Each cell of higher organism adults is derived from a fertilized egg through a series of divisions, during which mutations can occur. Both the rate and timing of mutations can have profound impacts on both the individual and the population, because mutations that occur at early cell divisions will affect more tissues and are more likely to be transferred to the next generation. Using large-scale multigeneration screening experiments for recessive lethal or nearly lethal mutations of Drosophila melanogaster and recently developed statistical analysis, we show for male D. melanogaster that (i) mutation rates (for recessive lethal or nearly lethal) are highly variable during germ cell development; (ii) first cell cleavage has the highest mutation rate, which drops substantially in the second cleavage or the next few cleavages; (iii) the intermediate stages, after a few cleavages to right before spermatogenesis, have at least an order of magnitude smaller mutation rate; and (iv) spermatogenesis also harbors a fairly high mutation rate. Because germ-line lineage shares some (early) cell divisions with somatic cell lineage, the first conclusion is readily extended to a somatic cell lineage. It is conceivable that the first conclusion is true for most (if not all) higher organisms, whereas the other three conclusions are widely applicable, although the extent may differ from species to species. Therefore, conclusions or analyses that are based on equal mutation rates during development should be taken with caution. Furthermore, the statistical approach developed can be adopted for studying other organisms, including the human germ-line or somatic mutational patterns.within-host coalescent | mutation cluster | likelihood

The sperm or eggs of sexual organisms go through a series of cell divisions from the fertilized egg; mutations can occur at each division. Mutations in the lineage of cells leading to the sperm or eggs are of particular importance because many such mutations may be shared by somatic tissues and also may be inherited, thus having a lasting consequence. For decades, little has been known about the pattern of the mutation rates along the germline development. Recently it was shown from a small portion of data that resulted from a large-scale mutation screening experiment that the rates of recessive lethal or nearly lethal mutations differ dramatically during the germline development of Drosophila melanogaster males. In this paper the full data set from the experiment and its analysis are reported by taking advantage of a recent methodologic advance. By analyzing the mutation patterns with different levels of recessive lethality, earlier published conclusions based on partial data are found to remain valid. Furthermore, it is found that for most nearly lethal mutations, the mutation rate at the first cell division is even greater than previous thought compared with those at other divisions. There is also some evidence that the mutation rate at the second division decreases rapidly but is still appreciably greater than those for the rest of the cleavage stage. The mutation rate at spermatogenesis is greater than late cleavage and stem-cell stages, but there is no evidence that rates are different among the five cell divisions of the spermatogenesis. We also found that a modestly biased sampling, leading to slightly more primordial germ cells after the eighth division than those reported in the literature, provides the best fit to the data. These findings provide conceptual and numerical basis for exploring the consequences of differential mutation rates during individual development.

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Mutator activity associated with the common male recombination (MR) chromosomes in Drosophila melanogaster appears to be suppressed in natural populations. Crosses between geographically separated populations, however, lead to the release of mutator activity as measured by a significant increase in visible mutations. Such an increase in mutation in hybrid individuals may be a powerful factor in inducing or releasing variation in nature, and in more extreme instances may contribute to the separation of microdifferentiated populations. Although genetic variation provides the basis for adaptation to changing environments, an incomplete picture of adaptability is given by measuring levels of variation alone. It is incomplete because it assumes that the rate at which new variants are produced in natural populations is low and essentially constant-assumptions that have been brought into question by studies of mutator factors in Drosophila melanogaster (1-4).Although it is clear that various environmental and genetic factors can influence mutation rates (5), genetic factors have been difficult to study because of the technical problems involved in their identification and in the measurement of their activity in natural populations. Recently, however, the study of mutator activity has been given a significant boost. Hiraizumi (6) found that, contrary to common belief, low levels of recombination can occur in the hybrid male progeny of some wild-caught Drosophila melanogaster strains crossed to laboratory marker stocks. Male recombination (MR) was subsequently found to be correlated with mutator activity, chromosome breakage, hybrid sterility, distortion of segregation, and other genetic events (2, 7). Thus, MR can be used as a simple assay for mutator strains, providing a unique opportunity to survey mutator activity in natural populations. One of the most surprising discoveries to come from these surveys is the finding that the factors responsible for MR activity are extremely common in nature, being found world-wide in up to 100% of the wild isofemale strains tested (2).In considering their potential impact upon the genetic structure of natural populations, a second important discovery was that the activity of mutators appears to be genetically suppressed within any particular population (4,8). Upon crossing a wild strain and a laboratory stock, however, suppression breaks down, resulting in the release of mutator activity and an explosive increase in genetic variation. This breakdown in suppression of mutator activity has been called hybrid release (4). MATERIALS AND METHODSThe objective of this study was to measure the spontaneous mutation rate of sex-linked visible mutations in sampled natural populations and in hybrids produced by crossing individuals from these populations. The following wild-caught isofemale lines were used: M-4 (collected by P. A. Parsons, Melbourne,

The superoxide dismutases (SODs) protect oxygen-using cells against reactive oxygen species, the potentially toxic by-products of respiration, oxidative metabolism, and radiation. We have previously shown that genetic disruption of CuZn SOD (SOD1) in Drosophila imparts a recessive phenotype of reduced lifespan, infertility, and hypersensitivity to oxidative stress. We now show that the absence of SOD1 increases spontaneous genomic damage. The increase in spontaneous mutation rate occurs in SOD1-null mutants in somatic cells as well as in the germ line. Further, we show that specific DNA repair-defective mutations, which are easily tolerated in SOD1(+) flies, lead to high mortality when introduced into the SOD1-null homozygous mutant background.