A blended genome and exome sequencing method captures genetic variation in an unbiased, high-quality, and cost-effective manner.
Journal: bioRxiv : the preprint server for biology
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Affiliated Institutions:
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Psychiatry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
Department of Psychiatry, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Broad Clinical Labs (BCL), Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Microbiology, Immunology, and Parasitology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Department of Immunology & Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Institute for Genomics in Health, The State University of New York, Brooklyn, NY, USA.
Department of Mental Health, Moi Teaching and Referral Hospital, Eldoret, Kenya.
Department of Medical Laboratory Sciences, School of Health Sciences, Alupe University, Busia, Kenya.
Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
School of Biomedical Sciences, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
Department of Pharmacology and Toxicology, Moi University School of Medicine, Eldoret, Kenya.
Department of Psychiatry, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
Department of Computer Science, University of California Los Angeles, Los Angeles, CA, USA.
Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya.
Department of Quantitative and Computational Biology, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA.
Ampath Laboratories, Moi University School of Medicine, Eldoret, Kenya.
Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast,, Kilifi, Kenya.
Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
SA MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town and Neuroscience Institute, Cape Town, South Africa.
Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
Department of Mental Health and Behavioural Sciences, School of Medicine, Moi University College of Health Sciences, Eldoret, Kenya.
Neurosciences Unit, Clinical Department, KEMRI-Wellcome Trust Research Programme-Coast, Kilifi, Kenya.
Executive Dean's Office, Faculty of Health Sciences, Nelson Mandela University, Gqebera, South Africa.
Rutgers University, New Brunswick, NJ, USA.
Department of Psychiatry, University of Antioquia, University of Antioquia, Medellín, Antioquia, Colombia.
BD: Breakthrough Discoveries for thriving with Bipolar Disorder, Santa Monica, CA, USA.
Abstract summary
We deployed the Blended Genome Exome (BGE), a DNA library blending 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. This technology is cost-effective, empowers most genomic discoveries possible with deep whole genome sequencing, and provides an unbiased method to capture the diversity of common SNP variation across the globe. To evaluate this new technology at scale, we applied BGE to sequence >53,000 samples from the Populations Underrepresented in Mental Illness Associations Studies (PUMAS) Project, which included participants across African, African American, and Latin American populations. We evaluated the accuracy of BGE imputed genotypes against raw genotype calls from the Illumina Global Screening Array. All PUMAS cohorts had concordance ≥95% among SNPs with MAF≥1%, and never fell below ≥90% for SNPs with MAF<1%. Furthermore, concordance rates among local ancestries within two recently admixed cohorts were consistent among SNPs with MAF≥1%, with only minor deviations in SNPs with MAF<1%. We also benchmarked the discovery capacity of BGE to access protein-coding copy number variants (CNVs) against deep whole genome data, finding that deletions and duplications spanning at least 3 exons had a positive predicted value of ~90%. Our results demonstrate BGE scalability and efficacy in capturing SNPs, indels, and CNVs in the human genome at 28% of the cost of deep whole-genome sequencing. BGE is poised to enhance access to genomic testing and empower genomic discoveries, particularly in underrepresented populations.
Authors & Co-authors:
Boltz Toni A TA
Chu Benjamin B BB
Liao Calwing C
Sealock Julia M JM
Ye Robert R
Majara Lerato L
Fu Jack M JM
Service Susan S
Zhan Lingyu L
Medland Sarah E SE
Chapman Sinéad B SB
Rubinacci Simone S
DeFelice Matthew M
Grimsby Jonna L JL
Abebe Tamrat T
Alemayehu Melkam M
Ashaba Fred K FK
Atkinson Elizabeth G EG
Bigdeli Tim T
Bradway Amanda B AB
Brand Harrison H
Chibnik Lori B LB
Fekadu Abebaw A
Gatzen Michael M
Gelaye Bizu B
Gichuru Stella S
Gildea Marissa L ML
Hill Toni C TC
Huang Hailiang H
Hubbard Kalyn M KM
Injera Wilfred E WE
James Roxanne R
Joloba Moses M
Kachulis Christopher C
Kalmbach Phillip R PR
Kamulegeya Rogers R
Kigen Gabriel G
Kim Soyeon S
Koen Nastassja N
Kwobah Edith K EK
Kyebuzibwa Joseph J
Lee Seungmo S
Lennon Niall J NJ
Lind Penelope A PA
Lopera-Maya Esteban A EA
Makale Johnstone J
Mangul Serghei S
McMahon Justin J
Mowlem Pierre P
Musinguzi Henry H
Mwema Rehema M RM
Nakasujja Noeline N
Newman Carter P CP
Nkambule Lethukuthula L LL
O'Neil Conor R CR
Olivares Ana Maria AM
Olsen Catherine M CM
Ongeri Linnet L
Parsa Sophie J SJ
Pretorius Adele A
Ramesar Raj R
Reagan Faye L FL
Sabatti Chiara C
Schneider Jacquelyn A JA
Shiferaw Welelta W
Stevenson Anne A
Stricker Erik E
Stroud Rocky E RE
Tang Jessie J
Whiteman David D
Yohannes Mary T MT
Yu Mingrui M
Yuan Kai K
Akena Dickens D
Atwoli Lukoye L
Kariuki Symon M SM
Koenen Karestan C KC
Newton Charles R J C CRJC
Stein Dan J DJ
Teferra Solomon S
Zingela Zukiswa Z
Pato Carlos N CN
Pato Michele T MT
Lopez-Jaramillo Carlos C
Freimer Nelson N
Ophoff Roel A RA
Olde Loohuis Loes M LM
Talkowski Michael E ME
Neale Benjamin M BM
Howrigan Daniel P DP
Martin Alicia R AR
Study Outcome
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