Adaptive evolution of genes underlying schizophrenia Bernard Crespi, Kyle Summers, Steve Dorus
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Adaptive evolution of genes underlying schizophrenia Bernard Crespi, Kyle Summers, Steve Dorus
Proceedings of the Royal Society, 2007
Deborah Bird December 5, 2008
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Schizophrenia
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Schizo--phrenia
Split Mind
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Schizophrenia
Integration Disorder
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Symptoms of schizophrenia:
Poorly functioning perception andexpression of reality
Auditory hallucinations
Delusions
Paranoia
Disorganized thinking and speech
Social dysfunction
Schizophrenia is a polygenic, hetergeneous disorder. Multiple genes in complex interactions with environment combine to produce susceptibility to schizophrenia.
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Eugen Bleuler, 1908
“Schizophrenias”
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Question:
How is it that schizophrenia persists at a level of nearly 1% of the human population when it is highly heritable and reduces fitness?
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Question:
How is it that schizophrenia persists at a level of nearly 1% of the human population when it is highly heritable and reduces fitness?
Hypothesis:
Schizophrenia is a maladaptive byproduct of the adaptive evolution of human cognitive complexity.
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Question:
How is it that schizophrenia persists at a level of nearly 1% of the human population when it is highly heritable and reduces fitness?
Hypothesis:
Schizophrenia is a maladaptive byproduct of the adaptive evolution of human cognitive complexity.
Prediction:
Genes making us more susceptible to schizophrenia have been subjected to positive selection in the evolutionary history of the human lineage and related primate lineage.
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FINDING POSITIVE SELECTION
Choose 76 schizophrenia risk genes.
Analyse their molecular evolution
using two methods:
Hap Map
Phylogeny-based Maximum Likelihood
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Hap Map
Linkage disequilibrium-based analysis
Identified selective sweeps and resulting haplotypes as the signatures of recent positive selection
Used International Human Haplotype Map to detect positive
selection among 76 candidate genes across human
populations in Africa, Europe and Asia.
Compared frequency of positive selection in 76 candidate
genes to frequency of positive selection in 300
control “neuronal activity” genes.
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Results of Hap Map study:
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Hap MapProportion of genes inferred to be under positive selection, comparing candidate vs. control genes:
Schizophrenia risk genes: 18.3% (14 of 76)
Control genes: 9.0% (27 of 300)
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PAMLUsed phylogeny-based maximum likelihood analysis of the 76 candidate genes to probe for signatures of
positive selection in human and non-human
primate lineagesHuman
Chimpanzee
Macaque
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PAML
Data used: Alligned sequences of schizophrenia-related genes and their orthologs from mammalian species
Every codon in the alligned sequences is analyzed for non-synonymous substitutions
value: the ratio of non-synonymous to synonymous substitutions
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PAMLProportion of genes inferred to be under positive selection, comparing candidate vs control genes across lineages:
All lineages: Schizophrenia risk genes: 15% (11 of 76)Control genes: 8.3% (10 of 120)
Human lineage:Schizophrenia risk genes: 5.6% (4 of 76)Control genes: 0% (0 of 120)
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General Conclusions:
Evolutionary-genomic analyses can provide insights into the
functions of the genes that underlie the aetiologies
of schizophrenia. Probing for signatures of positive selection can highlight
allelic variants that help us understand the cognitive
changes in human evolutionary history.
Further study: To explore processes affecting the persistance ofschizophrenia:
Multilocus balancing selectionAntagonistic pleiotropySexual selectionConnection between schizotypal cognition
andcreativity.
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