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April 13th, 2025
Version: 6
University of Southern California
genomics
biorxiv

Genotyping sequence-resolved copy number variationusing pangenomes reveals paralog-specific global diversityand expression divergence of duplicated genes

Ma, W.Open in Google Scholar•Chaisson, M.Open in Google Scholar

Copy number variant (CNV) genes are important in evolution and disease, yet sequence variation in CNV genes remains a blind spot in large-scale studies. We present ctyper, a method that leverages pangenomes to produce allele-specific copy numbers with locally phased variants from next-generation sequencing (NGS) reads. Benchmarking on 3,351 CNV genes, including HLA, SMN, and CYP2D6, and 212 challenging medically relevant (CMR) genes that are 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 requires 1.5 hours per genome on a single CPU. The results improve prediction of gene expression compared to known expression quantitative trait loci (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 conversion, 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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