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Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease

Nature Reviews Neuroscience volume 13, pages 453–464 (2012)Cite this article

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Key Points

  • New sequencing technologies have allowed the examination of genetic variability at unprecedented resolution and scale. From testing millions of known markers in thousands of individuals to identifying very rare or novel mutations in smaller cohorts, these technologies have changed how genetics can inform disease phenotype.

  • Whole-genome genotyping has allowed genome-wide association studies to be performed, which have greatly increased our knowledge of how genetics plays a role in common diseases. It is also an efficient method for performing homozygosity mapping to pinpoint pathogenic mutations in recessive kindreds.

  • Whole-exome sequencing has allowed the rapid and cost-effective identification of Mendelian genes. This point is clearly illustrated by the growing list of published papers identifying mutations in these genes.

  • As the costs associated with sequencing continue to fall, whole-genome sequencing will probably replace whole-exome sequencing. However, the ability to make sense of non-coding variability is still limited.

  • The integration of genotyping data with expression and proteomics' results will be necessary for researchers to fully understand the effects of genetic variability (both coding and non-coding).

Abstract

Over the past five years the field of neurogenetics has yielded a wealth of data that have facilitated a much greater understanding of the aetiology of many neurological diseases. Most of these advances are a result of improvements in technology that have allowed us to determine whole-genome structure and variation and to examine its impact on phenotype in an unprecedented manner. Genome-wide association studies have provided information on how common genetic variability imparts risk for the development of various complex diseases. Moreover, the identification of rare disease-causing mutations have led to the discovery of novel biochemical pathways that are involved in disease pathogensis. Here, we review these advances and discuss how they have changed the approaches being used to study neurological disorders.

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Figure 1: Homozygosity mapping using high-density arrays.
Figure 2: Simplified workflows for whole-exome, whole-genome and transcriptome sequencing.
Figure 3: Comparison of whole-exome and whole-genome sequencing results.
Figure 4: Many genes at a single genome-wide association study locus.

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Authors and Affiliations

  1. Reta Lilla Weston Laboratories and Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, WC1N 3BG, London, UK

    Jose Bras, Rita Guerreiro & John Hardy

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  1. Jose Bras
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  2. Rita Guerreiro
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Correspondence to John Hardy.

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Supplementary information

Supplementary information S1 (table)

Genes identified through exome or genome sequencing in neurological or brain-related conditions (PDF 329 kb)

Related links

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FURTHER INFORMATION

John Hardy's homepage

DATABASES

Online Mendelian Inheritance in Man database

Catalogue of published genome-wide association studies

Glossary

Case–control studies

Studies in which genetic variability in genes of interest are compared between a group of cases (for example, patients) and a group of controls from the same population.

Mendelian genes

Genes in which mutations cause disease in a Mendelian manner. The disease can be recessive or dominant in its inheritance mode.

Sporadic diseases

Diseases that occur with no known genetic background and therefore no family history of occurence.

Sanger DNA sequencing

A method used to determine the nucleotides present in a fragment of DNA. It is based on the chain-terminator method developed by Frederick Sanger, but currently uses labelling of the chain-terminator dideoxynucleotides (ddNTPs), which allows sequencing in a single reaction.

Genotyping

A method used to determine the bases (genotypes) present at specific positions in the genome. This can be done for a small number of genotypes or for millions of genotypes spread throughout the genome (using whole-genome genotyping arrays).

Autosomal recessive diseases

Patterns of disease inheritance in which both alleles (one from each parent) need to present the genetic defect for the disease to manifest itself.

Consanguinity

This refers to individuals who are related by blood.

Minor allele frequency

For a single-nucleotide polymorphism this is the frequency of the less frequent allele in a population.

Epistatic interactions

Events that occur when the effects of one gene are modulated by one or several other independent genes.

Odds ratios

Measures of effect size, defined as the ratio of the odds of an event occurring in one group to the odds of it occurring in another group. In the context of a genetic-association study, this might be the odds of major depression occurring in one genotype group against the odds of it occurring in another genotype group.

Genotyping arrays

These are a type of DNA microarray that are used to detect polymorphisms in DNA samples.

Single-nucleotide polymorphisms

(SNPs). The most common form of variation in human DNA sequences. They occur when a single nucleotide (for example, thymine) replaces one of the other three nucleotides (for example, cytosine).

Pseudoexon

A fragment of DNA that has characteristics of an exon, but plays no part in splicing events and thus does not code for a protein sequence.

Copy number variation

A change in the normal number of copies of a given gene/loci. Usually, there are two copies of each locus, but if, for example, duplications or triplications occur the number of copies will increase.

Point mutation

A change in one single nucleotide that occurs very rarely in the population.

Genetic phase

Refers to the allelic combinations that an individual received from its parents. If two alleles originated from the same parent they are said to be in cis phase. If each allele originated from a different parent they are said to be in trans phase.

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Bras, J., Guerreiro, R. & Hardy, J. Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease. Nat Rev Neurosci 13, 453–464 (2012). https://doi.org/10.1038/nrn3271

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