1. 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,
Presented by Nancy Baker

2. 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

3. 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)

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

5. Step 1: Find SNPs associated with disease
OMIM (Online Mendelian Inheritence in Man)
Picked OMIM SNPs with link to SwissProt
Extracted SwissProt sequences
Ended up with 2128 variants of 310 genes

6. 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

7. 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

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

9. 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

10. 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

11. Value of paper Makes use of available data – no lab work involved
Provides data, but …
Little vague on some methods
Control set