Shai Shen-Orr [email protected]. Nothing in Biology Makes Sense Except in the Light of Evolution...
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![Page 2: Shai Shen-Orr shenorr@stanford.edu. Nothing in Biology Makes Sense Except in the Light of Evolution Theodosius Dobzhansky 1973.](https://reader035.fdocuments.us/reader035/viewer/2022062516/56649daa5503460f94a990bc/html5/thumbnails/2.jpg)
Nothing in Biology Makes Sense Except in the Light of Evolution
Theodosius Dobzhansky 1973
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Jeffrey Decoster, Stanford Medical Magazine, Summer 06http://stanmed.stanford.edu/2006summer/evolutionary-medicine.html
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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
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Genome sequences
http://www.genomesonline.org/gold.cgi
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Genomes sequenced as of today
http://www.genomesonline.org/gold.cgi
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http://www.genomesonline.org/gold.cgi
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Fitch et al. PNAS 1997
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Bush et al. Science 1999
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Sawyer et al. PNAS 2005
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Sawyer et al. PNAS 2005
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Kaiser et al. Science 2007
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Kaiser et al. Science 2007
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Arabidopsis thaliana 114.5 Mb genome
(Sequenced 2000 )
Chlamydomonas reinhardtii 95 Mb genome
(Sequenced 2004)
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Li et al. Cell 2004
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Li et al. Cell 2004
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Ala et al. PLoS Comp Bio 2008
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Ala et al. PLoS Comp Bio 2008
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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 ?
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Disease Gene Expression Signatures can be obtained from microarray
Diseased Subjects Control subjects
Subtract
Disease gene expression signature
Rank Normalize
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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
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Comparison of Disease Gene Expression Signatures yields a between experiment similarity value
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Human Disease gene expression signature
Mou
se D
isease
gen
e e
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ressio
n sig
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Spearman’s ρ = 0.28
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-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
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Dise
ase
gene e
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signatu
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Spearman’s ρ = 0.28
Spearman’s ρ Rank Correlation
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-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
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Multiple Disease Gene Expression Signatures can be obtained from public data
Spearman’s ρ Rank Correlation
Cross-speciesMouse X MouseHuman X Human
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Cross-species DMD Similarity is lower than within species
Spearman’s ρ Rank Correlation
Cross-speciesMouse X MouseHuman X Human
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Mouse models of human disease recapitulate human disease signatures poorly
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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
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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