Allelic instability in mitosis: a unified model for dominant disorders.

Abstract

Recent findings indicate that tandemly repeated triplet sequences in certain disease-causing human genes may render these genes highly unstable not only in meiosis but also in mitosis. Typically, a dominant mutation arises upon expansion in the number of these repeated elements. We have considered how mitotic instability of this sort might affect both phenotypic expression and allele transmission. A model based on these considerations leads to the following predictions: (i) Phenotypic severity among individuals who inherit an unstable allele should be highly variable due to stochastic variation in the stage of its earliest mutagenic expansion. (ii) Strikingly increased severity or decreased age of onset in some offspring should arise because of parental germ-line mosaicism for an expanded or mutant allele. (iit) The magnitude of genetic anticipation should be more strongly correlated with paternal than with maternal age at the time of conception. (iv) Given a child born with a severe phenotype, the recurrence risk for a second severely affected child should be significantly elevated. (v) The severity of phenotype in a child should be positively correlated with that in a parent. Available data on fragile X syndrome, Huntington disease, and myotonic dystrophy are shown to be consistent with the model, and implications for an understanding of achondroplasia and other dominant disorders are discussed.

Evidence for genetic anticipation in nodal osteoarthritis

“…When the single paternal/offspring pair was eliminated from the analysis, the correlation between age of symptom onset in the offspring and parental age at conception remained weakly negative but was not statistically significant. This finding is in keeping with the phenomena of genetic anticipation as in some diseases in which unstable trinucleotide repeats have been demonstrated, older fathers tend to have children with a younger age of disease onset 5. This probably reflects ongoing mitosis throughout the lifetime of the paternal germ cells, with increasing chances of unstable premutant alleles expanding over time.…”

“…Evidence exists for a direct correlation between the size of the expansion and the severity of the disease, and an inverse correlation with the age of onset 4. An inverse correlation also exists, in some disorders displaying anticipation, between the parental age of conception and the offspring age of disease onset 5. This correlation is greater with paternal than maternal age and may reflect ongoing mitosis throughout the lifetime of the paternal germ cells, with an increasing chance of unstable alleles expanding over time.…”

Does genetic anticipation occur in familial rheumatoid arthritis?

“…These diseases all demonstrate genetic anticipation to some degree, with earlier age of disease onset and increasing disease severity over the generations correlating with a progressively expanding trinucleotide repeat sequence.2 In both MD and Huntington's disease it has been demonstrated that paternal age at which the patient was conceived is negatively associated with age of onset of the disease.3 While a number of mechanisms may be responsible for this, Zheng et al argue that this reflects the germ cells continuing to divide mitotically (and hence be subject to continued expansion) in the postembryonic state only in males. 3 Recently, genetic anticipation and premutation phenomena have been described in genetically complex diseases such as bipolar affective disorder,4 and psoriasis.5 In this preliminary investigation, we have sought evidence for similar observations in RA.…”

New Hypotheses in the Genetics of Psoriasis and Other ‘Complex’ Diseases

“…Their instabilities and their activations in meiosis could account for genomic imprinting with a paternal effect since the father’s germline cells undergo many more mitoses than the mother’s. This would explain why psoriasis and some other ‘complex diseases’ are more frequently inherited when the father is affected [42,43,44]. It can also be speculated that the activation of repetitive sequences is dependent on their location in genomic DNA – their transcription occurring when they are aberrantly inserted close to an active promoter.…”