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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 Chimpanzee: Pan troglodytes Our closest living relative (MRCA ~6 million years ago) Similar Different Disease HIV-1/SIV Anatomy Thumbs AIDS, Alzheimer's, heart disease Hair, brain size Behavior Culture, tools Agriculture Language Numeracy Spoken language Comparative Medicine Humans Heart disease Chimps Infectious disease Dogs Cancer Cancer Predation Heart failure Stroke Assault Kidney failure Leading Causes of Death • Naturally occurring variation in disease susceptibility likely has some genetic basis. • What DNA changes are responsible? Human genome 2001 Mouse genome 2002 Chimp genome 2005 Comparison to Human Genome Chimp Mouse Overall identity 95% 28% Aligned bases 97% 40% Identity at aligned bases 99% 69% Identity in genes 99% 85% 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? 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 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 Comparative Genomics 2009 44 vertebrates 20 genome projects 24 2x mammals 35mya 75mya 25mya 6mya 8mya Human Chimp Gorilla Old World Monkeys New World Monkeys ~300mya Mouse ~400mya Chicken Fish 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 Human Accelerated Regions HAR1: novel RNA gene Human-Chimp Differences Likelihood Ratio Test 202 Human Accelerated Regions (HARs) Highly Conserved Elements Human Mouse Altered regulation of developmental genes Guillemot Lab HAR2: limb enhancer Pollard et al. (2006) Nature, Pollard et al. (2006) PLoS Genetics Rubin Lab Location of HARs • Mostly non-coding elements – 66% intergenic – 32% intronic – 1.5% protein coding – 0.5% UTR 11 predicted RNA genes 38 change a known TF binding site ITPR1, SPRY4, hypothetical protein NGN2 (3’ UTR) • Nearby genes involved in transcriptional regulation, development, and disease. HAR170 - Intron of the “speech gene” FOXP2 - RNA structure - Many human changes 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 noncoding changes, e.g. gene regulation. • 99% vs. 99.9% identity human genomes Pollard (2009) Scientific American Collaborators University of California, Santa Cruz David Haussler Sofie Salama Tim Dreszer Adam Siepel (Cornell) Jakob Pedersen (Copenhagen) University of Brussels (ULB), Belgium Pierre Vanderhaeghen Nelle Lambert Marie-Alexandra Lambot Sandra Coppens National Institute for Medical Research (MRC), England Francois Guillemot Laura Galinanes-Garcia Gladstone Institutes, UCSF Dennis Kostka Genevieve Erwin Alisha Holloway Joshua Ladau Samantha Riesenfeld Thomas Sharpton Alex Zambon (UCSD) Uppsala University Matthew Webster Jonus Berglund Indiana University Matthew Hahn