Moderating the neutralist–selectionist debate: exactly which propositions are we debating, and which arguments are valid?

Abstract

Half a century after its foundation, the neutral theory of molecular evolution continues to attract controversy. The debate has been hampered by the coexistence of different interpretations of the core proposition of the neutral theory, the ‘neutral mutation–random drift’ hypothesis. In this review, we trace the origins of these ambiguities and suggest potential solutions. We highlight the difference between the original, the revised and the nearly neutral hypothesis, and re‐emphasise that none of them equates to the null hypothesis of strict neutrality. We distinguish the neutral hypothesis of protein evolution, the main focus of the ongoing debate, from the neutral hypotheses of genomic and functional DNA evolution, which for many species are generally accepted. We advocate a further distinction between a narrow and an extended neutral hypothesis (of which the latter posits that random non‐conservative amino acid substitutions can cause non‐ecological phenotypic divergence), and we discuss the implications for evolutionary biology beyond the domain of molecular evolution. We furthermore point out that the debate has widened from its initial focus on point mutations, and also concerns the fitness effects of large‐scale mutations, which can alter the dosage of genes and regulatory sequences. We evaluate the validity of neutralist and selectionist arguments and find that the tested predictions, apart from being sensitive to violation of underlying assumptions, are often derived from the null hypothesis of strict neutrality, or equally consistent with the opposing selectionist hypothesis, except when assuming molecular panselectionism. Our review aims to facilitate a constructive neutralist–selectionist debate, and thereby to contribute to answering a key question of evolutionary biology: what proportions of amino acid and nucleotide substitutions and polymorphisms are adaptive?

Genetic diversity of murine norovirus populations less susceptible to chlorine

“…Notably, the susceptible populations had significantly higher π S in VP1 than other proteins ( Figure 3A ). These results suggest that the appearance of synonymous mutations could be caused by weak selective pressures ( de Jong et al, 2024 ). Meanwhile, the less-susceptible populations had significantly lower π S in VP1 than the susceptible populations ( Figure 3A ).…”

Evolution and diversity of nucleotide and dinucleotide composition in poxviruses

“…Examples at the genomic level are the enrichment in G/C-ending codons in mammal genomes, the global trend in vertebrate genomes to display a lower than expected CpG dinucleotide frequency or the under-representation of the TpA dinucleotide in all animal genomes [120,121]. The global framework for understanding compositional biases is the mutation-selection-gene conversion-drift hypothesis, albeit it is not always evident to pinpoint the actual differences between neutralist and selectionist approaches, beyond over-simplifications [122]. For our focus here on dinucleotide frequencies, a mutational explanation for the CpG under-representation posits that cytosine methylation, common in vertebrate genomes, increases C→U→T mutation rate, although this process does not explain the CpG depletion observed also in vertebrate mitochondrial genomes [47,49,55,120].…”

L-Shaped Distributions of the Relative Substitution Rates (c/micro) in SARS-COV-2 with or without Molecular Clocks, Challenging Mainstream Evolutionary Theories

“…Assuming all NT sites undergo strictly neutral selection only (i.e. the fraction of strictly neutral sites is one, f 0 = 1; Genomic Substitution Rate Model/GSRM[13]; the Strict neutrality hypothesis [11]), the observed mutation rate at any NT site j (substitution rate, c j ) is equal to the spontaneous mutation rate in individual organisms ( c = μ Figure 3 ) [3, 4]. Therefore, the substitution rate for any genetic segment, UTR, TRS, sub-genetic segment is a constant that is equal to the spontaneous mutation rate (μ), leading to a global molecular clock.…”

“…Along the same line of KNT, ONNT [7, 8] predicts while most NT sites are under negative selection ( f ― > f 0 ), the sites under strictly neutral selection (c/µ=1) or nearly neutral selection (c/µ∼1, f ′ 0 :the fraction of near neutral sites) aremuch more abundant than the sites under positive selection ( f + ≈ 0, f ′ 0 > f 0 ≫ f + ). Hallmarks of ONNT are population-size dependent substitution rate ( Eqn 6 : c = μ( f 0 + q (1 ― f 0 ); q : time-dependent proportion of deleterious mutations that reach fixation, which is dependent on the effective population size ( N e ), environmental conditions and selective pressures[11]) and an asymmetric distribution around c/µ=1 due to mostly slightly deleterious near neutral mutations ( Table 2 ). In ST [2], NT positions largely exhibit natural selection (c j /µ≠1) and few sites under strictly neutral selection ( Table 2 ).…”