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Peer-reviewedCC BYNature Genetics

A blended genome and exome sequencing method captures genetic variation in an unbiased and cost-effective manner

  • Toni A. Boltz1,2
  • Benjamin B. Chu3
  • Matthew T. DeFelice4
  • Calwing Liao1,5,2
  • Julia Sealock1,5,2
  • Robert Ye1,5,2
  • Jacqueline I. Goldstein1,2
  • Lerato Majara1,6,2
  • Jack M. Fu7,5
  • Susan K. Service8
  • Lingyu Zhan8,9
  • Sarah Elizabeth Medland10
86 more authors
  • Sinéad B. Chapman1,11,5,2
  • Simone Rubinacci12,13,5
  • Jonna Grimsby4
  • Tamrat Abebe14
  • Melkam Alemayehu Kebede15
  • Fred K. Ashaba16
  • Elizabeth G. Atkinson17,18
  • Tim B. Bigdeli19
  • Amanda B Bradway4
  • Harrison Brand20,5
  • Lori Beth Chibnik21,22,2
  • DeLuca Samuel4
  • Ana M. Díaz‐Zuluaga8
  • Abebaw Fekadu23,15
  • Michael Gatzen4
  • Bizu Gelaye21,24,2
  • Stella Gichuru25
  • M. Gildea4
  • Toni C Hill4
  • Hailiang Huang1,11,5,2
  • Kalyn M. Hubbard4
  • Wilfred E. Injera26
  • Roxanne James27
  • M Joloba28
  • C. Kachulis4
  • Phillip R Kalmbach4
  • Rogers Kamulegeya28
  • Gabriel Kigen29
  • S Y Kim1,30,5,2
  • Nastassja Koen27,31
  • Edith K. Kwobah25
  • Joseph Kyebuzibwa32
  • Seungmo Lee33
  • Niall J. Lennon4
  • Penelope A. Lind10
  • Esteban A. Lopera-Maya8,34
  • Johnstone Makale35
  • Serghei Mangul36,37,38,39
  • Justin McMahon21,2
  • Pierre Mowlem40
  • Henry Musinguzi16
  • Rehema M. Mwema
  • Noeline Nakasujja32
  • Carter P. Newman21,2
  • Lethukuthula L. Nkambule1,2
  • Conor R O'Neil4
  • Ana Maria Olivares2
  • Catherine M. Olsen10

60 listed; 98 in total.

40 affiliations
  1. 1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
  2. 2Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  3. 3Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
  4. 4Broad Clinical Labs, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  5. 5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  6. 6Department of Psychiatry and Mental Health and South African Medical Council Research Unit on Risk and Resilience in Mental Disorders, Neuroscience Institute, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
  7. 7Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
  8. 8Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA
  9. 9The Collaboratory, Institute for Quantitative and Computational Biosciences, University of California Los Angeles, Los Angeles, CA, USA
  10. 10QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  11. 11BD2: Breakthrough Discoveries for thriving with Bipolar Disorder, Santa Monica, CA, USA
  12. 12Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
  13. 13Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
  14. 14Department of Microbiology, Immunology, and Parasitology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
  15. 15Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
  16. 16Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda
  17. 17Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
  18. 18Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  19. 19Institute for Genomics in Health, The State University of New York, Brooklyn, NY, USA
  20. 20Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
  21. 21Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
  22. 22Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
  23. 23Centre for Innovative Drug Development and Therapeutic Trials for Africa, Addis Ababa University, Addis Ababa, Ethiopia
  24. 24Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
  25. 25Department of Mental Health, Moi Teaching and Referral Hospital, Eldoret, Kenya
  26. 26Department of Medical Laboratory Sciences, School of Health Sciences, Alupe University, Busia, Kenya
  27. 27Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
  28. 28School of Biomedical Sciences, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda
  29. 29Department of Pharmacology and Toxicology, Moi University School of Medicine, Eldoret, Kenya
  30. 30Department of Medicine, Kyung Hee University College of Medicine, Seoul, Republic of Korea
  31. 31SA MRC Unit on Risk and Resilience in Mental Disorders, University of Cape Town and Neuroscience Institute, Cape Town, South Africa
  32. 32Department of Psychiatry, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda
  33. 33Department of Computer Science, University of California Los Angeles, Los Angeles, CA, USA
  34. 34Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
  35. 35Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya
  36. 36Department of Biological and Morphofunctional Sciences, College of Medicine and Biological Sciences, Stefan cel Mare University of Suceava, Suceava, Romania
  37. 37Department of Clinical Pharmacy, Alfred E. Mann School of Pharmacy, University of Southern California, Los Angeles, CA, USA
  38. 38Department of Computers, Informatics, and Microelectronics, Technical University of Moldova, Chisinau, Moldova
  39. 39Małopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland
  40. 40Ampath Laboratories, Moi University School of Medicine, Eldoret, Kenya
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Abstract

Here we developed and deployed the blended genome exome (BGE) method, a DNA library approach that generates low-pass whole-genome (1–4× mean depth) and deep whole-exome (30–40× mean depth) data in a single sequencing run. BGE is cost-effective, empowers most genomic discoveries possible with deep whole-genome sequencing and captures global common single-nucleotide polymorphism diversity. We applied BGE to sequence >53,000 samples from the PUMAS Project (Populations Underrepresented in Mental Illness Associations Studies), including African, African American and Latin American populations. Imputed genotypes showed high concordance with Illumina Global Screening Array calls ( R 2 ≥ 95% for minor allele frequency ≥1%; ≥90% for minor allele frequency <1%), with consistent performance across local ancestries in admixed cohorts. For protein-coding copy number variants, deletions and duplications spanning at least three exons had a positive predicted value of ~90% relative to deep whole-genome data. At ~28% of the cost of deep whole-genome sequencing, BGE provides a scalable, reliable platform to expand genomic discovery and equitable access to sequencing in underrepresented populations.

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Cite

BibTeXRIS
BibTeX
@article{boltz2026blended,
  title = {{A blended genome and exome sequencing method captures genetic variation in an unbiased and cost-effective manner}},
  author = {Toni A. Boltz and Benjamin B. Chu and Matthew T. DeFelice and Calwing Liao and Julia Sealock and Robert Ye and Jacqueline I. Goldstein and Lerato Majara and Jack M. Fu and Susan K. Service and Lingyu Zhan and Sarah Elizabeth Medland and Sinéad B. Chapman and Simone Rubinacci and Jonna Grimsby and Tamrat Abebe and Melkam Alemayehu Kebede and Fred K. Ashaba and Elizabeth G. Atkinson and Tim B. Bigdeli and Amanda B Bradway and Harrison Brand and Lori Beth Chibnik and DeLuca Samuel and Ana M. Díaz‐Zuluaga and Abebaw Fekadu and Michael Gatzen and Bizu Gelaye and Stella Gichuru and M. Gildea and Toni C Hill and Hailiang Huang and Kalyn M. Hubbard and Wilfred E. Injera and Roxanne James and M Joloba and C. Kachulis and Phillip R Kalmbach and Rogers Kamulegeya and Gabriel Kigen and S Y Kim and Nastassja Koen and Edith K. Kwobah and Joseph Kyebuzibwa and Seungmo Lee and Niall J. Lennon and Penelope A. Lind and Esteban A. Lopera-Maya and Johnstone Makale and Serghei Mangul and Justin McMahon and Pierre Mowlem and Henry Musinguzi and Rehema M. Mwema and Noeline Nakasujja and Carter P. Newman and Lethukuthula L. Nkambule and Conor R O'Neil and Ana Maria Olivares and Catherine M. Olsen},
  journal = {Nature Genetics},
  year = {2026},
  month = jul,
  doi = {10.1038/s41588-026-02669-w},
  url = {https://doi.org/10.1038/s41588-026-02669-w},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A blended genome and exome sequencing method captures genetic variation in an unbiased and cost-effective manner
AU  - Toni A. Boltz
AU  - Benjamin B. Chu
AU  - Matthew T. DeFelice
AU  - Calwing Liao
AU  - Julia Sealock
AU  - Robert Ye
AU  - Jacqueline I. Goldstein
AU  - Lerato Majara
AU  - Jack M. Fu
AU  - Susan K. Service
AU  - Lingyu Zhan
AU  - Sarah Elizabeth Medland
AU  - Sinéad B. Chapman
AU  - Simone Rubinacci
AU  - Jonna Grimsby
AU  - Tamrat Abebe
AU  - Melkam Alemayehu Kebede
AU  - Fred K. Ashaba
AU  - Elizabeth G. Atkinson
AU  - Tim B. Bigdeli
AU  - Amanda B Bradway
AU  - Harrison Brand
AU  - Lori Beth Chibnik
AU  - DeLuca Samuel
AU  - Ana M. Díaz‐Zuluaga
AU  - Abebaw Fekadu
AU  - Michael Gatzen
AU  - Bizu Gelaye
AU  - Stella Gichuru
AU  - M. Gildea
AU  - Toni C Hill
AU  - Hailiang Huang
AU  - Kalyn M. Hubbard
AU  - Wilfred E. Injera
AU  - Roxanne James
AU  - M Joloba
AU  - C. Kachulis
AU  - Phillip R Kalmbach
AU  - Rogers Kamulegeya
AU  - Gabriel Kigen
AU  - S Y Kim
AU  - Nastassja Koen
AU  - Edith K. Kwobah
AU  - Joseph Kyebuzibwa
AU  - Seungmo Lee
AU  - Niall J. Lennon
AU  - Penelope A. Lind
AU  - Esteban A. Lopera-Maya
AU  - Johnstone Makale
AU  - Serghei Mangul
AU  - Justin McMahon
AU  - Pierre Mowlem
AU  - Henry Musinguzi
AU  - Rehema M. Mwema
AU  - Noeline Nakasujja
AU  - Carter P. Newman
AU  - Lethukuthula L. Nkambule
AU  - Conor R O'Neil
AU  - Ana Maria Olivares
AU  - Catherine M. Olsen
PY  - 2026
DA  - 2026/07/08
JO  - Nature Genetics
DO  - 10.1038/s41588-026-02669-w
UR  - https://doi.org/10.1038/s41588-026-02669-w
AB  - Here we developed and deployed the blended genome exome (BGE) method, a DNA library approach that generates low-pass whole-genome (1–4× mean depth) and deep whole-exome (30–40× mean depth) data in a single sequencing run. BGE is cost-effective, empowers most genomic discoveries possible with deep whole-genome sequencing and captures global common single-nucleotide polymorphism diversity. We applied BGE to sequence >53,000 samples from the PUMAS Project (Populations Underrepresented in Mental Illness Associations Studies), including African, African American and Latin American populations. Imputed genotypes showed high concordance with Illumina Global Screening Array calls ( R 2 ≥ 95% for minor allele frequency ≥1%; ≥90% for minor allele frequency <1%), with consistent performance across local ancestries in admixed cohorts. For protein-coding copy number variants, deletions and duplications spanning at least three exons had a positive predicted value of ~90% relative to deep whole-genome data. At ~28% of the cost of deep whole-genome sequencing, BGE provides a scalable, reliable platform to expand genomic discovery and equitable access to sequencing in underrepresented populations.
SN  - 1061-4036
SN  - 1546-1718
ER  -