High levels of somatic DNA diversity at the myotonic dystrophy type 1 locus are driven by ultra-frequent expansion and contraction mutations

Abstract

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.

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

“…As it is reasonable to expect these rates to be randomly distributed throughout the spectrum, the results indicate that the overall model may be improved by introducing a nonlinear response in line with the biological consideration that small alleles may have a reduced propensity to expand and/or contract owing to possible size effects [16].…”

“…From these results, we concluded that mutations at the DM1 locus are ultra-frequent, much more frequent than might be concluded from the net gains or examination of the modal repeat length. In summary, both expansions and contractions have resulted in the characteristic shape of the repeat length distributions [16].…”

“…In [16], we assumed that the likelihood of a mutational event increased linearly with repeat length over a threshold number of repeats and it is this assumption and corresponding function definitions that we will refine in this paper, see the appendix for details. A key modelling assumption is that the cells acquire mutations independently of one another, and this was justified for DM1 blood cells [16]. Our application of the model to another disease and cell type, HD buccal cells, requires the assumption that buccal cells acquire mutations independently of one another.…”

“…The basic model, linearly proportional expansion and contraction over a threshold number of repeats, referred to as M 6b in [16] and here as M, is summarized in the appendix. We develop a new model, M a , by introducing a length-specific effect, R n (n, a), which is a function of repeat length, n, and the distance constraint, a, into model M. The length-specific effect is quantified using a combinatorial counting argument based on the length of the constraint (one interpretation being the distance between loop-outs), denoted as a, and the likelihood that mutation occurs.…”

Parental age effects, but no evidence for an intrauterine effect in the transmission of myotonic dystrophy type 1

“…However, as the DM1 CTG repeat is also highly unstable in the soma, [24][25][26][27][28] this approach frequently yields a diffuse smear for the expanded allele, from which it is only possible to estimate the modal allele length. 4,6,8,[10][11][12][13][14][15][16]20,29 As somatic mosaicism is expansion biased and age dependent, [24][25][26][27][28] the modal allele length thus measured also increases with age. 26 By performing multiple reactions with reduced amounts of input DNA, it is possible to use small pool PCR (SP-PCR) to resolve the diffuse smear into its component alleles 25 and estimate the progenitor allele length (PAL) transmitted from the affected parent.…”