The Fundamental Theorem of Neutral Evolution: Rates of Substitution and Mutation Should Factor in Premeiotic Clusters

Woodruff, R. C.; Thomson, J. N.

doi:10.1007/s10709-005-4982-7

Cited by 5 publications

(5 citation statements)

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“…However, our analyses suggest that the effect is likely to be modest and would, for instance, be insufficient to explain the present 2-fold discrepancy between direct and indirect estimates in human studies 17,18 . We confirmed by simulation that the rate of mosaicism does not significantly affect the rate of nucleotide substitution per generation or average fixation time 19 (Suppl. Figure 9).…”

supporting

confidence: 66%

Frequency of mosaicism points towards mutation-prone early cleavage cell divisions in cattle

Harland

Charlier

Karim

et al. 2016

Preprint

101

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It has recently become possible to directly estimate the germ-line de novo 11 mutation (dnm) rate by sequencing the whole genome of father-mother-12 offspring trios, and this has been conducted in human 1-5 , chimpanzee 6 , 13 mice 7 , birds 8 and fish 9 . In these studies dnm's are typically defined as 14 variants that are heterozygous in the offspring while being absent in both 15 parents. They are assumed to have occurred in the germ-line of one of the 16 parents and to have been transmitted to the offspring via the sperm cell or 17 oocyte. This definition assumes that detectable mosaïcism in the parent in 18 which the mutation occurred is negligible.However, instances of 19 detectable mosaïcism or premeiotic clusters are well documented in 20 humans and other organisms, including ruminants 10-12 . We herein take 21advantage of cattle pedigrees to show that as much as ~30% to ~50% of 22 dnm's present in a gamete may occur during the early cleavage cell 23 . CC-BY-NC-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was . http://dx.doi.org/10.1101/079863 doi: bioRxiv preprint first posted online Oct. 9, 2016; Mosaic DNMsPage 2/27 divisions in males and females, respectively, resulting in frequent 24 detectable mosaïcism and a high rate of sharing of multiple dnm's between 25 siblings. This should be taken into account to accurately estimate the 26 mutation rate in cattle and other species. 27To study the process of dnm's in the cattle germ-line, we sequenced the whole 28 genome of 54 animals from four pedigrees. Grand-parents, parents and offspring 29 (referred to as probands) were sequenced at average 26-fold depth (min = 21), 30 and grand-offspring at average 21-fold depth (min = 10). The source of DNA was 31 venous blood for females and sperm for males. The genome of one male proband 32 (Pr 1) was sequenced both from semen (26-fold depth) and blood DNA (37-fold 33 depth) ( Figure 1A). 34Using the standard definition, we identified 190 candidate dnm's as variants that 35 were (i) detected in a proband, (ii) absent in both parents (and grand-parents 36 when available), (iii) transmitted to at least one grand-offspring, and (iv) not 37 previously reported in unrelated individuals from the 1,000 Bulls project 13 38 (Suppl. Figure 1&2 and Suppl. Table 1). For confirmation, we developed 39 amplicons spanning 113 candidate dnm's and sequenced them at average depth 40 of ~2,187 in the 54 animals plus 55 relatives ( Figure 1A). This confirmed the 41 genuine nature of 110/113 variants, demonstrating the excellent specificity of 42 our bioinformatics pipeline. The three remaining ones were also detected in one 43 of the parents (although not in the grand-parents) in the confirmation, and 44 momentarily ignored. 45We first examined what proportion of dnm's detected in a proband might 46 actually have occurred during its development rather than being inherited via 47 . CC-BY-NC-ND 4.0 International license not peer-reviewed) i...

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supporting

confidence: 66%

Frequency of mosaicism points towards mutation-prone early cleavage cell divisions in cattle

Harland

Charlier

Karim

et al. 2016

Preprint

101

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“…However, a detailed understanding of mutation rates along individual development is also indispensable and an integral knowledge of biology and its importance has been widely recognized in medical genetics, particularly in the study of cancer/tumor development. A mutation that occurred early in the development will likely lead to more descendants (somatic or germ cells) than one that occurred later and thus will likely have more impact on the host as well as on its chance of survival in the population (Woodruff et al 1996; Huai and Woodruff 1997; Woodruff and Thompson 2005). Differential mutation rates during development also provide new insights on male-driven evolution (Gao et al 2011).…”

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confidence: 99%

Pattern of Mutation Rates in the Germline of Drosophila melanogaster Males from a Large-Scale Mutation Screening Experiment

Gao

Pan

et al. 2014

G3 Genes|Genomes|Genetics

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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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“…Mutant alleles, however, do not always arise as single events. Clusters of identical mutant alleles have been observed in all tested higher organisms and natural populations and occur for all types of genetic damage (Hall 1988;Woodruff and Thompson 1992;Drost and Lee 1995;Woodruff et al 1996;Huai and Woodruff 1997;Selby 1998;Thompson et al 1998;Woodruff et al 2004;Woodruff and Thompson 2005;Fischer et al 2006). For example, about 20-50% of mutations in Drosophila melanogaster occur in clusters (Mason et al 1985;Woodruff and Thompson 1992;Yang et al 2001).…”

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confidence: 99%

“…Extensive theoretical analysis has confirmed the significant impact that such clusters can have on a population. These premeiotic clusters increase the probability and decrease the time of fixation of new mutant alleles, reduce the cost of natural selection, increase the probability of reproductive isolation due to new mutant alleles, explain at least part of the overdispersed molecular clock, and alter the fundamental theorem of neutral evolution (Woodruff et al 1996;Woodruff 1997, 1998;Woodruff and Thompson 2002;Woodruff et al 2004;Woodruff and Thompson 2005). Because of their potential effect on the gene pool when they occur, a cluster of mutant alleles cannot be ignored or be counted as a single mutation.…”

mentioning

confidence: 99%

“…Mutations occurring at meiosis give rise to a single mutant allele, whereas mutations occurring before meiosis give rise to a premeiotic cluster of mutant alleles. Modified with permission from Woodruff and Thompson (2005). and s 5 0.2, it would take a cluster of size 10 to give about the same probability of fixation for new mutations versus the probability of fixation that depends on standing genetic variation.…”

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confidence: 99%

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Adaptation from Leaps in the Dark

Woodruff

Zhang

2008

Journal of Heredity

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Although many adaptations occur by selection of beneficial alleles transformed from neutral or deleterious standing variation, new identical mutant alleles that arise as premeiotic clusters have an increased probability of fixation that can rise to the levels that are similar to the fixation of standing variation. Hence, the evidence is still out on the proportion of adaptations that use preexisting variation and new mutations.

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The Fundamental Theorem of Neutral Evolution: Rates of Substitution and Mutation Should Factor in Premeiotic Clusters

Cited by 5 publications

References 69 publications

Frequency of mosaicism points towards mutation-prone early cleavage cell divisions in cattle

Frequency of mosaicism points towards mutation-prone early cleavage cell divisions in cattle

Pattern of Mutation Rates in the Germline of Drosophila melanogaster Males from a Large-Scale Mutation Screening Experiment

Adaptation from Leaps in the Dark

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