TY - JOUR
T1 - De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population
AU - Kessler, Michael D.
AU - Loesch, Douglas P.
AU - Perry, James A.
AU - Heard-Costa, Nancy L.
AU - Taliun, Daniel
AU - Cade, Brian E.
AU - Wang, Heming
AU - Daya, Michelle
AU - Ziniti, John
AU - Datta, Soma
AU - Celedón, Juan C.
AU - Soto-Quiros, Manuel E.
AU - Avila, Lydiana
AU - Weiss, Scott T.
AU - Barnes, Kathleen
AU - Redline, Susan S.
AU - Vasan, Ramachandran S.
AU - Johnson, Andrew D.
AU - Mathias, Rasika A.
AU - Hernandez, Ryan
AU - Wilson, James G.
AU - Nickerson, Deborah A.
AU - Abecasis, Goncalo
AU - Browning, Sharon R.
AU - Zöllner, Sebastian
AU - O’Connell, Jeffrey R.
AU - Mitchell, Braxton D.
AU - O’Connor, Timothy D.
N1 - Funding Information:
Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study” (phs000974) and “NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish” (phs000956) were performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1, 3R01HL121007-01S1). WGS for “NHLBI TOPMed: The Genetics and Epidemiology of Asthma in Barbados” (phs001143) was performed by Illumina, Inc. (3R01HL104608-04S1). WGS for “NHLBI TOPMed: The Cleveland Family Study (WGS)” (phs000954) and “NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica” (phs000988) were performed at the University of Washington Northwest Genomics Center (3R01HL098433-05S1, 3R37HL066289-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity quality control, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. A full list of TOPMed collaborators can be found at https://www.nhlbiwgs.org/topmedbanner-authorship. M.D.K. was supported by NIH grant T32CA154274. M.D.K. and T.D.O. were supported by funding from the Center for Health Related Informatics and Bioimaging at the University of Maryland School of Medicine, institutional support for the Institute for Genome Sciences and Program in Personalized Genomic Medicine at the University of Maryland School of Medicine, NIH Genomic Commons Award OT3 OD025459-01, NHLBI Trans-Omics for Precision Medicine Program High-performance Grant U01 HL137181-01, and National Human Genome Research Institute Genomic Innovator Grant 1 R35 HG010692-01 (to T.D.O.). D.P.L. was supported by NIH T32HL007698. This work was further supported by grants to the Amish research program (R01 HL121007, R01 AG18728, and U01 HL072515); a grant for the study of Asthma in Costa Rica (1P01HL132825-01 to S.T.W.); grants to study sleep apnea (R01-HL113338 to S.S.R., R35-HL135818 from Sleep Research Society Foundation to S.S.R. and with support for H.W., and K01-HL135405 from American Thoracic Society Foundation to B.E.C.); and Framingham Heart Study Grant HHSN268201500001 (to R.S.V.). Sequencing was funded by grants to the Genetics of Cardiometabolic Health in the Amish study (3R01HL121007-01S1), The Genetics and Epidemiology of Asthma in Barbados study (3R01HL104608-04S1), The Cleveland Family Study (3R01HL098433-05S1), The Genetic Epidemiology of Asthma in Costa Rica study (3R37HL066289-13S1), and Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study (3R01HL092577-06S1).
Funding Information:
ACKNOWLEDGMENTS. Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study” (phs000974) and “NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish” (phs000956) were performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1, 3R01HL121007-01S1). WGS for “NHLBI TOPMed: The Genetics and Epidemiology of Asthma in Barbados” (phs001143) was performed by Illumina, Inc. (3R01HL104608-04S1). WGS for “NHLBI TOPMed: The Cleveland Family Study (WGS)” (phs000954) and “NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica” (phs000988) were performed at the University of Washington Northwest Genomics Center (3R01HL098433-05S1, 3R37HL066289-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity quality control, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. A full list of TOPMed collaborators can be found at https://www.nhlbiwgs.org/topmed-banner-authorship. M.D.K. was supported by NIH grant T32CA154274. M.D.K. and T.D.O. were supported by funding from the Center for Health Related Informatics and Bioimaging at the University of Maryland School of Medicine, institutional support for the Institute for Genome Sciences and Program in Personalized Genomic Medicine at the University of Maryland School of Medicine, NIH Genomic Commons Award OT3 OD025459-01, NHLBI Trans-Omics for Precision Medicine Program High-performance Grant U01 HL137181-01, and National Human Genome Research Institute Genomic Innovator Grant 1 R35 HG010692-01 (to T.D.O.). D.P.L. was supported by NIH T32HL007698. This work was further supported by grants to the Amish research program (R01 HL121007, R01 AG18728, and U01 HL072515); a grant for the study of Asthma in Costa Rica (1P01HL132825-01 to S.T.W.); grants to study sleep apnea (R01-HL113338 to S.S.R., R35-HL135818 from Sleep Research Society Foundation to S.S.R. and with support for H.W., and K01-HL135405 from American Thoracic Society Foundation to B.E.C.); and Framingham Heart Study Grant HHSN268201500001 (to R.S.V.). Sequencing was funded by grants to the Genetics of Cardiometabolic Health in the Amish study (3R01HL121007-01S1), The Genetics and Epidemiology of Asthma in Barbados study (3R01HL104608-04S1), The Cleveland Family Study (3R01HL098433-05S1), The Genetic Epidemiology of Asthma in Costa Rica study (3R37HL066289-13S1), and Whole Genome Sequencing and Related Phenotypes in the Framing-ham Heart Study (3R01HL092577-06S1).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/2/4
Y1 - 2020/2/4
N2 - De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
AB - De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
KW - Amish
KW - De novo mutations
KW - Diversity
KW - Mutation rate
KW - Recombination
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UR - http://www.scopus.com/inward/citedby.url?scp=85079020940&partnerID=8YFLogxK
U2 - 10.1073/pnas.1902766117
DO - 10.1073/pnas.1902766117
M3 - Article
C2 - 31964835
AN - SCOPUS:85079020940
SN - 0027-8424
VL - 117
SP - 2560
EP - 2569
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5
ER -