Population genetics of induced mutations

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Abstract
The contribution of induced mutations to the burden of genetic disease in the context of population genetics is considered. A clear distinction is made between the effects of genetic disease and mutational events. Much of the existing burden of genetic disease is a consequence of mutations that occurred in the past. The problem of distinguishing between spontaneous and induced mutations is discussed. Molecular genetics techniques are blurring the definitions of these terms. Classical population genetics shows that the frequency of affected individuals will reach an equilibrium depending on the mutation rate and the selective pressure against affected individuals. Increasing the mutation rate or reducing the selective pressures would result in a new equilibrium with an increase in the frequency in subsequent generations of affected individuals with dominant and X‐linked mutant alleles. The increase in the number of recessive mutant alleles would be much slower and take many generations to reach the new equilibrium level. One assumption behind such equilibria is random mating. Changes in human demography with a rapid increase in population size, the breakup of small, relatively inbred subpopulations, and relaxed selective pressures will lead to a new equilibrium for recessive genes at probably higher frequencies.These factors will be the major contributors to increasing the burden of recessive genetic disease by increasing the total numbers of cases. The proportion of the population with a genetic disease will also continue to grow as a greater proportion of the population survives to late middle age and succumbs to diseases associated with old age, such as cancer, circulatory disease, dementias, and diabetes, each of which is likely to have a genetic component. One area where an increase in mutant heterozygotes may be of concern is when heterozygotes for recessive genes play a part in some of these diseases in later life when selective pressures have little effect. This suggests that the lower concern over the induction of harmful recessive mutations because of the long time span before they become prevalent should be tempered by the possibility that apparently asymptomatic heterozygotes, which will increase much more rapidly than homozygotes, may lead to an increased incidence of genetic disease later in life. The potential of molecular biology to provide a greater insight into the origins and causes of genetic mutations as well as to provide more accurate estimates of the true spontaneous and induced mutation rates is stressed.