- 作者: George Priya Doss C
- 作者服務機構: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Bio Sciences and Technology, VIT University, Tamil Nadu, India
- 中文摘要: --
- 英文摘要:
Background: In this study, instead of current biochemical methods, the effects of deleterious amino acid
substitutions in F8 and F9 gene upon protein structure and function were assayed by means
of computational methods and information from the databases. Deleterious substitutions of
F8 and F9 are responsible for Haemophilia A and Haemophilia B which is the most common
genetic disease of coagulation disorders in blood. Yet, distinguishing deleterious variants of
F8 and F9 from the massive amount of nonfunctional variants that occur within a single
genome is a significant challenge.
Methods: We performed an in silico analysis of deleterious mutations and their protein structure
changes in order to analyze the correlation between mutation and disease. Deleterious
nsSNPs were categorized based on empirical based and support vector machine based
methods to predict the impact on protein functions. Furthermore, we modeled mutant proteins
and compared them with the native protein for analysis of protein structure stability.
Results: Out of 510 nsSNPs in F8, 378 nsSNPs (74%) were predicted to be ‘intolerant’ by SIFT, 371
nsSNPs (73%) were predicted to be ‘damaging’ by PolyPhen and 445 nsSNPs (87%) as ‘less
stable’ by I-Mutant2.0. In F9, 129 nsSNPs (78%) were predicted to be intolerant by SIFT,
131 nsSNPs (79%) were predicted to be damaging by PolyPhen and 150 nsSNPs (90%) as
less stable by I-Mutant2.0. Overall, we found that I-Mutant which emphasizes support vector
machine based method outperformed SIFT and PolyPhen in prediction of deleterious nsSNPs
in both F8 and F9.
Conclusions: The models built in this work would be appropriate for predicting the deleterious amino acid
substitutions and their functions in gene regulation which would be useful for further
genotype–phenotype researches as well as the pharmacogenetics studies. These in silico
tools, despite being helpful in providing information about the nature of mutations, may also
function as a first-pass filter to determine the substitutions worth pursuing for further
experimental research in other coagulation disorder causing genes. - 中文關鍵字: --
- 英文關鍵字: In silico, F8, F9, Haemophilia A, Haemophilia B