Katherine S. Pollard Gladstone Institutes, Institute for Human Genetics and Division of Biostatistics - UCSF docpollard

1. What makes us human? Katherine S. Pollard Gladstone Institutes, Institute for Human Genetics and Division of Biostatistics - UCSF http://docpollard.com BioForum - California Academy of Sciences October 3, 2009

2. Chimpanzee: Pan troglodytes Our closest living relative (MRCA ~6 million years ago)

3. Comparative Medicine Leading Causes of Death • Naturally occurring variation in disease • susceptibility likely has some genetic basis. • What DNA changes are responsible?

4. Human genome 2001 Mouse genome 2002 Chimp genome 2005

5. Comparison to Human Genome

6. How different are our genes? ~30% of proteins are identical Average protein has 2 amino acid changes (1 per lineage) 15 genes where human disease variant is the only version in the chimp population  are we evolving away from ancestral version? The Chimp Genome Project

7. Our diet has changed a lot … Cooking: tubers, other hard foods Agriculture: grains, gluten Animal husbandry: dairy, eggs, more meat Some genes have adapted Lactose tolerance (LCT gene) High starch food sources (AMY gene)  Vary between worldwide human populations Evolution of Human Digestion

8. Non-coding ≠ “junk DNA” • ~5% of the human genome is functionally constrained and highly conserved in the mouse genome. • But only ~1% codes for proteins.  Most constrained sequences are non-coding Siepel et al. 2005

9. Human Chimp Gorilla Old World Monkeys New World Monkeys Mouse Chicken Fish Comparative Genomics 2009 6mya 8mya 44 vertebrates 20 genome projects 24 2x mammals 25mya 35mya 75mya ~300mya ~400mya

10. Substitution Rates Much of the DNA in eukaryotic genomes is evolving at a background (neutral) rate: Negative selection on functional elements decreases the number of substitutions: • Other forces increase substitutions... • Positive selection • Mutation rate increase

11. HAR1: novel RNA gene Likelihood Ratio Test Human Mouse Altered regulation of developmental genes Guillemot Lab HAR2: limb enhancer Rubin Lab Human Accelerated Regions Human-Chimp Differences 202 Human Accelerated Regions (HARs) Highly Conserved Elements Pollard et al. (2006) Nature, Pollard et al. (2006) PLoS Genetics

12. 11 predicted RNA genes 38 change a known TF binding site ITPR1, SPRY4, hypothetical protein NGN2 (3’ UTR) Location of HARs • Mostly non-coding elements • 66% intergenic • 32% intronic • 1.5% protein coding • 0.5% UTR • Nearby genes involved in transcriptional regulation, development, and disease. • HAR170 • Intron of the “speech • gene” FOXP2 • RNA structure • Many human changes

13. What have we learned? • Being human is not all about the brain. • Proteins are nearly identical to chimp’s. • We need to decipher the effects of non-coding changes, e.g. gene regulation. • 99% vs. 99.9% identity  human genomes Pollard (2009) Scientific American

15. Collaborators University of California, Santa Cruz Gladstone Institutes, UCSF David Haussler Dennis Kostka Sofie Salama Genevieve Erwin Tim Dreszer Alisha Holloway Adam Siepel (Cornell) Joshua Ladau Jakob Pedersen (Copenhagen)Samantha Riesenfeld Thomas Sharpton University of Brussels (ULB), Belgium Alex Zambon (UCSD) Pierre Vanderhaeghen Nelle Lambert Uppsala University Marie-Alexandra Lambot Matthew Webster Sandra Coppens Jonus Berglund National Institute for Medical Research Indiana University (MRC), England Matthew Hahn Francois Guillemot Laura Galinanes-Garcia