High levels of somatic DNA diversity at the myotonic dystrophy type 1 locus are driven by ultra-frequent expansion and contraction mutations
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2012-02-24Autor
Higham, Catherine
Morales Montero, Fernando
Cobbold, Christina
Haydon, Daniel
Monckton, Darren G.
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Several human genetic diseases are associated with inheriting an abnormally large unstable DNA simple sequence
repeat. These sequences mutate, by changing the number of repeats, many times during the lifetime
of those affected, with a bias towards expansion. These somatic changes lead not only to the presence of
cells with different numbers of repeats in the same tissue, but also produce increasingly longer repeats, contributing
towards the progressive nature of the symptoms. Modelling the progression of repeat length
throughout the lifetime of individuals has potential for improving prognostic information as well as providing
a deeper understanding of the underlying biological process. A large data set comprising blood DNA samples
from individuals with one such disease, myotonic dystrophy type 1, provides an opportunity to parameterize
a mathematical model for repeat length evolution that we can use to infer biological parameters of interest.
We developed new mathematical models by modifying a proposed stochastic birth process to incorporate
possible contraction. A hierarchical Bayesian approach was used as the basis for inference, and we estimated
the distribution of mutation rates in the population. We used model comparison analysis to reveal,
for the first time, that the expansion bias observed in the distributions of repeat lengths is likely to be the
cumulative effect of many expansion and contraction events. We predict that mutation events can occur
as frequently as every other day, which matches the timing of regular cell activities such as DNA repair
and transcription but not DNA replication.
External link to the item
10.1093/hmg/dds059
artículo científico (arbitrado)--Universidad de Costa Rica. Instituto de Investigaciones en salud y Escuela de Medicina, 2012. Este artículo es privado debido a limitaciones de derechos de autor.
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