Abstract
We are entering the era of personalized genomics as breakthroughs in sequencing technology have made it possible to sequence or genotype an individual person in an efficient and accurate manner. Preliminary results from HapMap and other similar projects have revealed the existence of tremendous genetic variations among world populations and among individuals. It is important to delineate the functional implication of such variations, i.e. whether they affect the stability and biochemical properties of proteins. It is also generally believed that the genetic variation is the main cause for different susceptibility to certain diseases or different response to therapeutic treatments. Understanding genetic variation in the context of human diseases thus holds the promise for "personalized medicine." In this work, we carried out a genome-wide analysis of single nucleotide polymorphisms (SNPs) that could potentially influence protein phosphorylation characteristics in human. Here, we defined a phosphorylation-related SNP (phosSNP) as a non-synonymous SNP (nsSNP) that affects the protein phosphorylation status. Using an in-house developed kinase-specific phosphorylation site predictor (GPS 2.0), we computationally detected that approximately 70% of the reported nsSNPs are potential phosSNPs. More interestingly, approximately 74.6% of these potential phosSNPs might also induce changes in protein kinase types in adjacent phosphorylation sites rather than creating or removing phosphorylation sites directly. Taken together, we proposed that a large proportion of the nsSNPs might affect protein phosphorylation characteristics and play important roles in rewiring biological pathways. Finally, all phosSNPs were integrated into the PhosSNP 1.0 database, which was implemented in JAVA 1.5 (J2SE 5.0). The PhosSNP 1.0 database is freely available for academic researchers.
Highlights
We are entering the era of personalized genomics as breakthroughs in sequencing technology have made it possible to sequence or genotype an individual person in an efficient and accurate manner
It was proposed that nonsense mutations or non-synonymous SNP (nsSNP) might result in Premature Termination Codons (PTCs), which could trigger the nonsensemediated mRNA decay (NMD) pathway to prohibit the expression of proteins (34 –36)
All phosphorylation-related SNP (phosSNP) were classified into five types as defined based on the definitions listed below (Fig. 2): (i) Type I, an nsSNP at a phosphorylatable position that directly creates (Type I (ϩ)) or removes (Type I (Ϫ)) the phosphorylation site; (ii) Type II, an nsSNP that creates (Type II (ϩ)) or removes (Type II (Ϫ)) one or multiple adjacent phosphorylation sites; (iii) Type III, an nsSNP that induces changes of protein kinases (PKs) types for one or multiple adjacent phosphorylation sites; (iv) Type IV, an nsSNP at a phosphorylation site that induces a change of PK types for the phosphorylation site; and (v) Type V, a stop codon nsSNP that removes downstream phosphorylation sites in the protein C terminus
Summary
We are entering the era of personalized genomics as breakthroughs in sequencing technology have made it possible to sequence or genotype an individual person in an efficient and accurate manner. Changes to amino acids in proteins, such as the non-synonymous SNPs (nsSNPs) in the gene coding regions, could account for nearly half of the known genetic variations linked to human inherited diseases [6] In this regard, numerous efforts have been made to elucidate how nsSNPs generate deleterious effects on the stability and function of proteins and their roles in cancers and diseases [7,8,9,10,11]. The human ether-a-gogo-related gene 1, ERG1/ KCNH2/Kv11.1 (NM_000238) channel protein, has a K897T nsSNP (rs1805123), which creates a new AKT phosphorylation site to prolong the QT interval of cardiac myocytes [30] In this regard, comprehensive studies of nsSNPs that alter protein phosphorylation will be helpful to further the understanding of how genetic polymorphisms are involved in regulating biological pathways and processes and how they affect susceptibility to diseases and to determine human population diversity and phenotypic plasticity
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