- 作者: George Priya Doss C; Rao Sethumadhavan
- 作者服務機構: Bioinformatics Division, School of Biotechnology, Chemical and Biomedical Engineering, Vellore Institute of Technology, Tamil Nadu, India
- 中文摘要: --
- 英文摘要:
Background :
A central focus of cancer genetics is the study of mutations that are causally
implicated in tumorigenesis. The identification of such causal mutations not only
provides insight into cancer biology but also presents anticancer therapeutic targets and
diagnostic markers. Missense mutations are nucleotide substitutions that change an amino
acid in a protein, the deleterious effects of these mutations are commonly attributed to
their impact on primary amino acid sequence and protein structure.
Methods
The method to identify functional SNPs from a pool, containing both functional
and neutral SNPs is challenging by experimental protocols. To explore possible
relationships between genetic mutation and phenotypic variation, we employed different
bioinformatics algorithms like Sorting Intolerant from Tolerant (SIFT), Polymorphism
Phenotyping (PolyPhen), and PupaSuite to predict the impact of these amino acid
substitutions on protein activity of mismatch repair (MMR) genes causing hereditary
nonpolyposis colorectal cancer (HNPCC).
Results :
SIFT classified 22 of 125 variants (18%) as ‘Intolerant.’’ PolyPhen classified 40
of 125 amino acid substitutions (32%) as ‘‘Probably or possibly damaging’’. The
PupaSuite predicted the phenotypic effect of SNPs on the structure and function of the
affected protein. Based on the PolyPhen scores and availability of three-dimensional
structures, structure analysis was carried out with the major mutations that occurred in the
native protein coded by MSH2 and MSH6 genes. The amino acid residues in the native
and mutant model protein were further analyzed for solvent accessibility and secondary
structure to check the stability of the proteins.
Conclusions :
Based on this approach, we have shown that four nsSNPs, which were predicted
to have functional consequences (MSH2-Y43C, MSH6-Y538S, MSH6-S580L, and
MSH6-K854M), were already found to be associated with cancer risk. Our study
demonstrates the presence of other deleterious mutations and also endorses with in vivo
experimental studies. - 中文關鍵字: --
- 英文關鍵字: --