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[Preprint]. 2025 Feb 20:2024.08.11.607269.
doi: 10.1101/2024.08.11.607269.

Genotyping sequence-resolved copy-number variations using pangenomes reveals paralog-specific global diversity and expression divergence of gene duplication

Walfred Ma, Mark Jp Chaisson

Genotyping sequence-resolved copy-number variations using pangenomes reveals paralog-specific global diversity and expression divergence of gene duplication

Walfred Ma et al. bioRxiv. .

Abstract

Copy-number variable (CNV) genes are important in evolution and disease, yet sequence variation in CNV genes remains a blindspot in large-scale studies. We present ctyper, a method that leverages pangenomes to produce allele-specific copy numbers with locally phased variants from NGS reads. Benchmarking on 3,351 CNV genes including HLA , SMN , and CYP2D6 , and 212 challenging medically-relevant (CMR) genes poorly mapped by NGS, ctyper captures 96.5% of phased variants with ≥99.1% correctness of copy number on CNV genes and 94.8% of phased variants on CMR genes. Applying alignment-free algorithms, ctyper takes only 1.5 hours to genotype a genome on a single CPU. Its results improve predictions of gene expression compared to known eQTL variants. Allele-specific expression quantified divergent expression on 7.94% of paralogs and tissue-specific biases on 4.68% of paralogs. We found reduced expression of SMN -2 due to SMN1 -conversions, potentially affecting spinal muscular atrophy, and increased expression of translocated duplications of AMY2B . Overall, ctyper enables biobank-scale genotyping of CNV and CMR genes.

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