Comparison of predicted and actual consequences of missense mutations

Lisa A. Miosge, Matthew A. Field, Yovina Sontani, Vicky Cho, Simon Johnson, Anna Palkova, Bhavani Balakishnan, Rong Liang, Yafei Zhang, Stephen Lyon, Bruce Beutler, Belinda Whittle, Edward M. Bertram, Anselm Enders, Christopher C. Goodnow, T. Daniel Andrewsa

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Each person's genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations revealed by sequencing in first-generation progeny of N-ethyl-N-nitrosourea- treated mice, involving 23 essential immune system genes. Poly- Phen2, SIFT, MutationAssessor, Panther, CADD, and Condel were used to predict each mutation's functional importance, whereas the actual effect was measured by breeding and testing homozygotes for the expected in vivo loss-of-function phenotype. Only 20% of mutations predicted to be deleterious by PolyPhen2 (and 15% by CADD) showed a discernible phenotype in individual homozygotes. Half of all possible missense mutations in the same 23 immune genes were predicted to be deleterious, and most of these appear to become subject to purifying selection because few persist between separate mouse substrains, rodents, or primates. Because defects in immune genes could be phenotypically masked in vivo by compensation and environment, we compared inferences by the same tools with the in vitro phenotype of all 2,314 possible missense variants in TP53; 42% of mutations predicted by PolyPhen2 to be deleterious (and 45% by CADD) had little measurable consequence for TP53-promoted transcription. We conclude that for de novo or low-frequency missense mutations found by genome sequencing, half those inferred as deleterious correspond to nearly neutral mutations that have little impact on the clinical phenotype of individual cases but will nevertheless become subject to purifying selection.

Original languageEnglish (US)
Pages (from-to)E5189-E5198
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number37
DOIs
StatePublished - Sep 15 2015

Fingerprint

Missense Mutation
Phenotype
Mutation
Homozygote
Genome
Ethylnitrosourea
Genes
Primates
Breeding
Immune System
Rodentia

Keywords

  • Cancer
  • De novo mutation
  • Evolution
  • Immunodeficiency
  • Nearly neutral

ASJC Scopus subject areas

  • General

Cite this

Miosge, L. A., Field, M. A., Sontani, Y., Cho, V., Johnson, S., Palkova, A., ... Andrewsa, T. D. (2015). Comparison of predicted and actual consequences of missense mutations. Proceedings of the National Academy of Sciences of the United States of America, 112(37), E5189-E5198. https://doi.org/10.1073/pnas.1511585112

Comparison of predicted and actual consequences of missense mutations. / Miosge, Lisa A.; Field, Matthew A.; Sontani, Yovina; Cho, Vicky; Johnson, Simon; Palkova, Anna; Balakishnan, Bhavani; Liang, Rong; Zhang, Yafei; Lyon, Stephen; Beutler, Bruce; Whittle, Belinda; Bertram, Edward M.; Enders, Anselm; Goodnow, Christopher C.; Andrewsa, T. Daniel.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 37, 15.09.2015, p. E5189-E5198.

Research output: Contribution to journalArticle

Miosge, LA, Field, MA, Sontani, Y, Cho, V, Johnson, S, Palkova, A, Balakishnan, B, Liang, R, Zhang, Y, Lyon, S, Beutler, B, Whittle, B, Bertram, EM, Enders, A, Goodnow, CC & Andrewsa, TD 2015, 'Comparison of predicted and actual consequences of missense mutations', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 37, pp. E5189-E5198. https://doi.org/10.1073/pnas.1511585112
Miosge, Lisa A. ; Field, Matthew A. ; Sontani, Yovina ; Cho, Vicky ; Johnson, Simon ; Palkova, Anna ; Balakishnan, Bhavani ; Liang, Rong ; Zhang, Yafei ; Lyon, Stephen ; Beutler, Bruce ; Whittle, Belinda ; Bertram, Edward M. ; Enders, Anselm ; Goodnow, Christopher C. ; Andrewsa, T. Daniel. / Comparison of predicted and actual consequences of missense mutations. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 37. pp. E5189-E5198.
@article{19c295cb09694e60962686b104f20caa,
title = "Comparison of predicted and actual consequences of missense mutations",
abstract = "Each person's genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations revealed by sequencing in first-generation progeny of N-ethyl-N-nitrosourea- treated mice, involving 23 essential immune system genes. Poly- Phen2, SIFT, MutationAssessor, Panther, CADD, and Condel were used to predict each mutation's functional importance, whereas the actual effect was measured by breeding and testing homozygotes for the expected in vivo loss-of-function phenotype. Only 20{\%} of mutations predicted to be deleterious by PolyPhen2 (and 15{\%} by CADD) showed a discernible phenotype in individual homozygotes. Half of all possible missense mutations in the same 23 immune genes were predicted to be deleterious, and most of these appear to become subject to purifying selection because few persist between separate mouse substrains, rodents, or primates. Because defects in immune genes could be phenotypically masked in vivo by compensation and environment, we compared inferences by the same tools with the in vitro phenotype of all 2,314 possible missense variants in TP53; 42{\%} of mutations predicted by PolyPhen2 to be deleterious (and 45{\%} by CADD) had little measurable consequence for TP53-promoted transcription. We conclude that for de novo or low-frequency missense mutations found by genome sequencing, half those inferred as deleterious correspond to nearly neutral mutations that have little impact on the clinical phenotype of individual cases but will nevertheless become subject to purifying selection.",
keywords = "Cancer, De novo mutation, Evolution, Immunodeficiency, Nearly neutral",
author = "Miosge, {Lisa A.} and Field, {Matthew A.} and Yovina Sontani and Vicky Cho and Simon Johnson and Anna Palkova and Bhavani Balakishnan and Rong Liang and Yafei Zhang and Stephen Lyon and Bruce Beutler and Belinda Whittle and Bertram, {Edward M.} and Anselm Enders and Goodnow, {Christopher C.} and Andrewsa, {T. Daniel}",
year = "2015",
month = "9",
day = "15",
doi = "10.1073/pnas.1511585112",
language = "English (US)",
volume = "112",
pages = "E5189--E5198",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "37",

}

TY - JOUR

T1 - Comparison of predicted and actual consequences of missense mutations

AU - Miosge, Lisa A.

AU - Field, Matthew A.

AU - Sontani, Yovina

AU - Cho, Vicky

AU - Johnson, Simon

AU - Palkova, Anna

AU - Balakishnan, Bhavani

AU - Liang, Rong

AU - Zhang, Yafei

AU - Lyon, Stephen

AU - Beutler, Bruce

AU - Whittle, Belinda

AU - Bertram, Edward M.

AU - Enders, Anselm

AU - Goodnow, Christopher C.

AU - Andrewsa, T. Daniel

PY - 2015/9/15

Y1 - 2015/9/15

N2 - Each person's genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations revealed by sequencing in first-generation progeny of N-ethyl-N-nitrosourea- treated mice, involving 23 essential immune system genes. Poly- Phen2, SIFT, MutationAssessor, Panther, CADD, and Condel were used to predict each mutation's functional importance, whereas the actual effect was measured by breeding and testing homozygotes for the expected in vivo loss-of-function phenotype. Only 20% of mutations predicted to be deleterious by PolyPhen2 (and 15% by CADD) showed a discernible phenotype in individual homozygotes. Half of all possible missense mutations in the same 23 immune genes were predicted to be deleterious, and most of these appear to become subject to purifying selection because few persist between separate mouse substrains, rodents, or primates. Because defects in immune genes could be phenotypically masked in vivo by compensation and environment, we compared inferences by the same tools with the in vitro phenotype of all 2,314 possible missense variants in TP53; 42% of mutations predicted by PolyPhen2 to be deleterious (and 45% by CADD) had little measurable consequence for TP53-promoted transcription. We conclude that for de novo or low-frequency missense mutations found by genome sequencing, half those inferred as deleterious correspond to nearly neutral mutations that have little impact on the clinical phenotype of individual cases but will nevertheless become subject to purifying selection.

AB - Each person's genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations revealed by sequencing in first-generation progeny of N-ethyl-N-nitrosourea- treated mice, involving 23 essential immune system genes. Poly- Phen2, SIFT, MutationAssessor, Panther, CADD, and Condel were used to predict each mutation's functional importance, whereas the actual effect was measured by breeding and testing homozygotes for the expected in vivo loss-of-function phenotype. Only 20% of mutations predicted to be deleterious by PolyPhen2 (and 15% by CADD) showed a discernible phenotype in individual homozygotes. Half of all possible missense mutations in the same 23 immune genes were predicted to be deleterious, and most of these appear to become subject to purifying selection because few persist between separate mouse substrains, rodents, or primates. Because defects in immune genes could be phenotypically masked in vivo by compensation and environment, we compared inferences by the same tools with the in vitro phenotype of all 2,314 possible missense variants in TP53; 42% of mutations predicted by PolyPhen2 to be deleterious (and 45% by CADD) had little measurable consequence for TP53-promoted transcription. We conclude that for de novo or low-frequency missense mutations found by genome sequencing, half those inferred as deleterious correspond to nearly neutral mutations that have little impact on the clinical phenotype of individual cases but will nevertheless become subject to purifying selection.

KW - Cancer

KW - De novo mutation

KW - Evolution

KW - Immunodeficiency

KW - Nearly neutral

UR - http://www.scopus.com/inward/record.url?scp=84941656377&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941656377&partnerID=8YFLogxK

U2 - 10.1073/pnas.1511585112

DO - 10.1073/pnas.1511585112

M3 - Article

C2 - 26269570

AN - SCOPUS:84941656377

VL - 112

SP - E5189-E5198

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

SN - 0027-8424

IS - 37

ER -