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Genome Biology & Applied Bioinformatics Mehmet Tevfik DORAK, MD PhD

Genome Biology & Applied Bioinformatics Mehmet Tevfik DORAK, MD PhD. Schedule. Schedule. 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

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Genome Biology & Applied Bioinformatics Mehmet Tevfik DORAK, MD PhD

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  1. Genome Biology & Applied Bioinformatics Mehmet Tevfik DORAK, MD PhD

  2. Schedule

  3. Schedule

  4. 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

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

  6. SNPs in Coding Regions May Cause Amino Acid Sequence Changes

  7. SNPs in Coding Regions May Cause Amino Acid Sequence Changes

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

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

  10. Expression Quantitative Trait Loci (eQTLs)

  11. eQTLs May be Tissue-specific

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

  13. Weak Correlation between mRNA and Protein Levels in Eukaryotes A total of 150 signature genes showed significant changes at either the protein and/or the mRNA level in two bovine bone marrow derived cell lines. 113 signature genes (76%) exhibited changes for mRNAs and their cognate proteins in the same direction (1st and 3rd quadrants), only 29 of them changed significantly at both mRNA and protein levels and were thus dubbed correlated genes (red). In contrast, 67 genes showed significant changes at the mRNA but not the protein level (green), whereas 52 genes showed significant changes at the protein but not the mRNA level (blue). Another two genes showed opposite expression patterns of mRNA and protein (brown). The correlation coefficient between mRNA and protein is 0.64 for the signature genes and 0.59 for all the genes examined. Tian, 2004 (www)

  14. Weak Correlation between mRNA and Protein Levels in Eukaryotes

  15. Weak Correlation between mRNA and Protein Levels in Eukaryotes

  16. Examples of Functional Variants and Associated Traits

  17. TNFRSF1A rs1800693

  18. Key Points - 80M+ SNPs are already known in the human genome (20M+ 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

  19. … Looking forward …..

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