BMI217 Evolution & Medicine

1. BMI217 Evolution & Medicine • Shai Shen-Orr shenorr@stanford.edu

2. Nothing in Biology Makes Sense Except in the Light of Evolution • Theodosius Dobzhansky 1973

3. http://stanmed.stanford.edu/2006summer/evolutionary-medicine.htmlhttp://stanmed.stanford.edu/2006summer/evolutionary-medicine.html Jeffrey Decoster, Stanford Medical Magazine, Summer 06

4. Negative (purifying) selection – selective removal of rare alleles that are deleterious • Positive selection – selection due to added fitness to a particular allele • Balancing selection – Selection due to heterozygote or frequency dependent advantage

5. Genome sequences http://www.genomesonline.org/gold.cgi

6. Genomes sequenced as of today http://www.genomesonline.org/gold.cgi

7. http://www.genomesonline.org/gold.cgi

9. Fitch et al. PNAS 1997

10. Bush et al. Science 1999

11. Sawyer et al. PNAS 2005

12. Sawyer et al. PNAS 2005

13. Kaiser et al. Science 2007

14. Kaiser et al. Science 2007

17. Arabidopsis thaliana 114.5 Mb genome (Sequenced 2000 ) Chlamydomonasreinhardtii95 Mb genome (Sequenced 2004)

18. Li et al. Cell 2004

19. Li et al. Cell 2004

20. Ala et al. PLoS Comp Bio 2008

21. Ala et al. PLoS Comp Bio 2008

22. The best laid plans of mice and menOften go awry -Robert Burns • How similar is the Disease Gene Expression Profile of a human disease and its mouse model ?

23. Disease Gene Expression Signatures can be obtained from microarray Diseased Subjects Control subjects Subtract Rank Normalize Disease gene expression signature

24. A case study of similarity: Duchenne Muscular DystrophyHow similar is the Disease Gene Expression Profile of a human disease and its mouse model ? Mouse Human DMD patients Control MDX mouse Wildtype Control Disease gene expression signature Disease gene expression signature Limit to Human – Mouse 1:1 orthologs

25. Comparison of Disease Gene Expression Signatures yields a between experiment similarity value Spearman’s ρ = 0.28 Mouse Disease gene expression signature Human Disease gene expression signature

26. Comparison of Disease Gene Expression Signatures yields a between experiment similarity value Spearman’s ρ = 0.28 Human Disease gene expression signature Mouse Disease gene expression signature Spearman’s ρ Rank Correlation

27. Multiple Disease Gene Expression Signatures can be obtained from public data Cross-species Mouse X Mouse Human X Human Spearman’s ρ Rank Correlation

28. Cross-species DMD Similarity is lower than within species Cross-species Mouse X Mouse Human X Human Spearman’s ρ Rank Correlation

29. Mouse models of human disease recapitulate human disease signatures poorly Cross-species Mouse X Mouse Human X Human Spearman’s ρ Rank Correlation

30. A Cross-specie gene expression Barrier to translational research Cross-species Mouse X Mouse Human X Human Spearman’s ρ Rank Correlation