Premeiotic clusters of mutation and the cost of natural selection

Haldane stated that there is a cost of natural selection for new beneficial alleles to be substituted over time. Most of this cost, which leads to "genetic deaths," is in the early generations of the substitution process when the new allele is low in frequency. It depends on the initial frequency and dominance value, but not the selection coefficient, of the advantageous allele. There have been numerous suggestions on how to reduce the cost for preexisting genetic variation that goes from disadvantageous, or neutral, to advantageous with a change in the environment. However, the cost of natural selection for new alleles that arise by mutation is assumed to be high, based on the assumption that new mutant alleles arise in natural populations as single events [1/(2N) of the total alleles]. However, not all mutant alleles arise as single events. Premeiotic mutations occur frequently in individuals (germinal mosaics), giving rise to multiple copies of identical mutant alleles called a "cluster" (C) with an initial allele frequency of C/(2N) instead of 1/(2N). These clusters of new mutant alleles reduce the cost of natural selection in direct proportion to the relative size of the cluster. Hence new advantageous alleles that arise by mutation have the greatest chance of going to fixation if they occur in large clusters in small populations.     

Elevated Mutagenicity in Meiosis and Its Mechanism

Diploid germ cells produce haploid gametes through meiosis, a unique type of cell division. Independent reassortment of parental chromosomes and their recombination leads to ample genetic variability among the gametes. Importantly, new mutations also occur during meiosis, at frequencies much higher than during the mitotic cell cycles. These meiotic mutations are associated with genetic recombination and depend on double‐strand breaks (DSBs) that initiate crossing over. Indeed, sequence variation among related strains is greater around recombination hotspots than elsewhere in the genome, presumably resulting from recombination‐associated mutations. Significantly, enhanced mutagenicity in meiosis may lead to faster divergence during evolution, as germ‐line mutations are the ones that are transmitted to the progeny and thus have an evolutionary impact. The molecular basis for mutagenicity in meiosis may be related to the repair of meiotic DSBs by polymerases, or to the exposure of single‐strand DNA to mutagenic agents during its repair.     

Bottleneck Effect on Evolutionary Rate in the Nearly Neutral Mutation Model

Variances of evolutionary rates among lineages in some proteins are larger than those expected from simple Poisson processes. This phenomenon is called overdispersion of the molecular clock. If population size N is constant, the overdispersion is observed only in a limited range of 2Nσ under the nearly neutral mutation model, where σ represents the standard deviation of selection coefficients of new mutants. In this paper, we investigated effects of changing population size on the evolutionary rate by computer simulations assuming the nearly neutral mutation model. The size was changed cyclically between two numbers, N(1) and N(2) (N(1) > N(2)), in the simulations. The overdispersion is observed if 2N(2)σ is less than two and the state of reduced size (bottleneck state) continues for more than ~0.1/u generations, where u is the mutation rate. The overdispersion results mainly because the average fitnesses of only a portion of populations go down when the population size is reduced and only in these populations subsequent advantageous substitutions occur after the population size becomes large. Since the fitness reduction after the bottleneck is stochastic, acceleration of the evolutionary rate does not necessarily occur uniformly among loci. From these results, we argue that the nearly neutral mutation model is a candidate mechanism to explain the overdispersed molecular clock.     

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

Mutations do not always arise as single events. Many new mutations actually occur in the cell lineage before germ cell formation or meiosis and are therefore replicated premeiotically. The increased likelihood of substitutions caused by these clusters of new mutant alleles can change the fundamental theorem of neutral evolution.     

Adaptation from leaps in the dark

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.     

The CYCLIN-A CYCA1;2/TAM Is Required for the Meiosis I to Meiosis II Transition and Cooperates with OSD1 for the Prophase to First Meiotic Division Transition

Meiosis halves the chromosome number because its two divisions follow a single round of DNA replication. This process involves two cell transitions, the transition from prophase to the first meiotic division (meiosis I) and the unique meiosis I to meiosis II transition. We show here that the A-type cyclin CYCA1;2/TAM plays a major role in both transitions in Arabidopsis. A series of tam mutants failed to enter meiosis II and thus produced diploid spores and functional diploid gametes. These diploid gametes had a recombined genotype produced through the single meiosis I division. In addition, by combining the tam-2 mutation with AtSpo11-1 and Atrec8, we obtained plants producing diploid gametes through a mitotic-like division that were genetically identical to their parents. Thus tam alleles displayed phenotypes very similar to that of the previously described osd1 mutant. Combining tam and osd1 mutations leads to a failure in the prophase to meiosis I transition during male meiosis and to the production of tetraploid spores and gametes. This suggests that TAM and OSD1 are involved in the control of both meiotic transitions.     

Dimerization of presenilin-1 in vivo: suggestion of novel regulatory mechanisms leading to higher order complexes

A growing body of evidence indicates that presenilins could exist and be active as oligomeric complexes. Using yeast two-hybrid and cell culture analysis, we provide evidence that presenilin-1 (PS1) may self-oligomerize giving rise to specific full-length/full-length homodimers. When expressed in N2A and HEK239T cultured cells, full-length PS1-wt and 5(')myc-PS1-wt form specific homodimers corresponding to twice their molecular weight. The Alzheimer's disease-associated PS1 mutations Y115H, M146L, L392V, deltaE10(PS1(1-289/320-467)), the gamma-secretase dominant negative mutant D257A, and the PS1 polymorphism mutant E318G do not affect their ability to self-oligomerize. Under non-denaturing conditions, endogenous PS1 forms specific homo-oligomers in human cultured cells. The results obtained herein suggest that PS1 associates intramolecularly to form higher order complexes, which may be needed for endoproteolytic cleavage and/or gamma-secretase-associated activity.     

Mate choice among yeast gametes can purge deleterious mutations

Meiosis in Saccharomyces yeast produces four haploid gametes that usually fuse with each other, an extreme form of self-fertilization among the products of a single meiosis known as automixis. The gametes signal to each other with sex pheromone. Better-quality gametes produce stronger signals and are preferred as mates. We suggest that the function of this signalling system is to enable mate choice among the four gametes from a single meiosis and so to promote the clearance of deleterious mutations. To support this claim, we construct a mathematical model that shows that signalling during automixis (i) improves the long-term fitness of a yeast colony and (ii) lowers its mutational load. We also show that the benefit to signalling is greater with larger numbers of segregating mutations.     

A strategy for generating rice apomixis by gene editing

Apomixis is an asexual reproduction way of plants that can produce clonal offspring through seeds.In this study, we introduced apomixis into rice(Oryza sativa) by mutating OsSPO11-1, OsREC8, OsOSD1,and OsMATL through a CRISPR/Cas9 system. The quadruple mutant showed a transformation from meiosis to mitosis and produced clonal diploid gametes. With mutated Osmatl, which gives rise to haploid induction in plants,the quadruple mutant is expected to be able to be produced apomictic diploid offspring. We named this quadruple mutant as AOP(Apomictic Offspring Producer)for its ability to produce apomictic offspring.     

Clusters of identical new mutation in the evolutionary landscape

In contrast to the common assumption that each new mutant results from a unique, independent mutation event, clusters of identical premeiotic mutant alleles are common. Clusters can produce large numbers of related individuals carrying identical copies of the same new genetic change. By entering the gene pool in multiple copies at one time, clusters can influence fundamental processes of population genetics. Here we report evidence that clusters can increase the arrival and fixation probabilities and can lengthen the average time to extinction of new mutations. We also suggest it may be necessary to reconsider other fundamental elements of population genetic theory.     

Understanding the overdispersed molecular clock

Rates of molecular evolution at some protein-encoding loci are more irregular than expected under a simple neutral model of molecular evolution. This pattern of excessive irregularity in protein substitutions is often called the "overdispersed molecular clock" and is characterized by an index of dispersion, R(T) > 1. Assuming infinite sites, no recombination model of the gene R(T) is given for a general stationary model of molecular evolution. R(T) is shown to be affected by only three things: fluctuations that occur on a very slow time scale, advantageous or deleterious mutations, and interactions between mutations. In the absence of interactions, advantageous mutations are shown to lower R(T); deleterious mutations are shown to raise it. Previously described models for the overdispersed molecular clock are analyzed in terms of this work as are a few very simple new models. A model of deleterious mutations is shown to be sufficient to explain the observed values of R(T). Our current best estimates of R(T) suggest that either most mutations are deleterious or some key population parameter changes on a very slow time scale. No other interpretations seem plausible. Finally, a comment is made on how R(T) might be used to distinguish selective sweeps from background selection.     

A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling

Large scale sequencing of the human mu-opioid receptor (hMOR) gene has revealed polymorphic mutations that occur within the coding region. We have investigated whether the mutations N40D in the extracellular N-terminal region, N152D in the third transmembrane domain, and R265H and S268P in the third intracellular loop alter functional properties of the receptor expressed in mammalian cells. The N152D receptor was produced at low densities. Binding affinities of structurally diverse opioids (morphine, diprenorphine, DAMGO and CTOP) and the main endogenous opioid peptides (beta-endorphin, [Met]enkephalin, and dynorphin A) were not markedly changed in mutant receptors (<3-fold). Receptor signaling was strongly impaired in the S268P mutant, with a reduction of efficacy and potency of several agonists (DAMGO, beta-endorphin, and morphine) in two distinct functional assays. Signaling at N40D and R265H mutants was highly similar to wild type, and none of the mutations induced detectable constitutive activity. DAMGO-induced down-regulation of receptor-binding sites, following 20 h of treatment, was identical in wild-type and mutant receptors. Our data show that natural sequence variations in hMOR gene have little influence on ligand binding or receptor down-regulation but could otherwise modify receptor density and signaling. Importantly, the S268P mutation represents a loss-of-function mutation for the human mu-opioid receptor, which may have an incidence on opioid-regulated behaviors or drug addiction in vivo.     

Aging as a metagenetic process

Genomes of eukaryotic cells are so complicated that spontaneous processes lead inevitably to a continuous formation of egoistic genetic elements from the normal ones. These elements convert the intracellular Cosmos into Chaos and therefore they can be named chaonogenes. They behave as endogenous genetic parasites and are able to evaluate. The rate of their evolution is very rapid, which unevitably results in senescence and death of not only cells and multicellular organisms but also of populations and species, because chaonogens are transmitted from somatic cells to gametes. Populations of chaonogenes are very sensitive to environmental changes, and different sets of intracellular or extracellular changes are commonly used in nature to put obstracles in deleterious evolution of chaonogenes or to stop their evolution. These changes can be moderate (as at mitosis) or crude (as at meiosis), or they can be predicted (as programmed biochemical changes in the course of mitosis, meiosis and gametogenesis) or unpredicred (mutations, somatic crossingover, random association of gamets), but in all the cases they lead eventually to some degree of rejuvenation. In somatic cell populations, the process of senescence in slowed down by means of epigenetically determined changes and mitotic divisions, at which both kinds of changes (programmed and accidental) are moderate, and for this reason only a small part of dividing cells dies. At meiosis both kinds of changes are so acute that the majority of cells die, but the formation of gametes and zygotes becomes almost completely rejuvenated. Only mutations leading to very acute changes in intracellular conditions (whose products act on chaonogenes similarly as new antibiotics on bacteria) can save aging populations of multicellular organisms from death (as do L. N. Gumilev's "mutations of passionarity"), and only accidentally appearing "catastrophic" macromutations can give rise to new (and, of the same time, young) species. It is concluded that the induction of acute temporal biochemical changes in the inner environment is to slow down processes of human senescence and to lead to rejuvenation.     

Somatic immunoglobulin sequence divergence and its implications for studies of evolutionary divergence

The divergence of immunoglobulin genes due to somatic mutation provides a natural example of DNA sequence divergence. This divergence was examined to gain insight into the processes of evolution and the determinants of the variance-to-mean ratio of sequence divergence. Normally, this ratio is found to be larger than expected (1.0 under Poisson assumptions) for the evolutionary divergence or most genes. Although not significantly less than one, all seven groups of immunoglobulin amino acid sequences have ratios smaller than expected, contrary to the evolutionary pattern generally observed. The substitutions in the immunoglobulin genes appear to be highly nonrandom and an excess of parallel changes (the major nonrandom feature of these mutations) is shown to cause smaller ratios. Because convergent or parallel mutations are often observed in the evolutionary divergence of genes, this suggests that forces causing the large observed ratios may actually have to be more powerful than previously expected. Further, since selection is one of the likely causes of parallel mutations, it should be noted that selection could significantly decrease the variance-to-mean ratio. The high frequency of parallel mutations and their resulting effects, as observed in the immunoglobulin genes, suggest that only poor inferences of sequence divergence can be made without actual knowledge of the ancestral sequence.     

Separation of meiotic and mitotic effects of claret non-disjunctional on chromosome segregation in Drosophila.

The claret (ca) locus in Drosophila encodes a kinesin-related motor molecule that is required for proper distribution of chromosomes in meiosis in females and in the early mitotic divisions of the embryo. Here we demonstrate that a mutant allele of claret non-disjunctional (ca(nd)), non-claret disjunctional Dominant (ncdD), causes abnormalities in meiotic chromosome segregation, but is near wild-type with respect to early mitotic chromosome segregation. DNA sequence analysis of this mutant allele reveals two missense mutations compared with the predicted wild-type protein. One mutation lies in a proposed microtubule binding region of the motor domain and affects an amino acid residue that is conserved in all kinesin-related proteins reported to date. This region of the motor domain can be used to distinguish meiotic and mitotic motor function, defining an amino acid sequence criterion for classifying motors according to function. ncdD's mutant meiotic effect, but near wild-type mitotic effect, suggests that interactions of the ca motor protein with spindle microtubules differ in meiosis and mitosis.     

Herbivory could unlock mutations sequestered in stratified shoot apices of genetic mosaics

Many higher plants have shoot apical meristems that possess discrete cell layers, only one of which normally gives rise to gametes following the transition from vegetative meristem to floral meristem. Consequently, when mutations occur in the meristems of sexually reproducing plants, they may or may not have an evolutionary impact, depending on the apical layer in which they reside. In order to determine whether developmentally sequestered mutations could be released by herbivory (i.e., meristem destruction), a characterized genetic mosaic was subjected to simulated herbivory. Many plants develop two shoot meristems in the leaf axils of some nodes, here referred to as the primary and secondary axillary meristems. Destruction of the terminal and primary axillary meristems led to the outgrowth of secondary axillary meristems. Seed derived from secondary axillary meristems was not always descended from the second apical cell layer of the terminal shoot meristem as is expected for terminal and primary shoot meristems. Vegetative and reproductive analysis indicated that secondary meristems did not maintain the same order of cell layers present in the terminal shoot meristem. In secondary meristems reproductively sequestered cell layers possessing mutant cells can be repositioned into gamete-forming cell layers, thereby adding mutant genes into the gene pool. Herbivores feeding on shoot tips may influence plant evolution by causing the outgrowth of secondary axillary meristems.     

Fixation probabilities for advantageous mutants: a note on multiplication and sampling

If the average number of gametes produced by the individual is small, as may be the case for haploid organisms, then sampling with and without replacement can lead to considerable differences in the fixation probabilities of mutant alleles. As a function of the population size N, these probabilities converge quickly to the survival probabilities given by branching processes with Poisson or Bernoulli offspring distributions.