Shai Shen-Orr shenorr@stanford.edu. Nothing in Biology Makes Sense Except in the Light of Evolution Theodosius Dobzhansky 1973.

BMI217 Evolution & Medicine

Shai Shen-Orrshenorr@stanford.edu

Nothing in Biology Makes Sense Except in the Light of Evolution

Theodosius Dobzhansky 1973

Jeffrey Decoster, Stanford Medical Magazine, Summer 06http://stanmed.stanford.edu/2006summer/evolutionary-medicine.html

Negative (purifying) selection – selective removal of rare alleles that are deleterious

Positive selection – selection due to added fitness to a particular allele

Balancing selection – Selection due to heterozygote or frequency dependent advantage

Genome sequences

http://www.genomesonline.org/gold.cgi

Genomes sequenced as of today

http://www.genomesonline.org/gold.cgi

http://www.genomesonline.org/gold.cgi

Fitch et al. PNAS 1997

Bush et al. Science 1999

Sawyer et al. PNAS 2005

Sawyer et al. PNAS 2005

Kaiser et al. Science 2007

Kaiser et al. Science 2007

Arabidopsis thaliana 114.5 Mb genome

(Sequenced 2000 )

Chlamydomonas reinhardtii 95 Mb genome

(Sequenced 2004)

Li et al. Cell 2004

Li et al. Cell 2004

Ala et al. PLoS Comp Bio 2008

Ala et al. PLoS Comp Bio 2008

The best laid plans of mice and menOften go awry -Robert Burns

How similar is the Disease Gene Expression Profile of a human disease and its mouse model ?

Disease Gene Expression Signatures can be obtained from microarray

Diseased Subjects Control subjects

Subtract

Disease gene expression signature

Rank Normalize

A case study of similarity: Duchenne Muscular DystrophyHow similar is the Disease Gene Expression Profile of a human disease and its mouse model ?

MDX mouse Wildtype ControlDMD patients Control

Disease gene expression signature Disease gene expression signature

Human Mouse

Limit to Human – Mouse 1:1 orthologs

Comparison of Disease Gene Expression Signatures yields a between experiment similarity value

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

Human Disease gene expression signature

Mou

se D

isease

gen

e e

xp

ressio

n sig

natu

re

Spearman’s ρ = 0.28

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

9

Comparison of Disease Gene Expression Signatures yields a between experiment similarity value

Human Disease gene expression signature

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1Mouse

Dise

ase

gene e

xpre

ssion

signatu

re

Spearman’s ρ = 0.28

Spearman’s ρ Rank Correlation

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

9

Multiple Disease Gene Expression Signatures can be obtained from public data

Spearman’s ρ Rank Correlation

Cross-speciesMouse X MouseHuman X Human

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

9

Cross-species DMD Similarity is lower than within species

Spearman’s ρ Rank Correlation

Cross-speciesMouse X MouseHuman X Human

Mouse models of human disease recapitulate human disease signatures poorly

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

Alzheimer's disease

SCID

Atherosclerosis

Cardiomyopathy

Cystic fibrosis

Huntington's disease

Bacterial infection

Senescence

Breast Cancer

Obesity

Type 2 Diabetes

DMD

Spearman’s ρ Rank CorrelationCross-speciesMouse X MouseHuman X Human

A Cross-specie gene expression Barrier to translational research

Spearman’s ρ Rank Correlation

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

Alzheimer's disease

SCID

Atherosclerosis

Cardiomyopathy

Cystic fibrosis

Huntington's disease

Bacterial infection

Senescence

Breast Cancer

Obesity

Type 2 Diabetes

DMD

-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 10

10

20

30

Cross-speciesMouse X MouseHuman X Human