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Large differences in proportions of harmful and benign amino acid substitutions between proteins and diseases

Schaafsma, Gerard C.P. LU and Vihinen, Mauno LU (2017) In Human Mutation 38(7). p.839-848
Abstract

Genes and proteins are known to have differences in their sensitivity to alterations. Despite numerous sequencing studies, proportions of harmful and harmless substitutions are not known for proteins and groups of proteins. To address this question, we predicted the outcome for all possible single amino acid substitutions (AASs) in nine representative protein groups by using the PON-P2 method. The effects on 996 proteins were studied and vast differences were noticed. Proteins in the cancer group harbor the largest proportion of harmful variants (42.1%), whereas the non-disease group of proteins not known to have a disease association and not involved in the housekeeping functions had the lowest number of harmful variants (4.2%).... (More)

Genes and proteins are known to have differences in their sensitivity to alterations. Despite numerous sequencing studies, proportions of harmful and harmless substitutions are not known for proteins and groups of proteins. To address this question, we predicted the outcome for all possible single amino acid substitutions (AASs) in nine representative protein groups by using the PON-P2 method. The effects on 996 proteins were studied and vast differences were noticed. Proteins in the cancer group harbor the largest proportion of harmful variants (42.1%), whereas the non-disease group of proteins not known to have a disease association and not involved in the housekeeping functions had the lowest number of harmful variants (4.2%). Differences in the proportions of the harmful and benign variants are wide within each group, but they still show clear differences between the groups. Frequently appearing protein domains show a wide spectrum of variant frequencies, whereas no major protein structural class-specific differences were noticed. AAS types in the original and variant residues showed distinctive patterns, which are shared by all the protein groups. The observations are relevant for understanding genetic bases of diseases, variation interpretation, and for the development of methods for that purpose.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Disease groups, Pathogenicity, Proteins, Sensitivity, Variation
in
Human Mutation
volume
38
issue
7
pages
839 - 848
publisher
John Wiley & Sons
external identifiers
  • scopus:85019655452
  • wos:000403352100009
ISSN
1059-7794
DOI
10.1002/humu.23236
language
English
LU publication?
yes
id
49b034a2-b7f3-4add-9665-afcafd0637fd
date added to LUP
2017-06-16 14:23:45
date last changed
2018-01-28 04:30:41
@article{49b034a2-b7f3-4add-9665-afcafd0637fd,
  abstract     = {<p>Genes and proteins are known to have differences in their sensitivity to alterations. Despite numerous sequencing studies, proportions of harmful and harmless substitutions are not known for proteins and groups of proteins. To address this question, we predicted the outcome for all possible single amino acid substitutions (AASs) in nine representative protein groups by using the PON-P2 method. The effects on 996 proteins were studied and vast differences were noticed. Proteins in the cancer group harbor the largest proportion of harmful variants (42.1%), whereas the non-disease group of proteins not known to have a disease association and not involved in the housekeeping functions had the lowest number of harmful variants (4.2%). Differences in the proportions of the harmful and benign variants are wide within each group, but they still show clear differences between the groups. Frequently appearing protein domains show a wide spectrum of variant frequencies, whereas no major protein structural class-specific differences were noticed. AAS types in the original and variant residues showed distinctive patterns, which are shared by all the protein groups. The observations are relevant for understanding genetic bases of diseases, variation interpretation, and for the development of methods for that purpose.</p>},
  author       = {Schaafsma, Gerard C.P. and Vihinen, Mauno},
  issn         = {1059-7794},
  keyword      = {Disease groups,Pathogenicity,Proteins,Sensitivity,Variation},
  language     = {eng},
  number       = {7},
  pages        = {839--848},
  publisher    = {John Wiley & Sons},
  series       = {Human Mutation},
  title        = {Large differences in proportions of harmful and benign amino acid substitutions between proteins and diseases},
  url          = {http://dx.doi.org/10.1002/humu.23236},
  volume       = {38},
  year         = {2017},
}