Amino acid substitutions in the human genome: evolutionary implications of single nucleotide polymorphisms

Gene ◽  
2003 ◽  
Vol 305 (2) ◽  
pp. 167-173 ◽  
Author(s):  
Jacek Majewski ◽  
Jurg Ott
Keyword(s):  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Human Genome ◽  
Amino Acid Substitutions ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

A STRUCTURAL BIOINFORMATICS APPROACH TO THE ANALYSIS OF NONSYNONYMOUS SINGLE NUCLEOTIDE POLYMORPHISMS (nsSNPs) AND THEIR RELATION TO DISEASE

2007 ◽  
Vol 05 (06) ◽  
pp. 1297-1318 ◽  
Author(s):  
CATHERINE L. WORTH ◽  
G. RICHARD J. BICKERTON ◽  
ADRIAN SCHREYER ◽  
JULIA R. FORMAN ◽  
TAMMY M. K. CHENG ◽  
...  
Keyword(s):  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Structure Prediction ◽  
Three Dimensional ◽  
Comparative Modeling ◽  
Divergent Evolution ◽  
Amino Acid Substitutions ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Human Proteins

The prediction of the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) on function depends critically on exploiting all information available on the three-dimensional structures of proteins. We describe software and databases for the analysis of nsSNPs that allow a user to move from SNP to sequence to structure to function. In both structure prediction and the analysis of the effects of nsSNPs, we exploit information about protein evolution, in particular, that derived from investigations on the relation of sequence to structure gained from the study of amino acid substitutions in divergent evolution. The techniques developed in our laboratory have allowed fast and automated sequence-structure homology recognition to identify templates and to perform comparative modeling; as well as simple, robust, and generally applicable algorithms to assess the likely impact of amino acid substitutions on structure and interactions. We describe our strategy for approaching the relationship between SNPs and disease, and the results of benchmarking our approach — human proteins of known structure and recognized mutation.

Single Nucleotide Polymorphisms Influence the Phenotype of Mutations P618A and R1336W found in the ADAMTS13 Gene of Congenital TTP Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2977-2977
Author(s):  
Barbara Plaimauer ◽  
Gabriele Mohr ◽  
Waltraud Wernhart ◽  
Katharina Bruno ◽  
Gerhard Antoine ◽  
...  
Keyword(s):  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Single Amino Acid ◽  
Paternal Allele ◽  
Amino Acid Substitutions ◽  
Common Snps ◽  
Nucleotide Polymorphisms ◽  
Adamts13 Activity ◽  
Maternal Allele ◽  
Single Nucleotide

Abstract ADAMTS13 cleaves plasmatic von Willebrand factor (VWF) between Tyr1605 and Met1606 and regulates thereby the hemostatic activity of VWF. Mutations in the ADAMTS13 gene leading to severe ADAMTS13 deficiency have been found in patients with congenital thrombotic thrombocytopenic purpura (TTP). We have analyzed the ADAMTS13 gene defects in two brothers with hereditary TTP [Antoine et al, Brit. J. Hematol., 2003] where we detected a total of six nucleotide exchanges causing point mutations. On the maternal allele we found an accumulation of five amino acid substitutions (R7W, Q448E, P618A, A732V, R1336W) and on the paternal allele a stop mutation (Q44X) leading to premature protein termination in the propeptide region. Both brothers were double heterozygotes with < 3% of ADAMTS13 activity, whereas their asymptomatic parents have ~ 50% activity. Four (R7W, Q448E, P618A, A732V) of the five maternal mutations constitute single nucleotide polymorphisms (SNP) but R1336W was identified as novel rare mutation in the second cub domain. To evaluate the biologic phenotype of a given haplotype, e.g. the functional significance of the presence of the various SNPs, we analyzed the functional impact of the individual mutations on ADAMTS13 antigen levels and ADAMTS13 activity. A series of mutant ADAMTS13 molecules was expressed which contained either single amino acid substitutions or combinations of mutations with each other. We found that the common SNPs R7W, Q448E and A732V, as single mutations, had either no or only a minor impact on ADAMTS13 secretion and ADAMTS13 activity, whereas P618A and R1336W conferred a dominant adverse effect on ADAMTS13 secretion levels. Co-expression of SNPs R7W or Q448E with SNP P618A lead to improved ADAMTS13 secretion levels and could therefore partly attenuate the detrimental effect of P618A. Concomitant expression of all four SNPs reconstituted secretion levels similar to wild-type implicating a complex synergistically interaction of SNPs located in different ADAMTS13 domain regions, however, functional activity was impaired to 50%. Mutation R1336W was shown to be, as a single amino acid exchange, responsible for reduced ADAMTS13 antigen levels, but in contrast to P618A, the negative effect of R1336W was rather enhanced by the co-expression of R7W and Q448E, than rescued, leading to the total absence of ADAMTS13 secretion from the maternal allele. Our findings provide for the first time evidence that fairly common SNPs, dependent on the presence or absence of other mutations, may differently modulate functional ADAMTS13 protease levels.

In-silico study to identify the pathogenic single nucleotide polymorphisms in the coding region of CDKN2A gene

2021 ◽  
Author(s):  
Farzaneh Ghasemi ◽  
Mehri Khatami ◽  
Mohammad Mehdi Heidari ◽  
Reyhane Chamani
Keyword(s):  
Amino Acid ◽  
High Risk ◽  
Tumor Suppressor ◽  
Single Nucleotide Polymorphisms ◽  
Amino Acid Substitutions ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Cdkn2a Gene ◽  
Missense Variants ◽  
Bioinformatics Tools

Background: CDKN2A, encoding two important tumor suppressor proteins p16 and p14, is a tumor suppressor gene. Mutations in this gene and subsequently the defect in p16 and p14 proteins lead to the downregulation of RB1/p53 and cancer malignancy. To identify the structural and functional effects of mutations, various powerful bioinformatics tools are available. The aim of this study is the identification of high-risk non-synonymous single nucleotide variants in the CDKN2A gene via bioinformatics tools. Materials and Methods: Among the identified polymorphisms in this gene, 353 missense variants are retrieved from the national center for biotechnology information/single nucleotide polymorphism database (NCBI/dbSNP). Then, the pathogenicity of missense variants are considered using different bioinformatics tools. The stability of these mutant proteins, conservation of amino acids and the secondary and tertiary structural changes are analyzed by bioinformatics tools. After the identification of high-risk mutations, the changes in the hydrophobicity of high-risk amino acid substitutions are considered. Results: Deleterious single nucleotide polymorphisms (SNPs) were screened step by step using the bioinformatics tools. The results obtained from the set of bioinformatics tools identify high-risk mutations in CDKN2A gene. Conclusion: 18 high-risk mutations including L16R/Q, G23D/R/S, L32P, N42K, G55D, G67D/R, P81R, H83R, G89D/S, A102E, G101R, G122R, and V126D were identified. According to the previous experimental studies, the association of L16R, G23D/R/S, L32P, G67R, H83R, G89D, G101R, and V126D amino acid substitutions with various cancers has been confirmed.

scholarly journals SINGLE-NUCLEOTIDE POLYMORPHISMS OF CALCIUM-SENSING RECEPTOR ENCODING GENE ASSOCIATED WITH CALCIUM KIDNEY STONE DISEASE IN BABYLON PROVINCE

2018 ◽  
Vol 11 (2) ◽  
pp. 417 ◽  
Author(s):  
Zahraa Isam ◽  
Rabab Omran ◽  
Ammad Hassan Mahmood
Keyword(s):  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Kidney Stone ◽  
Stone Disease ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Calcium Sensing Receptor ◽  
Single Nucleotide ◽  
Kidney Stone Disease ◽  
Calcium Sensing

  Objective: The calcium-sensing receptor (CASR) is a G-protein-coupled receptor that is mainly expressed in the parathyroid and the kidneys where it regulates parathyroid hormone secretion and renal tubular calcium reabsorption. Inactivating and activating CASR gene due to mutations severally caused hypercalcemia or hypocalcemia disorders. The aim of the study was to investigate the risk factor of CASR rs1801725 (Ala986Ser) patients with renal disease.Method: The blood samples were collected from 100 patients and divided into two groups, each one containing 50 samples; chronic kidney disease and end-stage renal disease, who admitted Merjan Teaching Hospital in Babylon Province, Iraq, from February to July 2016. In addition, healthy persons as a control group (50 samples). Genotyping of CASR single-nucleotide polymorphisms (SNP) was performed using a polymerase chain reaction technique, followed by single-strand conformation polymorphism. Accordingly, these DNA polymorphisms were confirmed using DNA sequencing.Results: The conformational haplotypes of CASR, exon7 NCBI Primer3plus reference were obtained in three patterns, including two, three, and four bands, due to the presence SNPs within the studied region. These SNPs leads to change three amino acid residues of CASR, including amino acid substitutions were Ala 128→ Ser 128, Leu 155→Tye 155, and Leu 156→ Ser 156 that may affect or modified the tertiary structure of the receptor, subsequently the function like the affinity to calcium ion may be effected.Conclusion: These results suggest that the variants of CASR SNP, namely, rs1801725 might be involved in susceptibility to kidney stone disease.

scholarly journals EFIN: predicting the functional impact of nonsynonymous single nucleotide polymorphisms in human genome

BMC Genomics ◽  
2014 ◽  
Vol 15 (1) ◽  
pp. 455 ◽  
Author(s):  
Shuai Zeng ◽  
Jing Yang ◽  
Brian Hon-Yin Chung ◽  
Yu Lau ◽  
Wanling Yang
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Human Genome ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Functional Impact
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