Structural variants involved in high-altitude adaptation detected using single-molecule long-read sequencing

Area of Science:

• Genomics
• Human Adaptation
• Population Genetics

Background:

• Structural variants (SVs) represent a significant portion of human genetic variation.
• SVs play a crucial role in enabling adaptation to diverse environmental conditions.
• Understanding SVs is essential for comprehending the genetic basis of human evolution.

Purpose of the Study:

• To investigate the role of structural variants (SVs) in high-altitude adaptation among Tibetan populations.
• To expand the known landscape of global SVs and analyze their contribution to population differentiation.
• To explore the functional impact of SVs on gene regulation and biological functions relevant to altitude adaptation.

Main Methods:

• Long-read sequencing of 320 Tibetan and Han samples.
• Application of selection and population differentiation models integrating SVs, SNPs, and InDels.
• Epigenomic analyses to identify enhancers, target genes, and biological functions associated with SVs.
• Functional validation using enhancer reporter assays, cellular knock-out, and DNA pull-down assays.

Main Results:

• Identification of numerous Tibetan-specific SVs significantly involved in high-altitude adaptation.
• Discovery of SVs impacting regulatory circuitry related to hypoxia response, energy metabolism, and pulmonary function.
• A specific Tibetan SV deletion was found to disrupt a super-enhancer, downregulating the EPAS1 gene.

Conclusions:

• Structural variants are critical drivers of human adaptation, particularly to high-altitude environments.
• Gene-regulatory circuitry rewiring through SVs is a key mechanism in human adaptation.
• SVs exhibit diverse functional roles in human biology, extending beyond simple sequence variation.