Imperial College London

Dr Nicky Whiffin

Faculty of MedicineNational Heart & Lung Institute

Research Fellow







Hammersmith HospitalHammersmith Campus






BibTex format

author = {Karczewski, KJ and Francioli, LC and Tiao, G and Cummings, BB and Alföldi, J and Wang, Q and Collins, RL and Laricchia, KM and Ganna, A and Birnbaum, DP and Gauthier, LD and Brand, H and Solomonson, M and Watts, NA and Rhodes, D and Singer-Berk, M and England, EM and Seaby, EG and Kosmicki, JA and Walters, RK and Tashman, K and Farjoun, Y and Banks, E and Poterba, T and Wang, A and Seed, C and Whiffin, N and Chong, JX and Samocha, KE and Pierce-Hoffman, E and Zappala, Z and ODonnell-Luria, AH and Vallabh, Minikel E and Weisburd, B and Lek, M and Ware, JS and Vittal, C and Armean, IM and Bergelson, L and Cibulskis, K and Connolly, JM and Covarrubias, M and Donnelly, S and Ferriera, S and Gabriel, S and Gentry, J and Gupta, N and Jeandet, T and Kaplan, D and Llanwarne, C and Munshi, J and Novod, S and Petrillo, N and Roazen, D and Ruano-Rubio, V and Saltzman, A and Schleicher, M and Soto, J and Tibbetts, K and Tolonen, C and Wade, G and Talkowski, ME and Genome, Aggregation Database gnom},
doi = {10.1038/s41586-020-2308-7},
journal = {Nature},
pages = {434--443},
title = {The mutational constraint spectrum quantified from variation in 141,456 humans},
url = {},
volume = {581},
year = {2020}

RIS format (EndNote, RefMan)

AB - Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism’s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved human mutation rate model, we classify human protein-coding genes along a spectrum representing tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.
AU - Karczewski,KJ
AU - Francioli,LC
AU - Tiao,G
AU - Cummings,BB
AU - Alföldi,J
AU - Wang,Q
AU - Collins,RL
AU - Laricchia,KM
AU - Ganna,A
AU - Birnbaum,DP
AU - Gauthier,LD
AU - Brand,H
AU - Solomonson,M
AU - Watts,NA
AU - Rhodes,D
AU - Singer-Berk,M
AU - England,EM
AU - Seaby,EG
AU - Kosmicki,JA
AU - Walters,RK
AU - Tashman,K
AU - Farjoun,Y
AU - Banks,E
AU - Poterba,T
AU - Wang,A
AU - Seed,C
AU - Whiffin,N
AU - Chong,JX
AU - Samocha,KE
AU - Pierce-Hoffman,E
AU - Zappala,Z
AU - ODonnell-Luria,AH
AU - Vallabh,Minikel E
AU - Weisburd,B
AU - Lek,M
AU - Ware,JS
AU - Vittal,C
AU - Armean,IM
AU - Bergelson,L
AU - Cibulskis,K
AU - Connolly,JM
AU - Covarrubias,M
AU - Donnelly,S
AU - Ferriera,S
AU - Gabriel,S
AU - Gentry,J
AU - Gupta,N
AU - Jeandet,T
AU - Kaplan,D
AU - Llanwarne,C
AU - Munshi,J
AU - Novod,S
AU - Petrillo,N
AU - Roazen,D
AU - Ruano-Rubio,V
AU - Saltzman,A
AU - Schleicher,M
AU - Soto,J
AU - Tibbetts,K
AU - Tolonen,C
AU - Wade,G
AU - Talkowski,ME
AU - Genome,Aggregation Database gnomAD Consortium
AU - Neale,BM
AU - Daly,MJ
AU - MacArthur,DG
DO - 10.1038/s41586-020-2308-7
EP - 443
PY - 2020///
SN - 0028-0836
SP - 434
TI - The mutational constraint spectrum quantified from variation in 141,456 humans
T2 - Nature
UR -
UR -
VL - 581
ER -