Point Mutations 



193 



induced point-mutation frequency increases 

 taster than linearly with dose — at least for 

 low doses — and an attenuated dose is less 

 mutagenic than a concentrated one. 



Point mutation is not restricted to the 

 genes of any particular kind of cell, occur- 

 ring in males and females, in somatic tissues 

 of all kinds, and in the diploid and haploid 

 cells of the germ line. Later stages in gam- 

 etogenesis and very early developmental 

 stages — perijertilization stages — are found 

 to be relatively rich in spontaneous point 

 mutations. Despite very great differences in 

 life span, one does not find correspondingly 

 great differences in the spontaneous germ 

 line mutation frequencies of flies, mice, and 

 men. This similarity in mutation frequency 

 is not surprising if most of these mutations 

 occur in the perifertilization stages, since 

 each of these organisms spends a comparable 

 length of time in these stages. Still another 

 similarity among these species is the com- 

 parable number of cell divisions required for 

 each to progress from a gamete of one gen- 

 eration to a gamete of the next. In fact, the 

 differences in mutation frequency for these 

 organisms are approximately proportional 

 to the differences in the number of germ 

 cell divisions per generation. 



When during the history of the gene does 

 mutation occur? The finding that the point 

 mutation frequencies in Drosophila, mouse, 

 and man are proportional to the number of 

 cell divisions they undergo suggests that some 

 of these mutations occur at synthesis of the 

 new gene, although the experimental results 

 do not specify whether it is the old or the 

 new gene that mutates. Aging of spermatids 

 and sperm of Drosophila is known to in- 

 crease the point mutation frequency. Since 

 the viability of these cells is not impaired 

 when aneuploid, the increase in point muta- 

 tions may be due to an effect upon the old, 

 physiologically quiescent gene, implying that 

 point mutational changes can occur while a 

 gene is linearly attached to its neighbors. 



The larger number of mutations obtained 

 from aged cells may also be explained as 

 resulting from a mutagen accumulated over 

 a period of time which acts on the old or 

 the new gene once gene replication is re- 

 sumed. The possibility also remains that 

 changes can occur in the steps leading to 

 gene synthesis — before the new gene is com- 

 pleted and attached to its linear neighbors; 

 such changes could be scored later as point 

 mutants. 



Phenotypic Effects of Point Mutants 



The biological fitness of a mutant gene — 

 pure or hybrid — is best described in terms 

 of its effect upon the organism's ability to 

 produce surviving offspring, that is, upon re- 

 productive potential. This potential includes 

 the mutant-carrying individual's capacity to 

 reach the reproductive stage and its fertility 

 and fecundity during this period, as well as 

 the viability of its offspring until sexual ma- 

 turity. Although each mutant has many 

 phenotypic effects, point mutants with small 

 phenotypic effects occur much more fre- 

 quently than those with large effects. For 

 instance, pure (homo- or hemizygous) mu- 

 tants which lower the viability of males with- 

 out being lethal are at least three to five 

 times more frequent than those which are 

 recessively lethal (Figure 13-3). 



The vast majority of point mutants have 

 a detrimental effect on the reproductive 

 potential; beneficial point mutants are 

 extremely rare. In terms of the past 

 evolutionary history of a species, it is under- 

 standable that in the great majority of cases, 

 mutants affecting a trait or organ cause its 

 degeneration. All the genotypes in a species 

 have been subjected to selection for many 

 generations, those producing the greatest re- 

 productive potential having been retained. 

 Although point mutation at any locus is a 

 rare event, many of the possible alternatives 

 for each gene must have occurred at least 

 several times in past history. Of these 



