occurs in the absence of beneficial mutations, when after the most-fit genotype has been lost, it cannot be regained by genetic recombination. Deterministic accumulation of mutation load occurs in asexuals when the deleterious mutation rate exceeds one per replication. Sexually reproducing species are expected to have lower genetic loads. This is one hypothesis for the evolutionary advantage of sexual reproduction. Purging of deleterious mutations in sexual populations is facilitated by synergistic epistasis among deleterious mutations. High load can lead to a small population size, which in turn increases the accumulation of mutation load, culminating in extinction via mutational meltdown. The accumulation of deleterious mutations in humans has been of concern to many geneticists, including Hermann Joseph Muller, James F. Crow, Alexey Kondrashov, W. D. Hamilton, and Michael Lynch. Beneficial mutation In sufficiently genetically loaded populations, new beneficial mutations create fitter genotypes than those previously present in the population. When load is calculated as the difference between the fittest genotype present and the average, this creates a substitutional load. The difference between the theoretical maximum (which may not actually be present) and the average is known as the "lag load". Motoo Kimura's original argument for the neutral theory of molecular evolution was that if most differences between species were adaptive, this would exceed the speed limit to adaptation set by the substitutional load. However, Kimura's argument confused the lag load with the substitutional load, using the former when it is the latter that in fact sets the maximal rate of evolution by natural selection. More recent "travelling wave" models of rapid adaptation derive a term called the "lead" that is equivalent to the substitutional load, and find that it is a critical determinant of the rate of adaptive evolution. Inbreeding Inbreeding increases homozygosity. In the short run, an increase in inbreeding increases the probability with which offspring get two copies of a recessive deleterious alleles, lowering fitnesses via inbreeding depression. In a species that habitually inbreeds, e.g. through self-fertilization, a proportion of recessive deleterious alleles can be purged. Likewise, in a small population of humans practicing endogamy, deleterious alleles can either overwhelm the population's gene pool, causing it to become extinct, or alternately, make it fitter. Recombination/segregation Combinations of alleles that have evolved to work well together may not work when recombined with a different suite of coevolved alleles, leading to outbreeding depression. Segregation load occurs in the presence of overdominance,