Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pgen.0010083
Title: Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene
Authors: Brunham L.R. 
Singaraja R.R. 
Pape T.D.
Kejariwal A.
Thomas P.D.
Hayden M.R. 
Keywords: ABC transporter
ABC transporter A1
cholesterol
complementary DNA
amino acid substitution
article
cell line
genetic variability
genetics
genome
human
metabolism
missense mutation
molecular evolution
nucleotide sequence
phenotype
reverse transcription polymerase chain reaction
single nucleotide polymorphism
Amino Acid Substitution
ATP-Binding Cassette Transporters
Cell Line
Cholesterol
Conserved Sequence
DNA, Complementary
Evolution, Molecular
Genome, Human
Humans
Mutation, Missense
Phenotype
Polymorphism, Single Nucleotide
Reverse Transcriptase Polymerase Chain Reaction
Variation (Genetics)
Issue Date: 2005
Citation: Brunham L.R., Singaraja R.R., Pape T.D., Kejariwal A., Thomas P.D., Hayden M.R. (2005). Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene. PLoS Genetics 1 (6) : 739-747. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pgen.0010083
Rights: Attribution 4.0 International
Abstract: The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to define the functional significance of genetic variation in the ABCA1 gene, a cholesterol transporter crucial for the metabolism of high density lipoprotein cholesterol. To predict the functional consequence of each coding single nucleotide polymorphism and mutation in this gene, we calculated a substitution position-specific evolutionary conservation score for each variant, which considers site-specific variation among evolutionarily related proteins. To test the bioinformatics predictions experimentally, we evaluated the biochemical consequence of these sequence variants by examining the ability of cell lines stably transfected with the ABCA1 alleles to elicit cholesterol efflux. Our bioinformatics approach correctly predicted the functional impact of greater than 94% of the naturally occurring variants we assessed. The bioinformatics predictions were significantly correlated with the degree of functional impairment of ABCA1 mutations (r2 = 0.62, p = 0.0008). These results have allowed us to define the impact of genetic variation on ABCA1 function and to suggest that the in silico evolutionary approach we used may be a useful tool in general for predicting the effects of DNA variation on gene function. In addition, our data suggest that considering patterns of positive selection, along with patterns of negative selection such as evolutionary conservation, may improve our ability to predict the functional effects of amino acid variation. ? 2005 Brunham et al.
Source Title: PLoS Genetics
URI: https://scholarbank.nus.edu.sg/handle/10635/161875
ISSN: 15537390
DOI: 10.1371/journal.pgen.0010083
Rights: Attribution 4.0 International
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