NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD The Neurogenomics View of Neurological Diseases Shoji Tsuji, MD, PhD he availability of high-throughput genome sequencing technologies is expected to revo- lutionize our understanding of not only hereditary neurological diseases but also spo- radic neurological diseases. The molecular bases of sporadic diseases, particularly those of sporadic neurodegenerative diseases, largely remain unknown. As potential mo- Tlecular bases, various mechanisms can be considered, which include those underlying apparently sporadic neurological diseases with low-penetrant mutations in the gene for hereditary diseases, sporadic diseases with de novo mutations, and sporadic diseases with variations in disease- susceptible genes. With unprecedentedly robust power, high-throughput genome sequencing tech- nologies will enable us to explore all of these possibilities. These new technologies will soon be applied in clinical practice. It will be a new era of datacentric clinical practice. JAMA Neurol. 2013;70(6):689-694. Published online April 9, 2013. doi:10.1001/jamaneurol.2013.734 The elucidation of the molecular bases of ologicpathwaysunderliebothhereditaryand neurological diseases is fundamental to the sporadic neurodegenerative diseases. development of disease-modifying and pre- In contrast to the molecular bases of he- ventive therapies.1 Over the past 3 decades, reditary neurological diseases, the molecu- we have witnessed remarkable progress in lar bases of sporadic neurological diseases, the identification of the genes that cause he- particularly those of sporadic neurodegen- reditary neurological diseases (Figure 1).2-4 erative diseases, largely remain unknown. This has been accomplished mainly on the A potential clue to the molecular bases of basisoftheresearchparadigmknownas“po- sporadic neurological diseases may be the sitional cloning,”5,6 which uses linkage stud- clinical observation that siblings and rela- ies to pinpoint the position of genes on chro- tives of a patient with a neurological dis- mosomes followed by the identification of ease are at an increased risk of developing thecausativegene.Theidentificationofcaus- the same disease; this phenomenon has been ative genes has further made it possible to observed with regard to Parkinson disease develop disease models for hereditary neu- (PD)12 and amyotrophic lateral sclerosis.13 rological diseases7-10 and to develop thera- These clinical observations suggest the in- peutic strategies.11 volvement of genetic factors in these dis- The majority of neurological diseases, eases (Figure 1). Until recently, it has been however, are sporadic without any obvious difficult to elucidate the genetic factors un- familial occurrence. We are thus faced with derlying sporadic neurological diseases. the challenge of elucidating the molecular bases of sporadic diseases. Intriguingly, the CME available online at clinical presentations and neuropathologi- jamanetworkcme.com cal findings of hereditary forms of neurode- and questions on page 683 generative diseases are often indistinguish- able from those of sporadic diseases, raising Rapid advancements in genome science, the possibility that common pathophysi- particularly the availability of massively Author Affiliations: Department of Neurology, Graduate School of Medicine, parallel sequencing technologies that use University of Tokyo, and Medical Genome Center, University of Tokyo Hospital, next-generation sequencers (NGSs), are Japan. revolutionizing the neurogenomics view of JAMA NEUROL/ VOL 70 (NO. 6), JUNE 2013 WWW.JAMANEURO.COM 689 ©2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 exome sequence analysis, the enrichment of exonic se- Road Map to Personal Genome Medicine quences using oligonucleotide “baits,” which is followed by sequencing, has been preferentially used. With this strat- Human genome sequence (April 2003) egy, all exonic sequences in the human genome can be ef- ficiently enriched.18-20 With this approach, more than 90% Human genome variation of target regions can be enriched, and these enriched ge- Pharmacogenomics nomic regions are then subjected to massively parallel se- Sporadic diseases Hereditary diseases (complex trait) (Mendelian trait) quencing using NGSs. This approach is currently being used a lot for the identification of disease-relevant variants21-31 Variants: related to Variants: susceptibility Variants: causative and even for diagnostic purposes.32-35 drug reactions mutations Given the ever-increasing throughput of NGSs and the • Differences in drug • Diagnosis • Diagnosis dramatically decreasing costs, it will soon be a realistic response and • Disease-modifying • Disease-modifying adverse effects therapy therapy approach to conduct whole-genome sequencing for vari- ous research applications (Figure 2).36-40 Studies have shown that there are more than 3 million variations in Personal genome medicine 40 Optimization of treatment and prevention the human genome of each individual. In one study, of disease based on personal genome among the 3.3 million single-nucleotide polymor- phisms (SNPs), 8996 known nonsynonymous SNPs and 1573 novel nonsynonymous SNPs were identified. In- Figure 1. Diagram showing the road map to personal genome medicine. Since the completion of the human genome sequence in 2003, the research focus in terestingly, 32 alleles exactly matched mutations previ- human genetics has moved to how human genome variations affect human ously registered in the Human Gene Mutation Data- health. Human genome variations are considered to be associated not only base. In addition, 345 insertions/deletions were observed with hereditary diseases but also with sporadic diseases. In addition, human genome variations are also associated with differences in drug responses and to overlap in a coding sequence and may alter protein 40 adverse effects. Optimization of treatment and prevention based on personal function. These findings indicate that, among the nu- genome information will soon be a realistic paradigm in clinical practice. merous candidate variations, it will be a challenge to de- termine which variations are relevant to diseases. sporadic neurological diseases. The elucidation of the ge- Given the enormous number of short read sequences nomic variants underlying sporadic diseases is expected to (~100 bp), informatics analyses, including mapping to ref- provide some answers that will help us to develop disease- erence sequences and indentifying variations, require a huge modifying and preventive therapies. computational power.41-45 Furthermore, mutations can be Another important field is pharmacogenomics, in variable, including single base substitutions, insertions/ which genomic variations underlie differences in drug deletions, and structural variations. It is difficult to effi- responses and adverse drug effects (Figure 1). This field ciently identify all the variations using currently avail- is currently being introduced into clinical practice. able NGSs and software. For example, expansions of repeat Thus, it will be essential to better understand how hu- motifs identified in frontotemporal dementia and amyo- man genome variations affect our health with regard to trophic lateral sclerosis46 are difficult to identify using NGSs. diseases with Mendelian or complex traits, as well as with As already stated, most of the currently available NGSs regard to pharmacogenomics. Herein, the neuroge- produce billions of short reads of 100 to 150 bp. This is nomics view of neurological diseases and the future di- the limitation in analyzing various structural variations, rections of clinical practice are discussed. some of which may be relevant to neurological diseases. Very recently, single-molecule sequencing technology has HIGH-THROUGHPUT GENOME become available from Pacific Biosciences; this type of SEQUENCING TECHNOLOGIES technology enables the acquisition of nucleotide se- quences as large as 10 kilobases.47,48 Another single- Emerging new technologies for nucleotide sequencing molecule sequencing technology using nanopores, which have brought about a remarkable revolution in analyses allows for the acquisition of much longer sequences,49 of the human genome sequence. Compared with a con- will soon become available. ventional technology (namely, the Sanger method),14,15 the throughput of massively parallel sequencing that uses EFFECT OF HIGH-THROUGHPUT GENOME NGSs16 is increasing dramatically, with the current SEQUENCING ON UNDERSTANDING throughput at 600 GB per run, which means that a suf- THE MOLECULAR BASES OF HEREDITARY ficient amount of sequence data can be obtained for whole- NEUROLOGICAL DISEASES genome sequencing of at least 4 individuals.17 In typical experiments, billions of short reads (100-150 base pairs The strategies for identifying causative genes for heredi- [bp]) are obtained. These short reads are aligned to hu- tary diseases have been well established.5,6 The chromo- man genome reference sequences, and sequence varia- somal localization of the disease-causing genes is pin- tions are called through computational analyses. pointed by linkage analysis using polymorphic DNA Currently, 2 types of sequencing strategy (namely, whole- markers.50-52 Although a number of genes have been iden- exome and whole-genome sequence analyses) are used. Be- tified by applying these technologies, more than 50% of cause the cost of whole-genome sequencing is still consid- the genes causing