Objective: We aimed to generate a population scale long-read sequencing dataset to begin to catalog structural variants in Parkinson’s disease (PD) to identify potential new variants associated with disease risk.

Background: PD is a common neurodegenerative disorder, affecting millions of individuals worldwide. A significant proportion of risk for PD is driven by genetics. Despite this, most of the common genetic variation that contributes to disease risk is unknown, in-part because previous genetic studies have focused solely on the contribution of single nucleotide variants. Structural variants represent a huge source of genetic variation in the human genome. However, as we have shown in recent studies (1), traditional sequencing methods such as short-read sequencing are not powered to detect most of the structural variants in the genome. Hence, they have not been cataloged on a genome-wide scale, and their contribution to the risk of PD remains unknown. Long-read sequencing technologies substantially overcome the limitations of short-reads but to date have not been considered as feasible replacement at scale due to a combination of being too expensive, not scalable enough, or too error-prone. 

Method: Here, we develop an efficient and scalable wet lab protocol for processing and Nanopore Long-read sequencing  human whole blood and brain samples that can yield 30X coverage and N50 ~30 Kb.

Results: We apply our protocol to PD samples and show that with this data we can detect thousands more structural variants. Further we demonstrate that using this data we can phase small and structural variants at megabase scales, better resolve disease-relevant haplotypes, and produce highly accurate haplotype-specific methylation calls.

Conclusion: In summary, here we develop a new wet-lab protocol for scalable long-read sequencing and show that this is a powerful dataset for detecting and genotyping new variants that were previously invisible to other sequencing methods.

References: 1. Billingsley, K. J. et al. Genome-Wide Analysis of Structural Variants in Parkinson Disease. Ann. Neurol. (2023) doi:10.1002/ana.26608.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/population-scale-long-read-sequencing-to-catalog-structural-variants-in-parkinsons-disease/