Neutralist/Selectionist Debate from GBE

The neutral and nearly neutral theories, introduced more than 50 yr ago, have raised and still raise passionate discussion regarding the forces governing molecular evolution and their relative importance. The debate, initially focused on the amount of within-species polymorphism and constancy of the substitution rate, has spread, matured, and now underlies a wide range of topics and questions. The neutralist/selectionist controversy has structured the field and influences the way molecular evolutionary scientists conceive their research.

Recombination reshuffles the alleles of a population through crossover and gene conversion. These mechanisms have considerable consequences on the evolution and maintenance of genetic diversity. Crossover, for example, can increase genetic diversity by breaking the linkage between selected and nearby neutral variants. Bias in favor of G or C alleles during gene conversion may instead promote the fixation of one allele over the other, thus decreasing diversity.

The nearly neutral theory predicts specific relations between effective population size (Ne) and patterns of divergence and polymorphism, which depend on the shape of the distribution of fitness effects (DFE) of new mutations. However, testing these relations is not straightforward, owing to the difficulty in estimating Ne.

We discuss the genetic, demographic, and selective forces that are likely to be at play in restricting observed levels of DNA sequence variation in natural populations to a much smaller range of values than would be expected from the distribution of census population sizes alone - Lewontin's Paradox.

The predicted effect of effective population size on the distribution of fitness effects and substitution rate is critically dependent on the relationship between sequence and fitness. This highlights the importance of using models that are informed by the molecular biology, biochemistry, and biophysics of the evolving systems.

The role of adaptation is a fundamental question in molecular evolution. Theory predicts that species with large effective population sizes should undergo a higher rate of adaptive evolution than species with low effective population sizes if adaptation is limited by the supply of mutations. Previous analyses have appeared to support this conjecture because estimates of the proportion of nonsynonymous substitutions fixed by adaptive evolution, ?, tend to be higher in species with large Ne.

A recent slew of ENCyclopedia Of DNA Elements (ENCODE) Consortium publications, specifically the article signed by all Consortium members, put forward the idea that more than 80% of the human genome is functional. This claim flies in the face of current estimates according to which the fraction of the genome that is evolutionarily conserved through purifying selection is less than 10%.

As both natural selection and population history can affect genome-wide patterns of variation, disentangling the contributions of each has remained as a major challenge in population genetics.

Despite substantial attention from theoreticians, the evolutionary mechanisms that drive intra- and interspecific variation in the mutation rate remain unclear. It has often been argued that mutation rates associated with the major replicative polymerases have been driven down to their physiological limits, defined as the point at which further enhancement in replication fidelity incurs a cost in terms of reproductive output, but no evidence in support of this argument has emerged for cellular organisms.

Errors in gene transcription can be costly, and organisms have evolved to prevent their occurrence or mitigate their costs. The simplest interpretation of the drift barrier hypothesis suggests that species with larger population sizes would have lower transcriptional error rates. However, Escherichia coli seems to have a higher transcriptional error rate than species with lower effective population sizes, for example Saccharomyces cerevisiae.

The nearly neutral theory, which proposes that most mutations are deleterious or close to neutral, predicts that the ratio of nonsynonymous over synonymous substitution rates (dN/dS), and potentially also the ratio of radical over conservative amino acid replacement rates (Kr/Kc), are negatively correlated with effective population size. Previous empirical tests, using life-history traits (LHT) such as body-size or generation-time as proxies for population size, have been consistent with these predictions.

The nearly neutral theory emphasizes the interaction of drift and weak selection in evolution. With progress of genome biology, the applicability of the nearly neutral theory has expanded. The genome-wide analyses of synonymous and nonsynonymous substitutions at protein-coding regions show prevalence of very weak selection.

GC-biased gene conversion (gBGC) is a process that tends to increase the GC content of recombining DNA over evolutionary time and is thought to explain the evolution of GC content in mammals and yeasts. Evidence for gBGC outside these two groups is growing but is still limited.

Under the neutral theory, species with larger effective population size are expected to harbor higher genetic diversity. However, across a wide variety of organisms, the range of genetic diversity is orders of magnitude more narrow than the range of effective population size. This observation has become known as Lewontin's paradox and although aspects of this phenomenon have been extensively studied, the underlying causes for the paradox remain unclear.