Near-neutrality in evolution of genes and gene regulation

“For example, the shape of the DFE influences the expected minor allele frequency of polymorphisms underlying complex traits (Eyre-Walker 2010), which may help explain the enrichment of low-frequency variants underlying metabolomic profiles for loblolly pine (Ohta 2002; Eckert et al. 2012).”

“Neutral evolution is considered the null model of molecular evolution against which the effects of selection can be distinguished [22-24].”

“Most current comparative genomics approaches to identify and classify functional regions are built on this paradigm (Waterston et al. 2002; Cooper et al. 2005; Siepel et al. 2005; Margulies et al. 2007; Pheasant and Mattick 2007; Eory et al. 2010; Goode et al. 2010; Pollard et al. 2010).”

“Ohta (2002, p. 16134) used another threshold still: ‘ The nearly neutral mutations are de fi ned such that their fate in the population depends on both selection and drift.”

“In this section, let us consider why such a large fraction of mutations both at the protein level and at the level of gene regulation are subject to weak selection.”

“However, the effectiveness of purifying selection on slightly deleterious mutations depends on the effective population size, being more effective in larger populations (Ohta 1973, 1976, 2002).”

“These differences also have parallels in regularity of sequencemotif usage,with species showing different levels of preference in codon usage (Sharp and Li 1987), consistency of regulatory sequences (Ohta 2002), and diversity of genic start and stop signals (e.”

“The evolution of Listeria sensu stricto sigB can therefore be more reasonably explained by the nearly neutral theory (48, 49).”

“…(positive) selection on the innate immune genes may fluctuate in space and time, depending on the selective pressures exerted by pathogens, purifying selection is a constant evolutionary force that preserves the functionality of these genes (Kimura & Ohta, 1969; Ohta, 2002; Mukherjee et al., 2009).”

“Traditionally, in population genetics and models based on continuous traits, the weak selection limit assumes very small differences between strategic agents or alleles resulting in small selective advantage (Kimura 1968; Ohta 2002).”

“Therefore, deficient purifying selection and accumulation of slightly deleterious substitutions by drift (Ohta, 2002), as predicted by the MA hypothesis, is a more parsimonious explanation for the observed IELC signal.”

“Changes in gene functions, in particular after gene duplication, can arise either due to changes in gene expression, through the action of positive selection or by the relaxation of selective constraints (Ohno, 1999; Ohta, 2002).”

“According to the “nearly neutral” theory of molecular evolution, the efficiency with which slightly deleterious variants can be removed from populations is predicted to depend on the extent of recombination and on effective population size (Ohta 1973, 2002; Lynch 2007; Hughes 2008).”

“We agree that these issues are complex, and that there are many competing considerations (see for example [29], or [30]).”

“…the advent of ribosome profiling has allowed the discovery of many neutrally evolving and potentially non-functional smORFs undergoing pervasive translation, whose significance remains to be determined (Crappé et al., 2013; Aspden et al., 2014; Bazzini et al., 2014; Olexiouk et al., 2016).”

“Thus, small intensities of selection seem to be biologically highly relevant (Ohta, 2002).”

“Thus, according to her publications (Ohta 1973, 1992, 2002), a substantial fraction of changes is caused by random fixation of nearly neutral changes, a class that includes intermediates between neutral and advantageous, as well as between neutral and deleterious classes, although other population…”

“Weak selection means that the fitness difference between the states is small, R − 1 1 (Ohta, 2002).”

“Ohta proposed the near-neutrality theory of evolution, in which mutation, genetic drift, and selection act simultaneously in evolution (Ohta 2002), which may be able to explain the evolution of ALDH2.”

“turnover of transcription factor binding sites (Ludwig 2002; Ohta 2002; Lusk and Eisen 2010).”

“This weak selection assumption is the mathematical articulation of the broadly held belief by evolutionary biologists that selection forces are typically small, and thus evolution is nearly neutral (47).”

“The ability of transcriptional regulatory regions to undergo rapid sequence divergence while retaining function is well established (reviewed in Ohta 2002; Tautz 2000).”

“The cause of this rapid evolution could be attributed to adaptation to 349 the humid and warm environment of Yakushima Island, island effects, and/or a population bottleneck 350 as predicted by the nearly neutral theory (Ohta, 2002).”

“…have no effect (King & Jukes, 1969), that the majority of the genome is non-functional and thus the majority of mutations are of no effect (Ohno, 1972), and that the majority of the genome consists of regulatory regions where mutations often have little effect (King & Wilson, 1975; Ohta, 2002).”

“Ohta [ 80 ] (not surprisingly) has explicitly reclaimed the “slightly advantageous” as nearly neutral ground by arguing that the fate of slightly advantageous mutations is very much governed by both selection and drift.”

“Violet-eared waxbills, however, also have a broad range in southern Africa [73], and population sizes for this species therefore must also be large enough to effectively purge slightly deleterious mutations that would otherwise elevate genomic estimates of v [74].”

“…to be selectively neutral, a few studies have demonstrated that silent sites in coding sequences can be subject to weak selection (Akashi 1995; Ohta 2002; Singh et al. 2007) due to their functional roles in mRNA splicing (Chamary and Hurst 2005), RNA editing (Shabalina et al. 2006, 2013) and…”

“The nearly neutral theory (Ohta, 1973, 1992, 2002) insists that most fixed mutations satisfy |Nes| ≤ 2.”

“26 For a sampling of the myriad molecular interpretations of how fitness and survival are accomplished at the cellular level during molecular evolution, consider some of the following references”

“In agreement with theories on neutral evolution (Kimura 1955, 1983; Ohta 2002), simulations of gene regulatory networks and models of other biological systems have indicated that increasing mutational robustness may increase a system’s propensity to adapt (Whitacre and Bender 2010b; Ciliberti et…”

“This model assumes that the polymorphism pattern reflects mostly the primary mutation rate and implies the presence of mutations with weak negative effects in the population, because these would be lost only over longer evolutionary time [11].”

“Furthermore, apart from specific details, our observations are in good agreement with what sound population genetics and logic would predict, and our work reflects an expansion, not a reversal, of previous studies [1–29].”

“Although existence of a molecular clock has been incorporated into population genetics theory by an inverse relationship between population size and generation time (Kimura 1983; Gillispie 1991; Ohta 2002), the molecular origin and nonlinear time dependence of such mutations have generally remained obscure in mutagene…”

“Population geneticists have extensively examined how drift and selection affect allele frequencies depending on the strength of selection and the effective population size [13–15], and the same principles should presumably hold for species-level competitive dynamics [16]: in situations where fitness inequalities are s…”

“Ohta later argued that some features of the molecular clock, including its overdispersion, could be best explained by the nearly neutral theory (Ohta 2002).”

“Ohta (2002) has suggested that if the relative advantage or disadvantage, σ, of a particular allele is less than twice the reciprocal of the effective population size N (i.e., the scaled selection coefficient N |σ| 2) the allele’s trajectory is nearly neutral.”

“It is generally believed that most mutations are neutral, with a small tendency toward deleterious mutations [15, 16].”

“Even when mutation rates are well below one per individual per generation, Ohta and others [11–16] have shown that most mutations have such small biological effects that they must be “nearly neutral” (effectively neutral), and must routinely escape the influence of selection, leading to continuous accumulation.”

“The nearly neutral theory emphasizes that slightly deleterious mutations may also be fixed as effectively neutral variants in small populations, and the importance of near neutrality is increasingly supported by evidence [18].”

“TOMOKO OHTA (OHTA 1973, 2002) expanded the neutral gene theory of evolution to include not only a large number of neutral and of deleterious mutations, but also a large number of nearly neutral mutations that are slightly deleterious; that is that they have a very small selective effect, and…”

“Although Kimura initially described such mutations as ‘neutral’, Ohta [3–6] argued that such mutations should more accurately be termed ‘nearly neutral’, and Kimura later agreed [7, 8].”

“The distribution and fate of mutations in populations is well-approximated by the nearly neutral theory of molecular evolution, originally proposed by Tomoko Ohta as an expansion of Motoo Kimura’s neutral theory ( Ohta 1973, 2002; Kimura 1977).”

“Furthermore, to the extent that beneficial mutations may be extremely rare, the question arises — “how can there be any net gain in total biological f itness?” This question arises because it is widely recognized that in large genomes most mutations should have very small effects, and so large numbers of low-impact de…”

“The nearly neutral model (Ohta 2002) predicts that lineages with small population size have higher substitution rates because mutations are more easily fixed due to genetic drift.”

“Strongly deleterious mutations are eliminated quickly by purifying selection, but slightly deleterious mutations may persist in populations for long times, since the effectiveness of purifying selection depends on effective population size and the frequency of recombination (Ohta, 1973, 1976, 2002).”

“Recently, evolutionary biology has had a resurgent interest in the role of fitness neutrality in evolution [2] [24] [25] [26] [27] [28] [29] [10] [5].”

“Neutral theories of evolution (Kimura, 1991; Ohta, 2002) assert that most observed genetic change is the result of the random fixation of selectively neutral mutations, rather than the result of positive selection.”

“In addition to selection, the time-dependency of substitution rates is also influenced by drift (Ohta 1987, 2002, see also Bromham and Penny 2003).”

“Although there have been hints that the models could be applied to morphological (or, at least phenotypic) evolution as well,13 recently, Ohta (2002) has argued more explicitly for applying the nearly neutral model to morphological evolution.”

“new variants are neutral or quasi-neutral; if the population size is not so large, genetic drift can be a stronger force than selection [51, 56, 57].”

“…noncoding regions such as regulatory regions could contribute a wealth of nearly neutral mutations to the overall load of nearly neutral mutations in the genome (e.g., Ohta 2002), we compared the estimated proportion of nearly neutral new mutations at intergenic ACRs to other regions of the genome.”