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
