Working Group 5 – Genomic Structural Variation

Ammar Al-Chalabi, Ahmad Al Kheilfat, A. Nazli Basak, Ross Byrne, Cinzia Gellera, Alfredo Iacoangeli, Victoria López, Russell L. McLaughlin, Matthieu Moisse, Michael A. van Es, Jan H. Veldink, Patrick Vourc’h.

Background

Large genome wide association analyses have been performed on many thousands of genomes using microarrays and short-read whole-genome sequence (WGS) data to discover ALS-related single nucleotide polymorphisms (SNPs). These researches mostly returned non-causal variants associated to ALS. In order to discover the genetic cause, it is essential to identify genetic variations that are larger than a single base pair, like repeat expansions, copy number variants (CNVs) and structural variants (SVs). An important finding that emphasizes this is the discovery of the repeat expansion in the C9ORF72 gene, which explains approximately 40% of the familial and 6% of the sporadic ALS cases. These large genetic changes are more difficult to detect than SNPs, because evidence of these large changes are often unintentionally disregarded or misinterpreted during WGS or wetlab analysis.

Objectives

1. Further develop software and use of existing software to study existing and detect novel short repeats related to ALS from Illumina short-read WGS data.
2. Use existing tools to detect large CNVs and SVs related to ALS from short-read Illumina WGS data.
3. Explore long-read technologies or platforms, e.g. Pacbio and Nanopore, to detect long repeats, CNVs and SVs related to ALS.
4. Validate findings using wet-lab techniques across the consortium.