What makes us human?
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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

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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

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Chimpanzee: Pan troglodytes

Our closest living relative

(MRCA ~6 million years ago)

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Comparative Medicine

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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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

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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

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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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Old World Monkeys

New World Monkeys




Comparative Genomics 2009



44 vertebrates

20 genome projects

24 2x mammals






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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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HAR1: novel RNA gene

Likelihood Ratio Test



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

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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

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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

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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