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Adaptive evolution of genes underlying schizophrenia Bernard Crespi, Kyle Summers, Steve Dorus

Adaptive evolution of genes underlying schizophrenia Bernard Crespi, Kyle Summers, Steve Dorus Proceedings of the Royal Society, 2007 Deborah Bird December 5, 2008. Schizophrenia.

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Adaptive evolution of genes underlying schizophrenia Bernard Crespi, Kyle Summers, Steve Dorus

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  1. Adaptive evolution of genes underlying schizophrenia Bernard Crespi, Kyle Summers, Steve Dorus Proceedings of the Royal Society, 2007 Deborah Bird December 5, 2008

  2. Schizophrenia

  3. Schizo--phrenia Mind Split

  4. Schizophrenia Integration Disorder

  5. Symptoms of schizophrenia: Poorly functioning perception and expression 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.

  6. Eugen Bleuler, 1908 “Schizophrenias”

  7. 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?

  8. 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.

  9. 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.

  10. FINDING POSITIVE SELECTION Choose 76 schizophrenia risk genes. Analyse their molecular evolution using two methods: Hap Map Phylogeny-based Maximum Likelihood

  11. 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.

  12. Results of Hap Map study:

  13. Hap Map Proportion 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)

  14. PAML Used phylogeny-based maximum likelihood analysis of the 76 candidate genes to probe for signatures of positive selection in human and non-human primate lineages Human Chimpanzee Macaque

  15. 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

  16. PAML Proportion 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)

  17. 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 selection Antagonistic pleiotropy Sexual selection Connection between schizotypal cognition and creativity.

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