Anticipation, the increasing severity or earlier onset of a genetic disorder in successive generations, has been regarded by geneticists as an artefact, probably due to ascertainment bias, ever since the work of Lionel Penrose in 1948. Clinicians, however, have continued to record it in a number of inherited diseased especially myotonic dystrophy, Huntington’s chorea and fragile-X mental retardation. Recent work suggests that the clinicians may well have been right.
Geneticists dismissed anticipation largely because it seemed a kind of Lamarckism and there was no known mechanism for a mutant gene to get worse or to express itself earlier. Gene mutations were regarded as changes from one stable state to another equally stable state. A second reason for rejection was that anticipation had been reported in the early years of this century well before the basic laws of genetics were known. At that time it was often regarded as nature’s way of removing the unfit from the population and was associated with ‘‘degenerates’’, frequently with racial overtones. It is hardly surprising that, in 1948 when memories of the Nazis’ racial theories were fresh, the rejection of anticipation by as influential a geneticist as Penrose was accepted without question.
Within the last two years, a molecular basis for anticipation has been discovered, first in the fragile-X syndrome (Verkerk et al, 1991), and then in myotonic dystrophy (Harper et al, 1992). The biological basis of anticipation is the unstable DNA sequences found in the genes responsible for these disorders. This unstable DNA can increase in length in successive generations and in myotonic dystrophy there is an approximate correlation between this length and both the severity and age of onset. In fragile-X, but not so far in myotonic dystrophy, the unstable DNA can also decrease in size which may partly explain why anticipation is a variable phenomenon.
The presence of inherited unstable DNA in the human genome not only explains anticipation in these two disorders (and perhaps also in Huntington’s chorea); it may also provide answers to some of the other aspects of human genetics which do not fit neatly into classical genetic theory. The discovery that unstable DNA has predictable phenotypic effects adds a new dimension to human genetic research and could lead to a greater understanding of a number of inherited disorders.
References:
Penrose, L S. Ann. Eugenics, v14, p125, 1948.
Verkerk, A J M H et al, Cell, v65, p905,1991.
Harper, P S et al, Amer. J. Hum. Genet., v51, p10, 1992. John Timson