Highly variable recessive lethal or nearly lethal mutation rates during germ-line development of male Drosophila melanogaster

Abstract

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

Statistical Methods for Analyzing Drosophila Germline Mutation Rates

“…The recessive lethality d of a recessive mutation is defined as one minus the maximal percentage of the homozygote (among all survival offspring) for that mutation. The data reported by Gao et al (2011) correspond to those mutations with recessive lethality equal to 99%, that is, no more than 1% of survival offspring are z/z homozygote. Once a cell acquires a mutation with recessive lethality d, further mutation(s) is much more likely to increase lethality than to reverse it.…”

“…For Drosophila, multigeneration mutation screening has been well developed (Muller 1928;Woodruff et al 1984Woodruff et al , 1996Ashburner 1989;Greenspan 1997) and one such system was used by Gao et al (2011) for the purpose of identifying recessive lethal or nearly lethal mutations. More experimental detail can be found in Gao et al (2011) and for the main purpose of this article, it should suffice to outline the structure of information and the type of mutation being examined. The recessive lethality d of a recessive mutation is defined as one minus the maximal percentage of the homozygote (among all survival offspring) for that mutation.…”

“…Thus, if sperm are sampled after the 36th division, all have experienced exactly 36 divisions, but if they are sampled after, for example, the 38th division, some would have experienced 36 divisions, some 37, and some 38 divisions. The algorithm developed by Gao et al (2011), using the principle of coalescence (Kingman 1982;Ewens 2004), does not account for these differences.…”

“…This is partly due to the scarcity of appropriate experimental data and to lack of proper statistical methods for analyzing such data. Recently, Gao et al (2011) reported that mutation rates differ dramatically during germline development in Drosophila, with the rate for the first cell division the highest. But the method developed by Gao et al (2011) is limited to handling only families with at most two mutations each.…”

“…Recently, Gao et al (2011) reported that mutation rates differ dramatically during germline development in Drosophila, with the rate for the first cell division the highest. But the method developed by Gao et al (2011) is limited to handling only families with at most two mutations each. Also, their conclusions relied heavily on hypothesis testing and the statistical properties of the likelihood-ratio test they used are not known under such circumstances.…”