The Underappreciated Role of Reproductively Lethal Mutations in the Evolution of Living Beings

Reproductively lethal mutations (RLMs) are mutations that, upon expression of the encoded lethal phenotypes, cause individuals carrying them to die or to be sterile. An underappreciated fact is that loss-of-function RLMs in protein-coding genes can be phenotypically shielded by favorable environments rendering these genes conditionally non-essential, or by their sister alleles in diploid organisms. Absent of rigorous mitigation, such phenotype-shielding causes the number of genes incurring RLMs to increase over time, and simultaneously allows each RLM to reach high allele frequencies in a conspecific population. Over-accumulation of RLMs then sets the population up for eventual concurrent expression of large numbers of RLMs, and massive deaths in rapid succession, possibly even population-level extinction. This hypothetical scenario in turn predicts that organismal lineages that evolved means to minimize the allele frequencies of phenotypically shielded RLMs are favored by natural selection. We argue that bottlenecking the genome copies destined for reproduction is a universal strategy adopted by all living beings to compel phenotype-based RLM purging. We further postulate that primitive RNA replicons must first evolve bottlenecked reproduction before evolving the capacity to encode diffusible products. In more complex, multicellular organisms, RLM management through bottlenecked reproduction gains additional reinforcement through sexual reproduction. In short, the evidence chronicled in this essay strongly suggest that the Bottleneck, Isolate, Amplify, Select (BIAS) principle, originally proposed to explain intracellular evolutionary dynamics of viruses, may be universally applicable to all living beings.