Refining the drift barrier hypothesis: a role of recessive gene count and an inhomogeneous Muller`s ratchet

The drift-barrier hypothesis states that random genetic drift constrains the refinement of a phenotype under natural selection. The influence of effective population size and the genome-wide deleterious mutation rate were studied theoretically, and an inverse relationship between mutation rate and genome size has been observed for many species. However, the effect of the recessive gene count, an important feature of the genomic architecture, is unknown. In a Wright-Fisher model, we studied the mutation burden for a growing number of N completely recessive and lethal disease genes. Diploid individuals are represented with a binary $2 \times N$ matrix denoting wild-type and mutated alleles. Analytic results for specific cases were complemented by simulations across a broad parameter regime for gene count, mutation and recombination rates. Simulations revealed transitions to higher mutation burden and prevalence within a few generations that were linked to the extinction of the wild-type haplotype (least-loaded class). This metastability, that is, phases of quasi-equilibrium with intermittent transitions, persists over $100\,000$ generations. The drift-barrier hypothesis is confirmed by a high mutation burden resulting in population collapse. Simulations showed the emergence of mutually exclusive haplotypes for a mutation rate above 0.02 lethal equivalents per generation for a genomic architecture and population size representing complex multicellular organisms such as humans. In such systems, recombination proves pivotal, preventing population collapse and maintaining a mutation burden below 10. This study advances our understanding of gene pool stability, and particularly the role of the number of recessive disorders. Insights into Muller`s ratchet dynamics are provided, and the essential role of recombination in curbing mutation burden and stabilizing the gene pool is demonstrated.