Accurate Prediction of the Functional Significance of Single Nucleotide Polymorphisms and Mutations in the ABCA1 Gene Export

@article{citeulike:4160632, 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 ( r 2 = 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.}, author = {Brunham, Liam R. and Singaraja, Roshni R. and Pape, Terry D. and Kejariwal, Anish and Thomas, Paul D. and Hayden, Michael R.}, citeulike-article-id = {4160632}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pgen.0010083}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16429166}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16429166}, day = {30}, doi = {10.1371/journal.pgen.0010083}, issn = {1553-7404}, journal = {PLoS Genet}, keywords = {evolution, statistics}, month = {December}, number = {6}, pages = {e83+}, posted-at = {2009-11-06 18:51:45}, priority = {2}, publisher = {Public Library of Science}, title = {Accurate Prediction of the Functional Significance of Single Nucleotide Polymorphisms and Mutations in the ABCA1 Gene}, url = {http://dx.doi.org/10.1371/journal.pgen.0010083}, volume = {1}, year = {2005} }

TY - JOUR ID - citeulike:4160632 L3 - citeulike-article-id:4160632 N2 - 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 ( r 2 = 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. IS - 6 JF - PLoS Genet SN - 1553-7404 TI - Accurate Prediction of the Functional Significance of Single Nucleotide Polymorphisms and Mutations in the ABCA1 Gene PB - Public Library of Science VL - 1 SP - e83 KW - evolution KW - statistics AU - Brunham, Liam AU - Singaraja, Roshni AU - Pape, Terry AU - Kejariwal, Anish AU - Thomas, Paul AU - Hayden, Michael PY - 2005/12/30/ UR - http://dx.doi.org/10.1371/journal.pgen.0010083 ER -