178 MUTATIONS 



altering the mechanism of rephcation of chromosomes and their genes, 

 or of their mitotic (or meiotic) separation. It is reasonable to sup- 

 pose that most drugs, were they to cause mutations, would do so in 

 this second way. This in turn suggests that during periods of rapid 

 cell division in the germ line the hazards of this type of chemical 

 mutagen should be especially great, and conversely, that during periods 

 of dormancy in the germ line the risk should be diminished. 



The main reason for trying to define periods of relative safety or 

 hazard is that if such an analysis were valid in man it would dictate 

 practical approaches to the reduction of genetic hazards of this type. 

 Can we make any quantitative estimates of the relative importance 

 of the various periods in human life? This is attempted in Figure 25, 

 for the male. The diagram depicts schematically from left to right 

 the period of about 30 years from zygote to zygote. Period 1 occupies 

 the first 3 months of fetal life, during which the zygote gives rise to 

 all the somatic cells as well as to an established line of primordial 

 germ cells (primary spermatogonia). The actual migration of early 

 germ cells into the gonadal areas and their rapid multiplication there 

 occupies a fairly brief period at about the sixth to eighth week of 

 fetal life. In the female, further differentiation to oocytes proceeds, 

 followed (it is thought) by dormancy throughout childhood and 

 thereafter until the final reduction divisions are completed, one ovum 

 at a time, during reproductive life. In the male it is probable that 

 stem cell divisions occur regularly (36) with degeneration of cells before 

 they reach the spermatozoon stage, throughout childhood (Period 2). 

 At puberty the regular maturation and shedding of sperm begins and 

 continues throughout reproductive life (Period 3), during which stem 

 cells continue to give rise, through unequal divisions, to sperm clones 

 and to more stem cells. Period 4 covers the maturation of any given 

 sperm clone. 



What is the probability, P, that a given sperm will be mutant with 

 respect to a particular gene? It is the product of the probability of 

 mutation of that gene per cell cycle by the number of times it has 

 been at risk in the replication process, i.e., the number of cell 

 divisions in the lineage of that sperm all the way back to the zygote, 

 or at least to the differentiation of germ cells in the young fetus. 



Let po be the probability that replication of a given gene in the 

 presence of a standard concentration (e.g., 1 M) of mutagen will lead 

 to one mutant progeny. I shall assume that for chemical mutagens, as 

 for radiation, there is a concentration effect, and that this is linear. 

 There is good evidence for a concentration effect in Novick's work 



