Understanding non-coding genomic variation in neurological disorders (360G-Wellcome-221951_Z_20_Z)

The vast majority of DNA is non-coding, repetitive, encompasses a significant proportion of disease risk and is divergent across populations. Major bottlenecks in the past restricted our understanding of this genomic region, including limited analysis techniques, inability to sequence large repetitive, homologous regions and the paucity of population control datasets. These restrictions have largely been overcome, and through early translation we have highlighted the importance of non-coding genomic factors with the identification of pathogenic recessive repeat expansions, homologous replicated regions and gene amplification events as major causes of neurological disease. The overarching theme of this proposal is to investigate four large diverse neurology cohorts, where genome sequencing has explained less than one-third of cases. Initially, we will examine non-coding, short- read genome sequencing data using optimised and newly developed algorithms. Next, to overcome the limitations of short-read sequencing, we will apply and integrate long-read Oxford Nanopore genome sequencing and optical genome mapping to a range of neurological disease trios and paired brain and blood samples. Finally, we will comprehensively interpret and validate data, reannotate against diverse control genomes, compare disease-relevant transcriptome builds, interrogate collaborator cohorts and use transcriptome sequencing to inform on pathogenicity, identify mechanisms and pathways impacted by genetic vulnerability.