Health and population effects of rare gene knockouts in adult humans with related parents

被引：193

作者：

Narasimhan, Vagheesh M. ^{[1
]}

Hunt, Karen A. ^{[2
]}

Mason, Dan ^{[3
]}

Baker, Christopher L. ^{[4
]}

Karczewski, Konrad J. ^{[5
,6
]}

Barnes, Mi El R. ^{[7
]}

Barnett, Anthony H. ^{[8
,9
]}

Bates, Chris ^{[10
]}

Bellary, Srikanth ^{[11
]}

Bockett, Nicholas A. ^{[2
]}

Giorda, Kristina ^{[12
]}

Griffiths, Christopher J. ^{[2
]}

Hemingway, Harry ^{[13
,14
]}

Jia, Zhilong ^{[7
]}

Kelly, M. Ann ^{[15
]}

Khawaja, Hajrah A. ^{[7
]}

Lek, Monkol ^{[5
,6
]}

McCarthy, Shane ^{[1
]}

McEachan, Rosie ^{[3
]}

O'Donnell-Luria, Anne ^{[5
,6
]}

Paigen, Kenneth ^{[4
]}

Parisinos, Constantinos A. ^{[2
]}

Sheridan, Eamonn ^{[3
]}

Southgate, Laura ^{[2
]}

Tee, Louise ^{[15
]}

Thomas, Mark ^{[1
]}

Xue, Yali ^{[1
]}

Schnall-Levin, Michael ^{[12
]}

Petkov, Petko M. ^{[4
]}

-Smith, Chris Tyler ^{[1
]}

Maher, Eamonn R. ^{[16
,17
,18
]}

Trembath, Richard C. ^{[2
,19
]}

MacArthur, Daniel G. ^{[5
,6
]}

Wright, John ^{[3
]}

Durbin, Richard ^{[1
]}

van Heel, David A. ^{[2
]}

机构：

[1] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[2] Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London E1 2AT, England

[3] Bradford Teaching Hosp Natl Hlth Serv NHS Fdn Tru, Bradford Inst Hlth Res, Bradford BD9 6RJ, W Yorkshire, England

[4] Jackson Lab, Ctr Genome Dynam, Bar Harbor, ME 04609 USA

[5] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[6] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[7] Queen Mary Univ London, Darts & London Sch Med & Dent, William Harvey Res Inst, London E1 2AT, England

[8] Heart England NHS Fdn Trust, Diabet & Endocrine Ctr, Birmingham B9 5SS, W Midlands, England

[9] Univ Birmingham, Birmingham B9 5SS, W Midlands, England

[10] TPP, Mill House,Troy Rd, Troy, NY USA

[11] Aston Univ, Aston Res Ctr Healthy Ageing, Birmingham B4 7ET, W Midlands, England

[12] 10X Genom, 7068 Koll Ctr Pkwy,Suite 415, Pleasanton, CA 94566 USA

[13] Farr Inst Hlth Informat Res, London NW1 2DA, England

[14] UCL, Inst Hlth Informat, London NW1 2DA, England

[15] Univ Birmingham, Sch Clin & Expt Med, Birmingham B15 2TT, W Midlands, England

[16] Univ Cambridge, Dept Med Genet, Box 238,Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[17] NIHR, Cambridge Biomed Res Ctr, Box 238,Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[18] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[19] Kings Coll London, Fac Life Sci & Med, London SE1 1UL, England

来源：

SCIENCE | 2016年 / 352卷 / 6284期

基金：

英国医学研究理事会; 英国惠康基金; 英国经济与社会研究理事会; 英国工程与自然科学研究理事会;

关键词：

RECOMBINATION HOTSPOTS; MEIOTIC RECOMBINATION; PRDM9; VARIANTS; GENOME; PHENOTYPES; MUTATIONS; COSTS; MICE;

D O I：

10.1126/science.aac8624

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.

引用

页码：474 / 477

页数：4

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