Genome Biology Applied Bioinformatics Mehmet Tevfik DORAK MD

Genome Biology & Applied Bioinformatics Mehmet Tevfik DORAK, MD Ph. D YOUR FUTURE STARTS WITH HOPE

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Single Nucleotide Polymorphisms Any nucleotide (A, C, G, T) > Another nucleotide C>T major allele > minor allele common allele > rare allele wildtype allele > variant allele (alternative terminology for SNP alleles) C>T A>B a>A 1>2 (coding for SNP alleles in analysis) Unless stated otherwise, a SNP association refers to an association with the minor allele

Alleles & Genotypes CG C: G Cp. G C T T C A C G Sense strand G A A G T G C Anti-sense strand Chromosome m ATG C A T G A C G Sense strand G T A C G C Anti-sense strand Chromosome p C: G basepair CG genotype Cp. G T dinucleotide ATG haplotype

SNPs in Coding Regions May Cause Amino Acid Sequence Changes

Genotyping - Genotyping is the process of obtaining genotypes for each SNP (or other variants) - Genotyping can be achieved by manual methods (most commonly Taq. Man Assay) or by microarrays.

Gene Expression 80% of disease-associated SNPs affect gene expression levels (i. e. , most disease-associated SNPs are e. QTLs)

Expression Quantitative Trait Loci (e. QTLs)

e. QTLs May be Tissue-specific

Gene Expression Regulation – Chromatin modifications – Transcriptional regulation (TF-mediated) – Post-transcriptional (nc. RNA-mediated) – Translational (RNA decay; ribosome occupancy)

Weak Correlation between m. RNA and Protein Levels in Eukaryotes A total of 150 signature genes showed significant changes at either the protein and/or the m. RNA level in two bovine bone marrow derived cell lines. 113 signature genes (76%) exhibited changes for m. RNAs and their cognate proteins in the same direction (1 st and 3 rd quadrants), only 29 of them changed significantly at both m. RNA and protein levels and were thus dubbed correlated genes (red). In contrast, 67 genes showed significant changes at the m. RNA but not the protein level (green), whereas 52 genes showed significant changes at the protein but not the m. RNA level (blue). Another two genes showed opposite expression patterns of m. RNA and protein (brown). The correlation coefficient between m. RNA and protein is 0. 64 for the signature genes and 0. 59 for all the genes examined. Tian, 2004 (www)

Weak Correlation between m. RNA and Protein Levels in Eukaryotes

Examples of Functional Variants and Associated Traits

TNFRSF 1 A rs 1800693

Key Points - 80 M+ SNPs are already known in the human genome (20 M+ common SNPs) - The number of SNPs is likely to increase as whole genome sequencing studies continue - Non-coding region SNPs are as important as coding region SNPs in human disease genetics - The most common intermediate phenotype affected by genetic variation is gene expression - Coding region variants may change the amino acid sequence of peptides, while non-coding region variants primarily influence gene expression levels

… Looking forward …. . YOUR FUTURE STARTS WITH HOPE

YOUR FUTURE STARTS WITH HOPE