Genome-wide profiling of highly similar paralogous genes using HiFi sequencing
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.
Authors
- Rachid Karam (ORCID: https://orcid.org/0000-0002-5645-498X)
- Ivan De Dios
- Egor Dolzhenko (ORCID: https://orcid.org/0000-0002-3296-0677)
- Michael A. Eberle (ORCID: https://orcid.org/0000-0001-8965-1253)
- Changrui Xiao (ORCID: https://orcid.org/0000-0001-9536-3389)
- Jonathan LoTempio (ORCID: https://orcid.org/0000-0001-6897-5419)
- Arthur Ko (ORCID: https://orcid.org/0000-0002-1523-7225)
- Andrea J. Cohen (ORCID: https://orcid.org/0000-0001-6838-3843)
- Isabelle Thiffault
- Miguel Almalvez
- Tomi Pastinen (ORCID: https://orcid.org/0000-0003-4016-5021)
- Christian Gilissen (ORCID: https://orcid.org/0000-0003-1693-9699)
- Alexander Hoischen (ORCID: https://orcid.org/0000-0002-8072-4476)
- Esther Yun-Hua Hsiao
- Lisenka E.L.M. Vissers (ORCID: https://orcid.org/0000-0001-6470-5497)
- D. N. Baker (ORCID: https://orcid.org/0000-0001-5909-0926)
- Scott Newman (ORCID: https://orcid.org/0000-0001-9309-4752)
- Bojan Losic (ORCID: https://orcid.org/0000-0002-8282-7874)
- Joseph M. Devaney (ORCID: https://orcid.org/0000-0003-3648-2737)
- Rhonda Brandon
- John Harting
- Dalia Kasperavičiūtė
- April Berlyoung
- Ya Cui (ORCID: https://orcid.org/0000-0003-1574-0928)
- Georgia Pitsava (ORCID: https://orcid.org/0000-0003-0249-8298)
- Emmanuèle C. Délot (ORCID: https://orcid.org/0000-0003-3541-3190)
- Emily Farrow (ORCID: https://orcid.org/0000-0002-8864-7073)
- Leandros Boukas (ORCID: https://orcid.org/0000-0002-6464-867X)
- Krista Bluske
- Xiao Chen (ORCID: https://orcid.org/0000-0002-1432-268X)
- Meghan Delaney (ORCID: https://orcid.org/0000-0003-1089-5787)
- Lucas Lochovsky (ORCID: https://orcid.org/0000-0003-2655-8494)
- Kathleen S. Hruska (ORCID: https://orcid.org/0000-0001-8468-2843)
- Jamie L. Fraser (ORCID: https://orcid.org/0000-0002-7794-8903)
- Sami Belhadj (ORCID: https://orcid.org/0000-0002-0528-9187)
- Seth Berger (ORCID: https://orcid.org/0000-0001-7517-4302)
- Paul Kruszka (ORCID: https://orcid.org/0000-0003-4949-0875)
- Jessica Noya
- Wei Li (ORCID: https://orcid.org/0000-0002-1924-3120)
- Charles H. King (ORCID: https://orcid.org/0000-0003-1409-4549)
- Vincent A. Fusaro (ORCID: https://orcid.org/0000-0002-0538-1047)
- Éric Vilain
- Lightning Auriga
Institutions
- Children's Mercy Hospital (US)
- Children's National (US)
- Radboud University Nijmegen (NL)
- University of California, Irvine (US)
- Radboud University Medical Center (NL)
- Genomics England (GB)
- Ambry Genetics (United States) (US)
- Pacific Biosciences (United States) (US)
- University of Missouri–Kansas City (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-08
- DOI
- https://doi.org/10.1038/s41467-025-57505-2
- Citations
- 5
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 4.03