Online: 2025-07-11

Publish Date: 2025-02-13

Abstract

Abstract

Founder events influence recessive diseases in highly endogamous populations. Several Indian populations have experienced significant founder events due to strict endogamy. However, the clinical implications of it remain underexplored. Therefore, we perform whole-exome sequencing of 281 individuals from four South Indian populations, characterized by high IBD scores. Our study reveals a high inbreeding rate of 59% across the populations. We identify ∼29.2% of the variants that are exclusively present in a single population and uncover 1284 unreported exonic variants, underscoring the underrepresentation of Indian populations in global databases. Among these, 23 are predicted to be deleterious, all of which are present in a heterozygous state; they may be pathogenic when homozygous, an expected phenomenon in endogamous populations. Approximately 16%–33% of the identified pathogenic variants showed significantly higher occurrence rates compared with the South Asian populations from 1000 Genomes dataset. Pharmacogenomic analysis revealed distinct allele frequencies of variants in CYP450 and non-CYP450 genes, highlighting heterogeneous drug responses and associated risks. We report a high prevalence of ankylosing spondylitis in Reddy population, linked to the HLA-B*27:04 allele and strong founder effect. Our findings highlight the need for extensive genomic research in understudied Indian populations for a better understanding of disease risk and evolving strategies for precision and preventive medicine.
- Founder event,
- Endogamy,
- Genetic variants,
- Runs of homozygosity,
- Pharmacogenomics

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References(46)

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