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

2. Chimpanzee: Pan troglodytes Our closest living relative (MRCA ~6 million years ago) SimilarDifferent DiseaseHIV-1/SIVAIDS, Alzheimer's, heart disease AnatomyThumbsHair, brain size BehaviorCulture, toolsAgriculture LanguageNumeracySpoken language

3. Comparative Medicine Leading Causes of Death HumansChimpsDogs Heart diseaseInfectious diseaseCancer PredationHeart failure StrokeAssaultKidney failure 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 ChimpMouse Overall identity95%28% Aligned bases97%40% Identity at aligned bases 99%69% Identity in genes99%85%

6. The Chimp Genome Project 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?

7. Evolution of Human Digestion 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

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 6mya 8mya 25mya 35mya 75mya ~300mya ~400mya Comparative Genomics 2009 44 vertebrates 20 genome projects 24 2x mammals

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

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

12. 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. 11 predicted RNA genes 38 change a known TF binding site ITPR1, SPRY4, hypothetical protein NGN2 (3’ UTR) 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 CruzGladstone Institutes, UCSF David HausslerDennis 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