Maternal lineage diversity and health-related haplogroups in the Gilgiti and Kohistani populations of northern Pakistan

Mitochondrial DNA (mtDNA) is a crucial genetic marker for tracing maternal ancestry, understanding population history, and identifying disease-associated variants. Northern Pakistan, particularly the Kohistani and Gilgiti populations, lies at a historically significant crossroads of human migration, yet remains genetically understudied. Previous studies on these populations have primarily focused on the mtDNA control region, limiting insights into their genetic diversity, demographic history, and health-related mutations. A comprehensive whole mitogenome analysis is essential to bridge this gap and provide a more complete understanding of their genetic landscape. This study presents the first whole mitogenome analysis of the Kohistani and Gilgiti populations, leveraging next-generation sequencing to examine 120 complete mitochondrial genomes. This approach allows for a more detailed exploration of genetic diversity, population structure, and disease-associated mutations. Our primary focus is to investigate population history, genetic affinities, and clinically relevant mtDNA variations in these groups, contributing to both evolutionary genetics and precision medicine. We observed high genetic diversity, with balancing selection evident in the Gilgiti population and signals of recent expansion in the Kohistani group. Additionally, we identified mtDNA mutations associated with Leber's Hereditary Optic Neuropathy (m.11778G > A, m.14484T > C), which are well established pathogenic variants known to exhibit incomplete penetrance in other populations, as well as MIDD and MELAS (m.3243 A > G) and metabolic syndrome (m.10398 A > G), revealing population-specific health risks that warrant cautious interpretation. These findings highlight the importance of population-specific genetic studies for disease risk assessment and healthcare planning. By characterizing the mitogenomic landscape of these populations, our study provides critical insights into the genetic history in Kohistani and Gilgiti population and biomedical significance. Overall, this work not only enriches our understanding of human migration dynamics in Northern Pakistan but also establishes a valuable reference for future anthropological and biomedical research.