The variation generated by germline mutation is essential for evolution, but individuals pay a steep price in the form of Mendelian disease and genetic predisposition to complex disease. Indeed, the health of a species is determined ultimately by the rate of germline mutation. Analysis of the factor IX gene in patients with hemophilia B has provided insights into the human germline mutational process. Herein, seven topics will be reviewed with emphasis on recent advances: (i) proposed mechanisms of deletions, inversions, and insertions; (ii) discordant sex ratios of mutation and associated age effects; (iii) somatic mosaicism; (iv) founder effects; (v) mutation rates; (vi) the factor IX gene as a germline mutagen test; and (vii) cancer as a possible mechanism for maintaining a constant rate of germline mutation.
Neurology 1996;46:273-275
For most multifactorial diseases in which twin studies have been performed, the concordance rates in monozygotic twins are substantially higher than the concordance rates in dizygotic twins, although dizygotic twins have a concordance rate substantially higher than the risk of disease in the general population. [1] These data are expected if the disease has a substantial genetic predisposition. In contrast, if environmental effects predominate, concordance rates in monozygotic and dizygotic twins are similar and these rates are higher than the risk among unrelated individuals because twins share a similar environment as children and, as a group, have similar diets, lifestyle, and occupational exposures as adults. [1]
There have been several twin studies in patients with Parkinson's disease (PD) (Table 1). [2-5] Although each study has some methodologic limitations, the conclusions of independent groups sampling different populations are puzzling: The concordance rates for monozygotic and dizygotic twins are equal and similar to the risk of PD in the general population. [6] At face value, these data suggest that neither genetics nor the environment has a role in PD. In the absence of a tenable explanation, many researchers have challenged the accuracy of the twin data. [7,8] Twin studies conducted thus far failed to account fully for heterochrony of disease expression among co-twins, for the possibility of formes frustes (e.g., isolated tremor), and for subclinical PD. In addition, the number of twins was insufficient to permit any definitive conclusion. [7] A recent18 fluorodopa positron emission tomography (PET) study of PD twin pairs has revealed subclinical abnormalities compatible with PD in clinically normal co-twins; [8,9] similar changes were detected by PET in patients with isolated tremor. This study hints that the concordance rate of PD twins may be higher than previously realized if subclinical …
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