Population sequencing data reveal a compendium of mutational processes in the human germ line

Vladimir B. Seplyarskiy; Ruslan A. Soldatov; Evan Koch; Ryan J. McGinty; Jakob M. Goldmann; Ryan D. Hernandez; Kathleen Barnes; Adolfo Correa; Esteban G. Burchard; Patrick T. Ellinor; Stephen T. McGarvey; Braxton D. Mitchell; Ramachandran S. Vasan; Susan Redline; Edwin Silverman; Scott T. Weiss; Donna K. Arnett; John Blangero; Eric Boerwinkle; Jiang He; Courtney Montgomery; D. C. Rao; Jerome I. Rotter; Kent D. Taylor; Jennifer A. Brody; Yii Der Ida Chen; Lisa De Las Fuentes; Chii Min Hwu; Stephen S. Rich; Ani W. Manichaikul; Josyf C. Mychaleckyj; Nicholette D. Palmer; Jennifer A. Smith; Sharon L.R. Kardia; Patricia A. Peyser; Lawrence F. Bielak; Timothy D. O'Connor; Leslie S. Emery; Christian Gilissen; Wendy S.W. Wong; Peter V. Kharchenko; Shamil Sunyaev

doi:10.1126/science.aba7408

Population sequencing data reveal a compendium of mutational processes in the human germ line

Vladimir B. Seplyarskiy, Ruslan A. Soldatov, Evan Koch, Ryan J. McGinty, Jakob M. Goldmann, Ryan D. Hernandez, Kathleen Barnes, Adolfo Correa, Esteban G. Burchard, Patrick T. Ellinor, Stephen T. McGarvey, Braxton D. Mitchell, Ramachandran S. Vasan, Susan Redline, Edwin Silverman, Scott T. Weiss, Donna K. Arnett, John Blangero, Eric Boerwinkle, Jiang HeCourtney Montgomery, D. C. Rao, Jerome I. Rotter, Kent D. Taylor, Jennifer A. Brody, Yii Der Ida Chen, Lisa De Las Fuentes, Chii Min Hwu, Stephen S. Rich, Ani W. Manichaikul, Josyf C. Mychaleckyj, Nicholette D. Palmer, Jennifer A. Smith, Sharon L.R. Kardia, Patricia A. Peyser, Lawrence F. Bielak, Timothy D. O'Connor, Leslie S. Emery, Christian Gilissen, Wendy S.W. Wong, Peter V. Kharchenko, Shamil Sunyaev

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

Original language	English
Pages (from-to)	1030-1035
Number of pages	6
Journal	Science
Volume	373
Issue number	6558
DOIs	https://doi.org/10.1126/science.aba7408
State	Published - Aug 27 2021

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Seplyarskiy, V. B., Soldatov, R. A., Koch, E., McGinty, R. J., Goldmann, J. M., Hernandez, R. D., Barnes, K., Correa, A., Burchard, E. G., Ellinor, P. T., McGarvey, S. T., Mitchell, B. D., Vasan, R. S., Redline, S., Silverman, E., Weiss, S. T., Arnett, D. K., Blangero, J., Boerwinkle, E., ... Sunyaev, S. (2021). Population sequencing data reveal a compendium of mutational processes in the human germ line. Science, 373(6558), 1030-1035. https://doi.org/10.1126/science.aba7408

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title = "Population sequencing data reveal a compendium of mutational processes in the human germ line",

abstract = "Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.",

author = "Seplyarskiy, {Vladimir B.} and Soldatov, {Ruslan A.} and Evan Koch and McGinty, {Ryan J.} and Goldmann, {Jakob M.} and Hernandez, {Ryan D.} and Kathleen Barnes and Adolfo Correa and Burchard, {Esteban G.} and Ellinor, {Patrick T.} and McGarvey, {Stephen T.} and Mitchell, {Braxton D.} and Vasan, {Ramachandran S.} and Susan Redline and Edwin Silverman and Weiss, {Scott T.} and Arnett, {Donna K.} and John Blangero and Eric Boerwinkle and Jiang He and Courtney Montgomery and Rao, {D. C.} and Rotter, {Jerome I.} and Taylor, {Kent D.} and Brody, {Jennifer A.} and {Ida Chen}, {Yii Der} and {De Las Fuentes}, Lisa and Hwu, {Chii Min} and Rich, {Stephen S.} and Manichaikul, {Ani W.} and Mychaleckyj, {Josyf C.} and Palmer, {Nicholette D.} and Smith, {Jennifer A.} and Kardia, {Sharon L.R.} and Peyser, {Patricia A.} and Bielak, {Lawrence F.} and O'Connor, {Timothy D.} and Emery, {Leslie S.} and Christian Gilissen and Wong, {Wendy S.W.} and Kharchenko, {Peter V.} and Shamil Sunyaev",

year = "2021",

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day = "27",

doi = "10.1126/science.aba7408",

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volume = "373",

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Seplyarskiy, VB, Soldatov, RA, Koch, E, McGinty, RJ, Goldmann, JM, Hernandez, RD, Barnes, K, Correa, A, Burchard, EG, Ellinor, PT, McGarvey, ST, Mitchell, BD, Vasan, RS, Redline, S, Silverman, E, Weiss, ST, Arnett, DK, Blangero, J, Boerwinkle, E, He, J, Montgomery, C, Rao, DC, Rotter, JI, Taylor, KD, Brody, JA, Ida Chen, YD, De Las Fuentes, L, Hwu, CM, Rich, SS, Manichaikul, AW, Mychaleckyj, JC, Palmer, ND, Smith, JA, Kardia, SLR, Peyser, PA, Bielak, LF, O'Connor, TD, Emery, LS, Gilissen, C, Wong, WSW, Kharchenko, PV & Sunyaev, S 2021, 'Population sequencing data reveal a compendium of mutational processes in the human germ line', Science, vol. 373, no. 6558, pp. 1030-1035. https://doi.org/10.1126/science.aba7408

TY - JOUR

T1 - Population sequencing data reveal a compendium of mutational processes in the human germ line

AU - Seplyarskiy, Vladimir B.

AU - Soldatov, Ruslan A.

AU - Koch, Evan

AU - McGinty, Ryan J.

AU - Goldmann, Jakob M.

AU - Hernandez, Ryan D.

AU - Barnes, Kathleen

AU - Correa, Adolfo

AU - Burchard, Esteban G.

AU - Ellinor, Patrick T.

AU - McGarvey, Stephen T.

AU - Mitchell, Braxton D.

AU - Vasan, Ramachandran S.

AU - Redline, Susan

AU - Silverman, Edwin

AU - Weiss, Scott T.

AU - Arnett, Donna K.

AU - Blangero, John

AU - Boerwinkle, Eric

AU - He, Jiang

AU - Montgomery, Courtney

AU - Rao, D. C.

AU - Rotter, Jerome I.

AU - Taylor, Kent D.

AU - Brody, Jennifer A.

AU - Ida Chen, Yii Der

AU - De Las Fuentes, Lisa

AU - Hwu, Chii Min

AU - Rich, Stephen S.

AU - Manichaikul, Ani W.

AU - Mychaleckyj, Josyf C.

AU - Palmer, Nicholette D.

AU - Smith, Jennifer A.

AU - Kardia, Sharon L.R.

AU - Peyser, Patricia A.

AU - Bielak, Lawrence F.

AU - O'Connor, Timothy D.

AU - Emery, Leslie S.

AU - Gilissen, Christian

AU - Wong, Wendy S.W.

AU - Kharchenko, Peter V.

AU - Sunyaev, Shamil

PY - 2021/8/27

Y1 - 2021/8/27

N2 - Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

AB - Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

UR - http://www.scopus.com/inward/record.url?scp=85113786848&partnerID=8YFLogxK

U2 - 10.1126/science.aba7408

DO - 10.1126/science.aba7408

M3 - Article

C2 - 34385354

AN - SCOPUS:85113786848

SN - 0036-8075

VL - 373

SP - 1030

EP - 1035

JO - Science

JF - Science

IS - 6558

ER -

Population sequencing data reveal a compendium of mutational processes in the human germ line

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