Most deleterious mutations have very slight effects on total fitness, and it has become clear that below a certain fitness effect threshold, such low-impact mutations fail to respond to natural selection. The existence of such a selection threshold suggests that many low-impact deleterious mutations should accumulate continuously, resulting in relentless erosion of genetic information. In this paper, we use numerical simulation to examine this problem of selection threshold.The objective of this research was to investigate the effect of various biological factors individually and jointly on mutation accumulation in a model human population. For this purpose, we used a recently-developed, biologically-realistic numerical simulation program, Mendel's Accountant. This program introduces new mutations into the population every generation and tracks each mutation through the processes of recombination, gamete formation, mating, and transmission to the new offspring. This method tracks which individuals survive to reproduce after selection, and records the transmission of each surviving mutation every generation. This allows a detailed mechanistic accounting of each mutation that enters and leaves the population over the course of many generations. We term this type of analysis genetic accounting.Across all reasonable parameters settings, we observed that high impact mutations were selected away with very high efficiency, while very low impact mutations accumulated just as if there was no selection operating. There was always a large transitional zone, wherein mutations with intermediate fitness effects accumulated continuously, but at a lower rate than would occur in the absence of selection. To characterize the accumulation of mutations of different fitness effect we developed a new statistic, selection threshold (ST d ), which is an empirically determined value for a given population. A population's selection threshold is defined as that fitness effect wherein deleterious mutations are accumulating at exactly half the rate expected in the absence of selection. This threshold is mid-way between entirely selectable, and entirely unselectable, mutation effects. Our investigations reveal that under a very wide range of parameter values, selection thresholds for deleterious mutations are surprisingly high. Our analyses of the selection threshold problem indicate that given even modest levels of noise affecting either the genotype-phenotype relationship or the genotypic fitness-survival-reproduction relationship, accumulation of low-impact mutations continually degrades fitness, and this degradation is far more serious than has been previously acknowledged. Simulations based on recently published values for mutation rate and effect-distribution in Biological Information Downloaded from www.worldscientific.com by 54.191.190.102 on 05/10/18. For personal use only. Can Purifying Selection Preserve Biological Information?233 humans show a steady decline in fitness that is not even halted by extremely intense selectio...

Background. In a companion paper, careful numerical simulation was used to demonstrate that there is a quantifiable selection threshold, below which low-impact deleterious mutations escape purifying selection and, therefore, accumulate without limit. In that study we developed the statistic, ST d , which is the mid-point of the transition zone between selectable and un-selectable deleterious mutations. We showed that under most natural circumstances, ST d values are surprisingly high, such that the large majority of all deleterious mutations are un-selectable. Does a similar selection threshold exist for beneficial mutations? Methods. As in our companion paper we here employ what we describe as genetic accounting to quantify the selection threshold (ST b) for beneficial mutations, and we study how various biological factors combine to determine its value. Results. In all experiments that employ biologically reasonable parameters, we observe high ST b values and a general failure of selection to preferentially amplify the large majority of beneficial mutations. High-impact beneficial mutations strongly interfere with selection for or against all lowimpact mutations. Conclusions. A selection threshold exists for beneficial mutations similar in magnitude to the selection threshold for deleterious ones, but the dynamics of that threshold are different. Our results suggest that for higher eukaryotes, minimal values for ST b are in the range of 10 −4 to 10 −3. It appears very likely that most functional nucleotides in a large genome have fractional contributions to fitness much smaller than this. This means that, given our current understanding of how natural selection operates, we cannot explain the origin of the typical functional nucleotide.

The process of deleterious mutation accumulation is influenced by numerous biological factors, including the way in which the accumulating mutations interact with one another. The phenomenon of negative mutation-to-mutation interactions is known as synergistic epistasis (SE). It is widely believed that SE should enhance selective elimination of mutations and thereby diminish the problem of genetic degeneration. We apply numerical simulation to test this commonly expressed assertion.We find that under biologically realistic conditions, synergistic epistasis exerts little to no discernible influence on mutation accumulation and genetic degeneration. When the synergistic effect is greatly exaggerated, mutation accumulation is not significantly affected, but genetic degeneration accelerates markedly. As the synergistic effect is exaggerated still more, degeneration becomes catastrophic and leads to rapid extinction. Even when conditions are optimized to enhance the SE effect, selection efficiency against deleterious mutation accumulation is not appreciably influenced.We also evaluated SE using parameters that result in extreme and artificially high selection efficiency ( truncation selection and perfect genotypic fitness heritability). Even under these conditions, synergistic epistasis causes accelerated degeneration and only minor reductions in the rate of mutation accumulation.When we included the effect of linkage within chromosomal segments in our SE analyses, it made degeneration still worse and even interfered with mutation elimination. Our results therefore strongly suggest that commonly held perceptions concerning the role of synergistic epistasis in halting mutation accumulation are not correct.

There is now abundant evidence that the continuous accumulation of deleterious mutations within natural populations poses a major problem for neo-Darwinian theory. It has been proposed that a viable evolutionary mechanism for halting the accumulation of deleterious mutations might arise if fitness depends primarily on an individual's "mutation-count". In this paper the hypothetical " mutation-count mechanism" (MCM) is tested using numerical simulation, to determine the viability of the hypothesis and to determine what biological factors affect the relative efficacy of this mechanism. The MCM is shown to be very strong when given all the following unnatural conditions: all mutations have an equal effect, low environmental variance, and full truncation selection. Conversely, the MCM effect essentially disappears given any of the following natural conditions: asexual reproduction, or probability selection, or accumulating mutations having a natural distribution of fitness effects covering several orders of magnitude. Realistic levels of environmental variance can also abolish or greatly diminish the MCM effect. Equal mutation effects when combined with partial truncation (quasi-truncation) can create a moderate MCM effect, but this disappears in the presence of less uniform mutation effects and reasonable levels of environmental variance. MCM does not appear to occur under most biologically realistic conditions, and so is not a generally applicable evolutionary mechanism. MCM is not generally capable of stopping deleterious mutation accumulation in most natural populations.

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