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

Author

Listed:
  • Xiao Chen

    (PacBio)

  • Daniel Baker

    (PacBio)

  • Egor Dolzhenko

    (PacBio)

  • Joseph M. Devaney

    (GeneDx)

  • Jessica Noya

    (GeneDx)

  • April S. Berlyoung

    (GeneDx)

  • Rhonda Brandon

    (GeneDx)

  • Kathleen S. Hruska

    (GeneDx)

  • Lucas Lochovsky

    (GeneDx)

  • Paul Kruszka

    (GeneDx)

  • Scott Newman

    (GeneDx)

  • Emily Farrow

    (Children’s Mercy Kansas City
    University of Missouri Kansas City
    Children’s Mercy Kansas City)

  • Isabelle Thiffault

    (Children’s Mercy Kansas City
    University of Missouri Kansas City
    Children’s Mercy Kansas City)

  • Tomi Pastinen

    (Children’s Mercy Kansas City
    University of Missouri Kansas City)

  • Dalia Kasperaviciute

    (Genomics England Ltd.)

  • Christian Gilissen

    (Radboud University Medical Center
    Radboud University Medical Center)

  • Lisenka Vissers

    (Radboud University Medical Center
    Radboud University Medical Center)

  • Alexander Hoischen

    (Radboud University Medical Center
    Radboud University Medical Center
    Radboud University Medical Center
    Radboud University Medical Center)

  • Seth Berger

    (Children’s National Hospital)

  • Eric Vilain

    (University of California)

  • Emmanuèle Délot

    (University of California)

  • Michael A. Eberle

    (PacBio)

Abstract

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.

Suggested Citation

  • 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 &, 2025. "Genome-wide profiling of highly similar paralogous genes using HiFi sequencing," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57505-2
    DOI: 10.1038/s41467-025-57505-2
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    References listed on IDEAS

    as
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