Polymorphisms – SNP, InDel, Transposon BMI/IBGP 730 Victor Jin, Ph.D. (Slides from Dr. Kun Huang) Department of Biomedical Informatics Ohio State University

The value of sequenced genome lies in the annotation. Gene discovery Polymorphism TSS CpG region ncRNA TF binding sites Annotation projects: HAVANA (Sanger Inst.) ENCODE CCDS

Polymorphisms Single Nucleotide Polymorphism (SNP) SNP projects SNP array Sequencing Other Polymorphisms Copy Number / LOH Database Search

Polymorphisms get lots of press

Genetic Variations Mutation Allele SNP In-Del Transposon Aneuploidy …

Polymorphisms Single Nucleotide Polymorphism (SNP) SNP projects SNP array Sequencing Other Polymorphisms Copy Number / LOH Database Search

Single Nucleotide Polymorphism At least 1% of a population has a different nucleotide There are many other classes of variants and these are no less important (e.g., deletions and duplications), SNP are simply the most abundant. First SNPs - RFLPs – D. Botstein The single nucleotide polymorphism (SNP) [pronounced "snip"] is the most common form of genetic variation. As the name suggests, each SNP is a difference in a single nucleotide (A,T,C,or G) of an individual's DNA sequence, such as having AAGG instead of ATGG. There may be from 1 to 10 million SNPs in the entire human genome, but perhaps only a few thousand relate to disease outcomes. The numbers seem to change with every news report.

Questions: How are SNP useful to biomedical sciences? How can bioinformatics help us use SNP?

Critical SNP concepts Marker SNP vs. Functional SNP SNPs highlights the spots for search (features, region of interest). SNP patterns from a target population can be compared with SNP patterns from unaffected populations to find genetic variations shared only by the affected group. The most useful SNPs are known as "functional SNPs." A single functional SNP or certain combinations of functional SNPs may help explain variability in individual responses to a given drug or pinpoint the subtle genetic differences that predispose some to diseases such as arthritis, Alzheimer's, cancer, diabetes, and depression.

Critical SNP concepts Understand evolution DNA fingerprinting – forensic applications Markers for polygenetic traits Genotype-specific medicine (personalized medicine)

Critical SNP concepts 1. Humans are diploid and exhibit significant heterogeneity and heterozygosity 3. DNA is essentially identical in every cell 4. The closer two SNP are the less likely they are to have segregated in a population (linkage disequilibrium) 5. Multiple variants/alleles can be combined into haplotypes (polygenic markers – quantitative trait loci or QTL)

Why SNP gets so much attention? Pharmcogenomics Personalized medicine

HapMap The International HapMap Project is a multi-country effort to identify and catalog genetic similarities and differences in human beings. Six participating countries: Japan, the United Kingdom, Canada, China, Nigeria, and the United States. The goal is to compare the genetic sequences of different individuals to identify chromosomal regions where genetic variants are shared. Data generated by the Project can be downloaded with minimal constraints.downloaded

NCBI SNP

SNP Array Affymetrix SNP 6.0 array More than 906,600 SNPs: Unbiased selection of 482,000 SNPs; historical SNPs from the SNP Array 5.0 Selection of additional 424,000 SNPs –Tag SNPs –SNPs from chromosomes X and Y –Mitochondrial SNPs –New SNPs added to the dbSNP database –SNPs in recombination hotspots More than 946,000 copy number probes

SNP Array Affymetrix SNP 5.0 array

$1000 genome project Solexa SOLiD 454 Re-sequencing using massive parallel sequencer

Polymorphisms Single Nucleotide Polymorphism (SNP) SNP projects SNP array Sequencing Other Polymorphisms Copy Number / LOH Database Search

In-Del Transposon Aneuploidy … Keiko et al, Genome Research 2008

Polymorphisms Single Nucleotide Polymorphism (SNP) SNP projects SNP array Sequencing Other Polymorphisms Copy Number / LOH Database Search

CGH – Comparative Genomic Hybridization

FISH - Fluorescence in situ Hybridization

Cytogenetics

Polymorphisms Single Nucleotide Polymorphism (SNP) SNP projects SNP array Sequencing Other Polymorphisms Copy Number / LOH Database Search