The paradox of extremely fast evolution driven by genetic drift in multi-copy gene systems

Multi-copy gene systems that evolve within, as well as between, individuals are common. They include viruses, mitochondrial DNAs, transposons and multi-gene families. The paradox is that their (neutral) evolution in two stages should be far slower than single-copy systems but the opposite is often true. As the paradox cannot be resolved by the standard Wright-Fisher (WF) model, we now apply the newly expanded WF-Haldane (WFH;(Ruan, et al. 2024)) model to mammalian ribosomal RNA (rRNA) genes. On average, rDNAs haveC∼ 150 - 300 copies per haploid in humans. While a neutral mutation of a single-copy gene would take 4Ngenerations (Nbeing the population size of an ideal population) to become fixed, the time should be 4NC*generations for rRNA genes (C*being the effective copy number). Note thatC*>> 1, butC*< (or >)Cwould depend on the drift strength. Surprisingly, the observed fixation time in mouse and human is < 4N, implying the paradox ofC*< 1. Genetic drift that encompasses all random neutral evolutionary forces appears as much as 100 times stronger for rRNA genes as for single-copy genes, thus reducingC*to < 1. The large increases in genetic drift are driven by the homogenizing forces of gene conversion, unequal crossover and replication slippage within individuals. This study is one of the first applications of the WFH model to track random genetic drift in multi-copy gene systems. Many random forces, often stronger than the WF model prediction, could be mis-interpreted as the working of natural selection.