A Large-scale Multi-omics Study To Investigate The Role Of Human Endogenous Retroviruses And Structural Variants In Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is caused by a combination of genetic and environmental factors. Many advances have been made in identifying genetic changes involved in the development of the disease. However, there is still much to be understood about the changes in our DNA that increase the risk of developing ALS as there is still no identified causative DNA risk which has been identified in the majority of ALS.

An overlooked source of genetic change in the human genome is the presence, absence or expansion of large DNA sequences called Structural Variants, despite one of these in the C9orf72 gene being the most common cause of ALS responsible for ~6% of all cases in European populations. One type of Structural variants is called human endogenous retroviruses.

These sequences integrated in our genomes up to millions of years ago as a result of ancient infections and currently comprise ~8% of our genome, whereas proteins comprise only 1%. Recent studies demonstrated that the expression of these elements, expression is toxic to cultured motor neurones, and causes a motor neurone disease in mice supporting their potential key role in the development of ALS.

However, many questions remain, for example, it is not clear if these effects are the consequence of a specific type, a group of them, or even if they occur in ALS patients. Moreover, the study of Structural variants and endogenous retroviruses is complicated and requires sophisticated bioinformatics and new sequencing technologies are able to characterise them with unprecedented accuracy and resolution.

In the recent years our laboratory has developed computational tools and laboratory protocols to study them and our preliminary results show that some the genome of some patients carry genetic variation compatible with their presence. However, the analysis of larger groups of people with and without ALS and a deeper investigation on their biological effects on other genes are required to prove their effective role on the development of ALS and clarify potential new avenues of treatment.

This proposal will enable us to expand our analysis to the wider Project MinE dataset which currently has over 8000 patient and 1400 control DNAs available. We will capitalise on data already generated through Project MinE to allow us to identify definitively if these elements are correlated with or are playing a role in development of ALS. We will also use a new technology, called long-read sequencing, to characterise their sequences with high resolution and accuracy and to understand what is their effect on the expression of other genes.

This will help us to understand wether they are a cause of the disease and how to design experiments that can help us understand how to trat them. This is a novel study that will complement traditional genomic analyses to address an important gap in our understanding of the genetic basis of ALS. Expanding the knowledge of the genetic causes of ALS will help in the understanding of the processes occurring in the disease and to develop targeted therapies which otherwise would remain elusive.