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”

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?

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.

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.

FINDING POSITIVE SELECTION

Choose 76 schizophrenia risk genes.

Analyse their molecular evolution

using two methods:

Hap Map

Phylogeny-based Maximum Likelihood

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:

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)

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

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)

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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