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Unveiling novel genetic variants in 370 challenging medically relevant genes using the long read sequencing data of 41 samples from 19 global populations

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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.

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Data availability

The data analyzed in the present study were all downloaded from public data repositories. Please find more details in Supplementary Table 2.

Abbreviations

CMRGs:

Challenging medically relevant genes

CNV:

Copy number variation

LRS:

Long-read sequencing

SRS:

Short-read sequencing

WES:

Whole-exome sequencing

WGS:

Whole genome sequencing

SNVs:

Single nucleotide variations

InDels:

Short insertions and deletions

GIAB:

Genome in a Bottle

PacBio:

Pacific Biosciences

ONT:

Oxford Nanopore Technology

SVs:

Structural variants

ADME:

Absorption, distribution, metabolism, and excretion

CLR:

Continuous long reads

HiFi:

Highly accurate long reads

DoC:

Depth of coverage

KIV-2:

Kringle IV type 2

OMIM:

Online Mendelian Inheritance in Man

HGMD:

Human Gene Mutation Database

SD:

Standard deviation

VEP:

Ensembl Variant Effect Predictor

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Acknowledgements

The authors thank Shuhang Li for the discussion of short variant calling.

Funding

S.F. is supported by grants from the National Key R&D Program of China (Grant No. 2020YFE0201600 and 2021YFC2500202), Shanghai Municipal Science and Technology (Grant No. 2017SHZDZX01), and the National Natural Science Foundation of China (Grant No. 31970563, 32370686). F.S is supported by NIH grants (UM1HG008898, 1U01HG011758-01).

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Authors and Affiliations

  1. State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, School of Life Science, Fudan University, Shanghai, 200438, China

    Yanfeng Ji, Junfan Zhao, Jiao Gong & Shaohua Fan

  2. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    Fritz J. Sedlazeck

  3. Department of Computer Science, Rice University, 6100 Main Street, Houston, TX, 77005, USA

    Fritz J. Sedlazeck

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  1. Yanfeng Ji
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  2. Junfan Zhao
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  3. Jiao Gong
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  4. Fritz J. Sedlazeck
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  5. Shaohua Fan
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Contributions

Conceptualization: S.F. and F.S; data curation: Y.J. and J.G.; formal analysis: Y.J. and J.Z; supervision: S.F. and F.S.; visualization: Y.J. and J.Z.; writing original draft: S.F.; writing review and editing: all authors.

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Correspondence to Fritz J. Sedlazeck or Shaohua Fan.

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F.S receives research support from Illumina, PacBio, and Oxford Nanopore.

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Communicated by Shuhua Xu.

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Ji, Y., Zhao, J., Gong, J. et al. Unveiling novel genetic variants in 370 challenging medically relevant genes using the long read sequencing data of 41 samples from 19 global populations. Mol Genet Genomics 299, 65 (2024). https://doi.org/10.1007/s00438-024-02158-x

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