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

2. Chimpanzee: Pan troglodytes
Our closest living relative
(MRCA ~6 million years ago)
Similar
Different
Disease
HIV-1/SIV
AIDS, Alzheimer's, heart disease
Anatomy
Thumbs
Hair, brain size
Behavior
Culture, tools
Agriculture
Language
Numeracy
Spoken language
I was part of the international consortium that published the initial sequence and analysis of the chimp genome.
This is a question that
will help us understand human-specific biology and health
gets at a more general question of how closely related species diverge

3. Leading Causes of Death
Comparative Medicine
Humans
Chimps
Dogs
Heart disease
Infectious disease
Cancer
Predation
Heart failure
Stroke
Assault
Kidney failure
Leading Causes of Death
Comparisons across many species will shed insight into human disease.
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

7. Comparison to Human Genome
Chimp
Mouse
Overall identity
95%
28%
Aligned bases
97%
40%
Identity at aligned bases
99%
69%
Identity in genes
85%

8. 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?

9. 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
Tubers, AMY1 = Nathaniel Dominy (UCSC)

10. 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

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

12. 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

13. Human Accelerated Regions
HAR1: novel RNA gene
Human-Chimp Differences
Likelihood Ratio Test
202 Human Accelerated Regions (HARs)
Altered regulation of developmental genes
Human
Mouse
Guillemot Lab
Median length 140 bp, mostly non-coding
HAR1 is transcribed - did 5’ RACE and identified two transcripts on opposite strands, overlapping in 5’ ends in HAR1 RNA structure
Expressed in fetal brain, low levels in adult brain, HAR1R in adult testes (no other tissues)
HAR2 drives limb expression in mouse embryos - hg version has a different pattern in the forearm and hand
Highly Conserved Elements
HAR2: limb enhancer
Rubin Lab
Pollard et al. (2006) Nature, Pollard et al. (2006) PLoS Genetics

14. 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

15. 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

17. 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