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<p>Variant calling is hindered in segmental duplications by sequence homology. We developed Paraphase, a HiFi-based informatics method that resolves highly similar genes by phasing all haplotypes of paralogous genes together. We applied Paraphase to 160 long (&gt;10 kb) segmental duplication regions across the human genome with high (&gt;99%) sequence similarity, encoding 316 genes. Analysis across five ancestral populations revealed highly variable copy numbers of these regions. We identified 23 paralog groups with exceptionally low within-group diversity, where extensive gene conversion and unequal crossing over contribute to highly similar gene copies. Furthermore, our analysis of 36 trios identified 7 de novo SNVs and 4 de novo gene conversion events, 2 of which are non-allelic. Finally, we summarized extensive genetic diversity in 9 medically relevant genes previously considered challenging to genotype. Paraphase provides a framework for resolving gene paralogs, enabling accurate testing in medically relevant genes and population-wide studies of previously inaccessible genes.</p>

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Genome-wide profiling of highly similar paralogous genes using HiFi sequencing

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月8日

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  • Xiao Chen,
  • Daniel Baker,
  • Egor Dolzhenko,
  • Joseph M. Devaney,
  • Jessica Noya,
  • April S. Berlyoung,
  • Rhonda Brandon,
  • Kathleen S. Hruska,
  • Lucas Lochovsky,
  • Paul Kruszka,
  • Scott Newman,
  • Emily Farrow,
  • Isabelle Thiffault,
  • Tomi Pastinen,
  • Dalia Kasperaviciute,
  • Christian Gilissen,
  • Lisenka Vissers,
  • Alexander Hoischen,
  • Seth Berger,
  • Eric Vilain,
  • Emmanuèle Délot,
  • Andrea Cohen,
  • Arthur Ko,
  • Georgia Pitsava,
  • Lightning Auriga,
  • Ya Cui,
  • Changrui Xiao,
  • Charles Hadley King,
  • Ivan de Dios,
  • Jonathan LoTempio,
  • Miguel Almalvez,
  • Vincent Fusaro,
  • Wei Li,
  • Jamie Fraser,
  • Meghan Delaney,
  • Leandros Boukas,
  • Bojan Losic,
  • Esther Yun-Hua Hsiao,
  • John Harting,
  • Krista Bluske,
  • Rachid Karam,
  • Sami Belhadj,
  • Michael A. Eberle

摘要

Variant calling is hindered in segmental duplications by sequence homology. We developed Paraphase, a HiFi-based informatics method that resolves highly similar genes by phasing all haplotypes of paralogous genes together. We applied Paraphase to 160 long (>10 kb) segmental duplication regions across the human genome with high (>99%) sequence similarity, encoding 316 genes. Analysis across five ancestral populations revealed highly variable copy numbers of these regions. We identified 23 paralog groups with exceptionally low within-group diversity, where extensive gene conversion and unequal crossing over contribute to highly similar gene copies. Furthermore, our analysis of 36 trios identified 7 de novo SNVs and 4 de novo gene conversion events, 2 of which are non-allelic. Finally, we summarized extensive genetic diversity in 9 medically relevant genes previously considered challenging to genotype. Paraphase provides a framework for resolving gene paralogs, enabling accurate testing in medically relevant genes and population-wide studies of previously inaccessible genes.