IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57505-2.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57505-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-57505-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Timofey Prodanov & Vikas Bansal, 2022. "Robust and accurate estimation of paralog-specific copy number for duplicated genes using whole-genome sequencing," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Yang Gao & Xiaofei Yang & Hao Chen & Xinjiang Tan & Zhaoqing Yang & Lian Deng & Baonan Wang & Shuang Kong & Songyang Li & Yuhang Cui & Chang Lei & Yimin Wang & Yuwen Pan & Sen Ma & Hao Sun & Xiaohan Z, 2023. "A pangenome reference of 36 Chinese populations," Nature, Nature, vol. 619(7968), pages 112-121, July.
    3. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    4. Wouter Steyaert & Lonneke Haer-Wigman & Rolph Pfundt & Debby Hellebrekers & Marloes Steehouwer & Juliet Hampstead & Elke Boer & Alexander Stegmann & Helger Yntema & Erik-Jan Kamsteeg & Han Brunner & A, 2023. "Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    6. Mitchell R. Vollger & Philip C. Dishuck & William T. Harvey & William S. DeWitt & Xavi Guitart & Michael E. Goldberg & Allison N. Rozanski & Julian Lucas & Mobin Asri & Katherine M. Munson & Alexandra, 2023. "Increased mutation and gene conversion within human segmental duplications," Nature, Nature, vol. 617(7960), pages 325-334, May.
    7. Wen-Wei Liao & Mobin Asri & Jana Ebler & Daniel Doerr & Marina Haukness & Glenn Hickey & Shuangjia Lu & Julian K. Lucas & Jean Monlong & Haley J. Abel & Silvia Buonaiuto & Xian H. Chang & Haoyu Cheng , 2023. "A draft human pangenome reference," Nature, Nature, vol. 617(7960), pages 312-324, May.
    8. Ting Wang & Lucinda Antonacci-Fulton & Kerstin Howe & Heather A. Lawson & Julian K. Lucas & Adam M. Phillippy & Alice B. Popejoy & Mobin Asri & Caryn Carson & Mark J. P. Chaisson & Xian Chang & Robert, 2022. "The Human Pangenome Project: a global resource to map genomic diversity," Nature, Nature, vol. 604(7906), pages 437-446, April.
    9. Xander Nuttle & Giuliana Giannuzzi & Michael H. Duyzend & Joshua G. Schraiber & Iñigo Narvaiza & Peter H. Sudmant & Osnat Penn & Giorgia Chiatante & Maika Malig & John Huddleston & Chris Benner & Fran, 2016. "Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility," Nature, Nature, vol. 536(7615), pages 205-209, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Leslie A. Smith & James A. Cahill & Ji-Hyun Lee & Kiley Graim, 2025. "Equitable machine learning counteracts ancestral bias in precision medicine," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    2. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    3. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Nicole Deflaux & Margaret Sunitha Selvaraj & Henry Robert Condon & Kelsey Mayo & Sara Haidermota & Melissa A. Basford & Chris Lunt & Anthony A. Philippakis & Dan M. Roden & Joshua C. Denny & Anjene Mu, 2023. "Demonstrating paths for unlocking the value of cloud genomics through cross cohort analysis," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    5. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    6. Mihail Halachev & Viktoria-Eleni Gountouna & Alison Meynert & Gannie Tzoneva & Alan R. Shuldiner & Colin A. Semple & James F. Wilson, 2024. "Regionally enriched rare deleterious exonic variants in the UK and Ireland," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Magdalena Zimoń & Yunfeng Huang & Anthi Trasta & Aliaksandr Halavatyi & Jimmy Z. Liu & Chia-Yen Chen & Peter Blattmann & Bernd Klaus & Christopher D. Whelan & David Sexton & Sally John & Wolfgang Hube, 2021. "Pairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    8. Katherine A. Kentistou & Brandon E. M. Lim & Lena R. Kaisinger & Valgerdur Steinthorsdottir & Luke N. Sharp & Kashyap A. Patel & Vinicius Tragante & Gareth Hawkes & Eugene J. Gardner & Thorhildur Olaf, 2025. "Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    9. H. Serhat Tetikol & Deniz Turgut & Kubra Narci & Gungor Budak & Ozem Kalay & Elif Arslan & Sinem Demirkaya-Budak & Alexey Dolgoborodov & Duygu Kabakci-Zorlu & Vladimir Semenyuk & Amit Jain & Brandi N., 2022. "Pan-African genome demonstrates how population-specific genome graphs improve high-throughput sequencing data analysis," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Hung-Lin Chen & Hsiu-Yin Chiang & David Ray Chang & Chi-Fung Cheng & Charles C. N. Wang & Tzu-Pin Lu & Chien-Yueh Lee & Amrita Chattopadhyay & Yu-Ting Lin & Che-Chen Lin & Pei-Tzu Yu & Chien-Fong Huan, 2024. "Discovery and prioritization of genetic determinants of kidney function in 297,355 individuals from Taiwan and Japan," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. Jonathan Mitchell & Niedzica Camacho & Patrick Shea & Konrad H. Stopsack & Vijai Joseph & Oliver S. Burren & Ryan S. Dhindsa & Abhishek Nag & Jacob E. Berchuck & Amanda O’Neill & Ali Abbasi & Anthony , 2025. "Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    12. Jeffrey D. Wall & J. Fah Sathirapongsasuti & Ravi Gupta & Asif Rasheed & Radha Venkatesan & Saurabh Belsare & Ramesh Menon & Sameer Phalke & Anuradha Mittal & John Fang & Deepak Tanneeru & Manjari Des, 2023. "South Asian medical cohorts reveal strong founder effects and high rates of homozygosity," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    13. Andrew D. Grotzinger & Travis T. Mallard & Zhaowen Liu & Jakob Seidlitz & Tian Ge & Jordan W. Smoller, 2023. "Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    14. Matthias Wuttke & Eva König & Maria-Alexandra Katsara & Holger Kirsten & Saeed Khomeijani Farahani & Alexander Teumer & Yong Li & Martin Lang & Burulca Göcmen & Cristian Pattaro & Dorothee Günzel & An, 2023. "Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Tobias T. Schmidt & Carly Tyer & Preeyesh Rughani & Candy Haggblom & Jeffrey R. Jones & Xiaoguang Dai & Kelly A. Frazer & Fred H. Gage & Sissel Juul & Scott Hickey & Jan Karlseder, 2024. "High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    16. Derek W. Brown & Liam D. Cato & Yajie Zhao & Satish K. Nandakumar & Erik L. Bao & Eugene J. Gardner & Aubrey K. Hubbard & Alexander DePaulis & Thomas Rehling & Lei Song & Kai Yu & Stephen J. Chanock &, 2023. "Shared and distinct genetic etiologies for different types of clonal hematopoiesis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    17. Wolfram Höps & Tobias Rausch & Michael Jendrusch & Jan O. Korbel & Fritz J. Sedlazeck, 2024. "Impact and characterization of serial structural variations across humans and great apes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    18. Can Luo & Yichen Henry Liu & Xin Maizie Zhou, 2024. "VolcanoSV enables accurate and robust structural variant calling in diploid genomes from single-molecule long read sequencing," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    19. Saaket Agrawal & Minxian Wang & Marcus D. R. Klarqvist & Kirk Smith & Joseph Shin & Hesam Dashti & Nathaniel Diamant & Seung Hoan Choi & Sean J. Jurgens & Patrick T. Ellinor & Anthony Philippakis & Me, 2022. "Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    20. Benjamin B. Sun & Stephanie J. Loomis & Fabrizio Pizzagalli & Natalia Shatokhina & Jodie N. Painter & Christopher N. Foley & Megan E. Jensen & Donald G. McLaren & Sai Spandana Chintapalli & Alyssa H. , 2022. "Genetic map of regional sulcal morphology in the human brain from UK biobank data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57505-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.