Imperial College London
Alternate

PROFESSOR H. TERENCE COOK

Faculty of Medicine, Department of Immunology and Inflammation

Emeritus Professor
 
 
 
//

Contact

 

+44 (0)20 3313 2009t.h.cook

 
 
//

Assistant

 

Miss Claudia Rocchi +44 (0)20 3313 2315

 
//

Location

 

9N9Commonwealth BuildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Wei:2019:10.1126/science.aau6520,
author = {Wei, W and Tuna, S and Keogh, MJ and Smith, KR and Aitman, TJ and Beales, PL and Bennett, DL and Gale, DP and Bitner-Glindzicz, MAK and Black, GC and Brennan, P and Elliott, P and Flinter, FA and Floto, RA and Houlden, H and Irving, M and Koziell, A and Maher, ER and Markus, HS and Morrell, NW and Newman, WG and Roberts, I and Sayer, JA and Smith, KGC and Taylor, JC and Watkins, H and Webster, AR and Wilkie, AOM and Williamson, C and Attwood, A and Brown, M and Brod, NC and Crisp-Hihn, A and Davis, J and Deevi, SVV and Dewhurst, EF and Edwards, K and Erwood, M and Fox, J and Frary, AJ and Hu, F and Jolley, J and Kingston, N and Linger, R and Mapeta, R and Martin, J and Meacham, S and Papadia, S and Rayner-Matthews, PJ and Samarghitean, C and Shamardina, O and Simeoni, I and Staines, S and Staples, E and Stark, H and Stephens, J and Titterton, C and Tuna, S and von, Ziegenweidt J and Watt, C and Whitehorn, D and Wood, Y and Yates, K and Yu, P and James, R and Ashford, S and Penkett, CJ },
doi = {10.1126/science.aau6520},
journal = {Science},
title = {Germline selection shapes human mitochondrial DNA diversity},
url = {http://dx.doi.org/10.1126/science.aau6520},
volume = {364},
year = {2019}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - INTRODUCTIONOnly 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear.Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans.RATIONALETo determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals.RESULTSPreviously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between
AU  - Wei,W
AU  - Tuna,S
AU  - Keogh,MJ
AU  - Smith,KR
AU  - Aitman,TJ
AU  - Beales,PL
AU  - Bennett,DL
AU  - Gale,DP
AU  - Bitner-Glindzicz,MAK
AU  - Black,GC
AU  - Brennan,P
AU  - Elliott,P
AU  - Flinter,FA
AU  - Floto,RA
AU  - Houlden,H
AU  - Irving,M
AU  - Koziell,A
AU  - Maher,ER
AU  - Markus,HS
AU  - Morrell,NW
AU  - Newman,WG
AU  - Roberts,I
AU  - Sayer,JA
AU  - Smith,KGC
AU  - Taylor,JC
AU  - Watkins,H
AU  - Webster,AR
AU  - Wilkie,AOM
AU  - Williamson,C
AU  - Attwood,A
AU  - Brown,M
AU  - Brod,NC
AU  - Crisp-Hihn,A
AU  - Davis,J
AU  - Deevi,SVV
AU  - Dewhurst,EF
AU  - Edwards,K
AU  - Erwood,M
AU  - Fox,J
AU  - Frary,AJ
AU  - Hu,F
AU  - Jolley,J
AU  - Kingston,N
AU  - Linger,R
AU  - Mapeta,R
AU  - Martin,J
AU  - Meacham,S
AU  - Papadia,S
AU  - Rayner-Matthews,PJ
AU  - Samarghitean,C
AU  - Shamardina,O
AU  - Simeoni,I
AU  - Staines,S
AU  - Staples,E
AU  - Stark,H
AU  - Stephens,J
AU  - Titterton,C
AU  - Tuna,S
AU  - von,Ziegenweidt J
AU  - Watt,C
AU  - Whitehorn,D
AU  - Wood,Y
AU  - Yates,K
AU  - Yu,P
AU  - James,R
AU  - Ashford,S
AU  - Penkett,CJ
AU  - Stirrups,KE
AU  - Bariana,T
AU  - Lentaigne,C
AU  - Sivapalaratnam,S
AU  - Westbury,SK
AU  - Allsup,DJ
AU  - Bakchoul,T
AU  - Biss,T
AU  - Boyce,S
AU  - Collins,J
AU  - Collins,PW
AU  - Curry,NS
AU  - Downes,K
AU  - Dutt,T
AU  - Erber,WN
AU  - Evans,G
AU  - Everington,T
AU  - Favier,R
AU  - Gomez,K
AU  - Greene,D
AU  - Gresele,P
AU  - Hart,D
AU  - Kazmi,R
AU  - Kelly,AM
AU  - Lambert,M
AU  - Madan,B
AU  - Mangles,S
AU  - Mathias,M
AU  - Millar,C
AU  - Obaji,S
AU  - Peerlinck,K
AU  - Roughley,C
AU  - Schulman,S
AU  - Scully,M
AU  - Shapiro,SE
AU  - Sibson,K
AU  - Simeoni,I
AU  - Sims,MC
AU  - Tait,RC
AU  - Talks,K
AU  - Thys,C
AU  - Toh,C-H
AU  - Van,Geet C
AU  - Westwood,J-P
AU  - Papadia,S
AU  - Mumford,AD
AU  - Ouwehand,WH
AU  - Freson,K
AU  - Laffan,MA
AU  - Tan,RYY
AU  - Harkness,K
AU  - Mehta,S
AU  - Muir,KW
AU  - Hassan,A
AU  - Traylor,M
AU  - Drazyk,AM
AU  - Markus,HS
AU  - Parry,D
AU  - Ahmed,M
AU  - Kazkaz,H
AU  - Vandersteen,AM
AU  - Aitman,TJ
AU  - Ormondroyd,E
AU  - Thomson,K
AU  - Dent,T
AU  - Brennan,P
AU  - Buchan,RJ
AU  - Bueser,T
AU  - Carr-White,G
AU  - Cook,S
AU  - Daniels,MJ
AU  - Harper,AR
AU  - Ware,JS
AU  - Watkins,H
AU  - Dixon,PH
AU  - Chambers,J
AU  - Cheng,F
AU  - Estiu,MC
AU  - Hague,WM
AU  - Marschall,H-U
AU  - Vazquez-Lopez,M
AU  - Williamson,C
AU  - Arno,G
AU  - Dewhurst,EF
AU  - Erwood,M
AU  - French,CE
AU  - Michaelides,M
AU  - Moore,AT
AU  - Sanchis-Juan,A
AU  - Carss,K
AU  - Webster,AR
AU  - Raymond,FL
AU  - Chinnery,PF
AU  - Griffiths,P
AU  - Horvath,R
AU  - Hudson,G
AU  - Jurkute,N
AU  - Pyle,A
AU  - Wei,W
AU  - Yu-Wai-Man,P
AU  - Whitworth,J
AU  - Adlard,J
AU  - Ahmed,M
AU  - Armstrong,R
AU  - Brewer,C
AU  - Casey,R
AU  - Cole,TRP
AU  - Evans,DG
AU  - Greenhalgh,L
AU  - Hanson,HL
AU  - Hoffman,J
AU  - Izatt,L
AU  - Kumar,A
AU  - Lalloo,F
AU  - Ong,KR
AU  - Park,S-M
AU  - Sear
DO  - 10.1126/science.aau6520
PY  - 2019///
SN  - 0036-8075
TI  - Germline selection shapes human mitochondrial DNA diversity
T2  - Science
UR  - http://dx.doi.org/10.1126/science.aau6520
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000469296000033&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/70789
VL  - 364
ER  -
Download