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Review
. 2023 Jan 13;18(1):4.
doi: 10.1186/s13024-022-00593-1.

Advances in sequencing technologies for amyotrophic lateral sclerosis research

Evan Udine  1   2 , Angita Jain  1   2   3 , Marka van Blitterswijk  4
Affiliations
Review

Advances in sequencing technologies for amyotrophic lateral sclerosis research

Evan Udine et al. Mol Neurodegener. .

Abstract

Amyotrophic lateral sclerosis (ALS) is caused by upper and lower motor neuron loss and has a fairly rapid disease progression, leading to fatality in an average of 2-5 years after symptom onset. Numerous genes have been implicated in this disease; however, many cases remain unexplained. Several technologies are being used to identify regions of interest and investigate candidate genes. Initial approaches to detect ALS genes include, among others, linkage analysis, Sanger sequencing, and genome-wide association studies. More recently, next-generation sequencing methods, such as whole-exome and whole-genome sequencing, have been introduced. While those methods have been particularly useful in discovering new ALS-linked genes, methodological advances are becoming increasingly important, especially given the complex genetics of ALS. Novel sequencing technologies, like long-read sequencing, are beginning to be used to uncover the contribution of repeat expansions and other types of structural variation, which may help explain missing heritability in ALS. In this review, we discuss how popular and/or upcoming methods are being used to discover ALS genes, highlighting emerging long-read sequencing platforms and their role in aiding our understanding of this challenging disease.

Keywords: Amyotrophic lateral sclerosis; DNA sequencing; Long-read sequencing; Multi-omics; Nanopore sequencing; SMRT sequencing.

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Conflict of interest statement

Not applicable.

Figures

Fig. 1
Fig. 1
Overview of short-read and long-read sequencing technologies. A Examples of widely used platforms for short-read and long-read sequencing technologies. B The primary difference between short-read and long-read sequencing technologies is the significant increase in read length. In contrast to short-read sequencing (150–300 bp), long-read sequencing has the capacity to sequence reads spanning multiple kilobases in one single read, thereby requiring fewer reads to cover the same gene. The read overlap seen with long-read data reduces the sequence gaps as observed in short-read data. C Semi-quantitative comparison of short-read and long-read sequencing of various features including the ability to detect single nucleotide variants (SNVs), structural variants, and complete genome phasing, as well as the overall read length, accuracy, throughput, and sequencing cost
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