By Stitziel, Tseng, Pervouchine, Goddeau, Kasif, Liang Structural Location of Disease-associated Single-nucleotide Polymorphisms By Stitziel, Tseng, Pervouchine, Goddeau, Kasif, Liang JMB, 2003, 327, 1021-1030 Presented by Nancy Baker

What is a SNP? Single nucleotide polymorphism – a single base change Most common form of human genetic variation 500,000 SNPs in human coding region nsSNPs (nonsynonymous cause amino acid changes) Can cause diseases in many different ways

Goal: is the location of a SNP important? Do disease causing SNPs occur in one site of a protein more than others? Possible geometric sites: Pocket or void Convex or shallow region Interior (have 0 solvent accessibility)

Another goal: Get evolutionary perspective Are SNPs conserved? Use HMM techniques.

Step 1: Find SNPs associated with disease OMIM (Online Mendelian Inheritence in Man) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM Picked OMIM SNPs with link to SwissProt Extracted SwissProt sequences Ended up with 2128 variants of 310 genes

Step 2: Control Dataset: SNPs not necessarily associated with disease dbSNP database is source They admit this is not a perfect control Extract sequences from Genbank sequences Use sequences to find structure entry in PDB End up with 973 variants on 504 genes

Step 3: Where is the SNP in the protein? Map to PDB structures For OMIM SNPs – 924 variants in 82 alleles mapped to 129 PDB structures For dbSNP – 558 variants in 339 alleles mapped to 263 PDB structures Classify locations: P: surface pocket or interior void S: convex or depressed regions I: interior

Results Location OMIM dbSNP P:surface pocket / void 88% 68% S: convex / shallow 9% 27% I: interior 3% 5%

Results Many disease-associated nsSNPs are located in pockets or voids – more likely than non-disease associated nsSNPs – binding pockets nsSNPs in shallow depressed or convex regions also cause disease - probably because these can also be binding pockets nsSNPs unlikely to be buried in protein – why? Buried sites not accessible for molecular recognition and binding Core mutations either do not affect stability or affect it so much the mutation is fatal – not in population

Results For interior nsSNPs – no tendency for disease-associated mutations to be conserved For SNPs in interior – disease-associated SNPs more likely to be conserved

Value of paper Makes use of available data – no lab work involved Provides data, but … http://gila.bioengr.uic.edu/snp Little vague on some methods Control set

http://www3.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147670