Population structure reverses selection of variants with proportionally scaled birth and death rates.

A widespread biological phenomenon is that higher reproduction rates are often accompanied by higher mortality. During tumor progression, variants can both reproduce and die faster; rapidly replicating viruses decay more quickly; arthropods with faster reproduction have shorter lifespans; and in ecological systems, more frequent reproduction can increase predation risk. Variants with proportionally scaled birth and death rates are termed quasi-neutral mutants. Although their lifetime reproductive success is unchanged, such mutants have fixation probabilities slightly lower (or higher) than neutral mutants if birth and death rates are proportionally larger (or smaller). Previous studies, limited to well-mixed populations, showed that quasi-neutral mutants deviate from neutrality but still exhibit fixation probabilities scaling with their initial frequencies. Here, we show that in deme- or spatially structured populations, variants with proportionally increased (decreased) birth and death rates become genuinely disadvantageous (advantageous). We calculate their effective fitness and further demonstrate that even when mutants have higher lifetime reproductive output, proportional increases in both birth and death rates can render them strongly disadvantageous-and vice versa. This effect intensifies in larger populations. These findings revise the relationship between lifetime reproductive success and selection, with implications for evolutionary dynamics across biological systems.