Genetic Modifiers of Neurological Disease

Abstract

Genetic modifiers make a significant contribution to the pathophysiology of neurological disease. A common feature of heritable neurological disease is phenotype variation among patients with the same mutation. Some of the observed phenotype variation can be attributed to genetic modifiers. Identifying modifier genes in humans is challenging due to limitations of sample size and confounding environmental effects. Complementary approaches in model organisms can facilitate the identification and characterisation of modifier genes. Identifying genetic modifiers can help elucidate the genetic and molecular basis of neurological disease. This knowledge can be used to improve genetic risk assessment and foster the development of personalised therapeutic strategies based on molecular diagnosis.

Key Concepts:

  • Genetic modifiers contribute to phenotype variability in neurological disorders.

  • Model organisms are a useful system for identifying modifier genes and studying underlying mechanisms.

  • Synergy between human genetics and model systems can facilitate modifier gene identification and validation.

  • Identifying pathways that are influenced by gene modifiers may suggest novel therapeutic strategies.

Keywords: modifier gene; genetics; neurological disease; nervous system disease; disease models; mice

Figure 1.

Integrated approach to identifying genetic modifiers of neurological disease. Primary neurological disease genes that have been identified in human patients can be introduced into model systems using available genetic tools. Model organisms can be used to screen for genetic modifiers that influence the phenotype. Genetic modifiers identified in model systems can then be tested for disease association in humans. Similarly, genetic modifiers identified in humans can be confirmed and studied in model systems.

Figure 2.

Genetic modifiers in mouse models. Systematic crossing of mouse models to different inbred strain backgrounds can reveal strain‐dependent phenotype variation, providing evidence that genetic modifiers contribute to phenotype expression. For this approach it is common to perform a strain survey, in which a mouse mutant (m/+, white) is crossed to wild‐type mice from different inbred strain backgrounds colors. F1 mutant offspring are examined for differences in phenotype compared to the mutant phenotype on the parental strain. Phenotype exacerbation or improvement provides suggestive evidence that an inbred strain carries modifier alleles. If the inbred strain background does not carry modifier variants, the phenotype will be unaltered.

Figure 3.

Interval‐specific congenic strains for fine mapping of modifier genes. The mapped interval from the strain carrying the modifier locus (donor, blue) is introgressed onto the unmodified strain background (recipient, red) by selective genotyping and breeding for at least five generations. Several lines carrying varying segments of the modifier interval are tested for the ability to modify the mutant phenotype in order to localise the critical interval. Line C (light blue) confers the modified phenotype, localising the modifier to the small region that is nonoverlapping with line B (star).

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Further Reading

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Van Ham TJ, Breitling R, Swertz MA et al. (2009) Neurodegenerative diseases: lessons from genome‐wide screens in small model organisms. EMBO Molecular Medicine 1(8–9): 360–370.

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Kearney, Jennifer A, and Jorge, Benjamin S(Apr 2012) Genetic Modifiers of Neurological Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023856]