Comparison of predicted and actual consequences of missense mutations
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...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 37; pp. E5189 - E5198 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
15.09.2015
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| 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 ofN-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 inTP53; 42% of mutations predicted by PolyPhen2 to be deleterious (and 45% by CADD) had little measurable consequence forTP53-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. |
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| AbstractList | Computational tools applied to any human genome sequence identify hundreds of genetic variants predicted to disrupt the function of individual proteins as the result of a single codon change. These tools have been trained on disease mutations and common polymorphisms but have yet to be tested against an unbiased spectrum of random mutations arising de novo. Here we perform such a test comparing the predicted and actual effects of de novo mutations in 23 genes with essential functions for normal immunity and all possible mutations in the
TP53
tumor suppressor gene. These results highlight an important gap in our ability to relate genotype to phenotype in clinical genome sequencing: the inability to differentiate immediately clinically relevant mutations from nearly neutral mutations.
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. PolyPhen2, 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. 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. PolyPhen2, 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. 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 ofN-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 inTP53; 42% of mutations predicted by PolyPhen2 to be deleterious (and 45% by CADD) had little measurable consequence forTP53-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. 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. PolyPhen2, 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.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. PolyPhen2, 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. |
| Author | Field, Matthew A. Balakishnan, Bhavani Cho, Vicky Palkova, Anna Sontani, Yovina Whittle, Belinda Beutler, Bruce Bertram, Edward M. Johnson, Simon Zhang, Yafei Enders, Anselm Miosge, Lisa A. Liang, Rong Goodnow, Christopher C. Andrews, T. Daniel Lyon, Stephen |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26269570$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles Copyright National Academy of Sciences Sep 15, 2015 |
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| DOI | 10.1073/pnas.1511585112 |
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| Keywords | de novo mutation nearly neutral cancer immunodeficiency evolution |
| Language | English |
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| Notes | SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-2 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Contributed by Christopher C. Goodnow, July 9, 2015 (sent for review February 24, 2015; reviewed by Jean-Laurent Casanova and Alain Fischer) Reviewers: J.-L.C., The Rockefeller University; and A.F., Imagine Institute, Hôpital Necker Enfants Malades. 2C.C.G. and T.D.A. contributed equally to this work. Author contributions: L.A.M., M.A.F., B. Beutler, B.W., E.M.B., A.E., C.C.G., and T.D.A. designed research; L.A.M., M.A.F., Y.S., V.C., S.J., A.P., B. Balakishnan, R.L., Y.Z., S.L., B.W., and T.D.A. performed research; S.L., B. Beutler, and T.D.A. contributed new reagents/analytic tools; L.A.M., M.A.F., Y.S., V.C., S.J., A.P., B. Balakishnan, R.L., Y.Z., S.L., B. Beutler, B.W., E.M.B., A.E., C.C.G., and T.D.A. analyzed data; and M.A.F., C.C.G. and T.D.A. wrote the paper. 1L.A.M. and M.A.F. contributed equally to this work. |
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| Snippet | Each person’s genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational... Computational tools applied to any human genome sequence identify hundreds of genetic variants predicted to disrupt the function of individual proteins as the... Each person's genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational... |
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| SubjectTerms | Animals Biological Sciences Codon Comparative analysis Computational Biology Computer Simulation Exome Experiments Genetic Variation Genome Genome, Human Genomes Genotype Humans Immune System Immunologic Deficiency Syndromes - genetics Mice Mice, Inbred C57BL Models, Genetic Mutation Mutation, Missense Neoplasms - genetics Phenotype PNAS Plus Predictions Rodents Software Tumor Suppressor Protein p53 - genetics |
| Title | Comparison of predicted and actual consequences of missense mutations |
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