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Multiple sclerosis (MS) is a genetic disease with a complex risk profile. It is more common in populations of European ancestry, and more common further from the equator within those populations. It is likely that this pattern has been shaped by natural selection (selection in response to environmental factors). Identifying genes that have undergone selection and are implicated in MS risk will improve understanding of what causes the disease. This project is designed to identify specific combinations of genetic changes that may result in MS onset and have undergone natural selection and help to understand the mechanisms of disease.
This study will carry out genome-wide scans for natural selection and target regions of the genome known to be associated with MS risk. This will generate knowledge regarding the selective forces that have driven the differences in MS risk between populations, enabling more informed targeting of the molecular mechanisms behind the disease.
Dr Bennet McComish and his team are examining the evolutionary causes of the strong latitude gradient in MS prevalence that is observed in some populations. Identifying specific genes that are under natural selection will help to better target therapies aimed at these risk factors.
The team is testing whether specific combinations of genetic changes that have undergone selection are associated with MS, giving us a more detailed picture of the genetic architecture that contributes to risk than we can see by considering changes one by one. Data from various parts of cell biology will be investigated to confirm the importance of any genes identified.
Dr McComish and his team have started identifying genes associated with MS risk that have undergone natural selection. They are narrowing down the search to find genetic changes that are most likely to have important effects on the functions within those genes. So far, the team has identified genes in the UK population linked to MS risk that are associated with ultraviolet (UV) levels and have undergone recent natural selection. This may explain why MS is more common further away from the equator.
The team will next refine their search for genetic changes that are under natural selection by looking for very recent genetic adaptations within populations. They will also carry out large-scale genomic analyses with data from the UK Biobank and will model the effects of UV exposure and other environmental effects on genetic selection. Genetic changes that are identified as being under selection will be analysed further to describe the genetic profile that confers MS risk. The project is also funded by a 4-year NHMRC Ideas Grant. Dr McComish is currently preparing a manuscript on this project for publication in a peer-reviewed journal.
Updated 31 March 2024
$124,843
2023
3 years
Current project
