PhD Student Saurabh Srinivasan
Investigating the evolution of schizophrenia in humans
Saurabh Srinivasan, MSc
The persistence of schizophrenia in humans has been called an evolutionary enigma. Those affected by this illness have higher mortality, lower fecundity and poor quality of life. With these evolutionary disadvantages, one would expect natural selection to have acted against it but it still affects 1% of global population and has been recorded through much of human history. Previous studies propose that schizophrenia is a side effect of human evolution and the genes responsible for causing schizophrenia could also have had some evolutionary advantage. Some even propose that schizophrenia is the price we paid for our ability to have language.
The aim of our project is to use evolutionary proxies to investigate if schizophrenia is indeed a by-product of being human. We use proxies from different periods of time which can help give us a timeframe when during the course of evolution, the vulnerability to schizophrenia increased. Schizophrenia is a polygenic disorder, which means that it is caused by a large number of loci with small effects. We therefore employ statistical tools built to study the polygenic architecture of complex human diseases, specifically tweaked to make use of the evolutionary proxies:
- Neanderthal selective sweep score (NSS): a likelihood index of positive selection after the divergence of human and Neanderthal lines (~ 30,000 years ago). It is obtained by aligning Neanderthal and human genome. Our recent work, using NSS suggests that SNPs that have undergone recent positive selections in humans are more likely to be associated with schizophrenia compared to those which are older.
- Human segmental duplication score (HSDs): index of affiliation to duplication events from the time period 4-5 million years ago when the primate branch split between old world monkeys and new world monkeys. The old world monkeys then further evolved to apes and humans and we see an increased segmental duplication in these regions.
- Ohnolog score: a proxy for evolution events which are even older than segmental duplications (around 500 million years ago) and are whole genome duplication events found all throughout the vertebrate lineage.
These three proxies help us give an estimate of the evolutionary time line of the development of the disease. In addition, the susceptibility variants in these regions can point to genes associated with various phenotypes, including other psychiatric illnesses. In turn, those among these that are related to structure, function and development of brain can help us deduce if schizophrenia is inherently associated with being human.