Katherine S. Pollard

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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
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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
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Comparative Medicine
Humans Chimps Dogs
Heart disease Infectious disease 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?

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Human genome 2001 Mouse genome 2002 Chimp genome
2005
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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
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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?

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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

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

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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
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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

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What have we learned?

• Being human is not all about the brain.
• Proteins are nearly identical to chimps.
• 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
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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