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 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. Proportion of genes inferred to be under positive selection, comparing
Hap Map
Proportion of genes inferred to be under
positive selection, comparing
candidate vs. control genes:
Schizophrenia risk genes: % (14 of 76)
Control genes: % (27 of 300)

14. PAML
Used phylogeny-based maximum likelihood analysis of the 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

19. Proportion of genes inferred to be under positive selection, comparing
PAML
Proportion of genes inferred to be under
positive selection, comparing
candidate vs control genes across lineages:
All lineages:
Schizophrenia risk genes: % (11 of 76)
Control genes: % (10 of 120)
Human lineage:
Schizophrenia risk genes: % (4 of 76)
Control genes: % (0 of 120)

20. To explore processes affecting the persistance ofschizophrenia:
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.