Language

English

Publication Date

7-7-2024

Journal

Molecular Genetics and Genomics

DOI

10.1007/s00438-024-02158-x

PMID

38972030

PMCID

PMC11955097

PubMedCentral® Posted Date

3-30-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: A large number of challenging medically relevant genes (CMRGs) are situated in complex or highly repetitive regions of the human genome, hindering comprehensive characterization of genetic variants using next-generation sequencing technologies. In this study, we employed long-read sequencing technology, extensively utilized in studying complex genomic regions, to characterize genetic alterations, including short variants (single nucleotide variants and short insertions and deletions) and copy number variations, in 370 CMRGs across 41 individuals from 19 global populations.

Results: Our analysis revealed high levels of genetic variants in CMRGs, with 68.73% exhibiting copy number variations and 65.20% containing short variants that may disrupt protein function across individuals. Such variants can influence pharmacogenomics, genetic disease susceptibility, and other clinical outcomes. We observed significant differences in CMRG variation across populations, with individuals of African ancestry harboring the highest number of copy number variants and short variants compared to samples from other continents. Notably, 15.79% to 33.96% of short variants were exclusively detectable through long-read sequencing. While the T2T-CHM13 reference genome significantly improved the assembly of CMRG regions, thereby facilitating variant detection in these regions, some regions still lacked resolution.

Conclusion: Our results provide an important reference for future clinical and pharmacogenetic studies, highlighting the need for a comprehensive representation of global genetic diversity in the reference genome and improved variant calling techniques to fully resolve medically relevant genes.

Keywords

Humans, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Genome, Human, Polymorphism, Single Nucleotide, Genetic Variation, Genetic Predisposition to Disease, Genetics, Population, INDEL Mutation, Long read sequencing, Challenging medically relevant genes, Genome sequencing, Single nucleotide polymorphism, Short insertion and deletion, Copy number variation

Published Open-Access

yes

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