title: Deleterious nonsynonymous single nucleotide polymorphisms in human solute carriers: the first comparison of three prediction methods.
abstract: Abundant nsSNPs have been found in genes coding for human solute carrier (SLC) transporters, but there is little known about the relationship between the genotype and phenotype of nsSNPs in these membrane proteins. It is unknown which prediction method is better suited for the prediction of nonneutral nsSNPs of SLC transporters. We have identified 2,958 validated nsSNPs in human SLC family members 1-47 from the Ensembl genome database and the NCBI SNP database. Using three different algorithms, 37-45 % of nsSNPs in SLC genes were predicted to have functional impacts on transporter function. Predictions largely agreed with the available experimental annotations. Overall, 76.5, 74.4, and 73.5 % of nonneutral nsSNPs were predicted correctly as damaging by SNAP, SIFT, and PolyPhen, respectively, while 67.4, 66.3, and 76.7 % of neutral nsSNPs were predicted correctly as nondamaging by the three methods, respectively. This study identified many amino acids that were likely to be functionally critical but have not yet been studied experimentally. There was a significant concordance between the predicted results of different methods. Evolutionarily nonneutral (destabilizing) amino acid substitutions are predicted to be the basis for the pathogenic alteration of SLC transporter activity that is associated with disease susceptibility and altered drug/xenobiotic response.
authors.affiliation: School of Environment, Biotechnology Institute, Dalian Jiaotong University, Dalian, 116028, China. haodc@126.com
authors.forename: Da-Cheng
authors.initials: DC
authors.lastname: Hao
authors.forename: Bing
authors.initials: B
authors.lastname: Xiao
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiang
authors.forename: Xue-Wei
authors.initials: XW
authors.lastname: Dong
authors.forename: Pei-Gen
authors.initials: PG
authors.lastname: Xiao
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000465:Algorithms; D019943:Amino Acid Substitution; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D005838:Genotype; D006801:Humans; D016623:Ion Pumps / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship
chemical_list: D018528:ATP-Binding Cassette Transporters; D016623:Ion Pumps; D026901:Membrane Transport Proteins