Modelling and inference reveal nonlinear length-dependent suppression of somatic instability for small disease associated alleles in myotonic dystrophy type 1 and Huntington disease

Higham, C. and Monckton, D. (2013) Modelling and inference reveal nonlinear length-dependent suppression of somatic instability for small disease associated alleles in myotonic dystrophy type 1 and Huntington disease. Journal of the Royal Society: Interface, 10(88), p. 20130605. (doi:10.1098/​rsif.2013.0605)

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Abstract

More than 20 human genetic diseases are associated with inheriting an unstable expanded DNA simple sequence tandem repeat, for example, CTG (cytosine–thymine–guanine) repeats in myotonic dystrophy type 1 (DM1) and CAG (cytosine–adenine–guanine) repeats in Huntington disease (HD). These sequences mutate by changing the number of repeats not just between generations, but also during the lifetime of affected individuals. Levels of somatic instability contribute to disease onset and progression but as changes are tissue-specific, age- and repeat length-dependent, interpretation of the level of somatic instability in an individual is confounded by these considerations. Mathematical models, fitted to CTG repeat length distributions derived from blood DNA, from a large cohort of DM1-affected or at risk individuals, have recently been used to quantify inherited repeat lengths and mutation rates. Taking into account age, the estimated mutation rates are lower than predicted among individuals with small alleles (inherited repeat lengths less than 100 CTGs), suggesting that these rates may be suppressed at the lower end of the disease-causing range. In this study, we propose that a length-specific effect operates within this range and tested this hypothesis using a model comparison approach. To calibrate the extended model, we used data derived from blood DNA from DM1 individuals and, for the first time, buccal DNA from HD individuals. In a novel application of this extended model, we identified individuals whose effective repeat length, with regards to somatic instability, is less than their actual repeat length. A plausible explanation for this distinction is that the expanded repeat tract is compromised by interruptions or other unusual features. We quantified effective length for a large cohort of DM1 individuals and showed that effective length better predicts age of onset than inherited repeat length, thus improving the genotype–phenotype correlation. Under the extended model, we removed some of the bias in mutation rates making them less length-dependent. Consequently, rates adjusted in this way will be better suited as quantitative traits to investigate cis- or trans-acting modifiers of somatic mosaicism, disease onset and progression.

Item Type:Articles (Other)
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Higham, Dr Catherine and Monckton, Professor Darren
Authors: Higham, C., and Monckton, D.
Subjects:Q Science > QA Mathematics
Q Science > QH Natural history > QH426 Genetics
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Science and Engineering > School of Mathematics and Statistics
Journal Name:Journal of the Royal Society: Interface
Publisher:The Royal Society
ISSN:1742-5689
ISSN (Online):1742-5662

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