[1][2][3] In order for a biological organism to evolve by natural selection, there must be a certain minimum probability that new, heritable variants are beneficial.
However, even after millions of years of evolution, exploring many sequences with similar function, no mutation might exist that gives this enzyme the ability to catalyze a different reaction.
While mutation is the ultimate source of heritable variation, its permutations and combinations also make a big difference.
The amount of variation generated can be adjusted in many different ways, for example via the mutation rate, via the probability of sexual vs. asexual reproduction, via the probability of outcrossing vs. inbreeding, via dispersal, and via access to previously cryptic variants through the switching of an evolutionary capacitor.
However, robustness may allow exploration of large regions of genotype space, increasing evolvability according to the second sense.
[17] For polygenic traits, neighborhood richness contributes more to evolvability than does genetic diversity or "spread" across genotype space.
[18] Temporary robustness, or canalisation, may lead to the accumulation of significant quantities of cryptic genetic variation.
When this happens, natural selection weeds out the very bad mutations, while leaving the others relatively unaffected.
An organism that learns gets to "sample" several different phenotypes during its early development, and later sticks to whatever worked best.
This increase in evolvability can happen when evolution is faced with crossing a "valley" in an adaptive landscape.
These combinations can evolve more easily when the landscape is first flattened, and the discovered phenotype is then fixed by genetic assimilation.
But if pleiotropy is restricted to within functional modules, then mutations affect only one trait at a time, and adaptation is much less constrained.
Other forces of selection also affect the generation of variation; for example, mutation and recombination may in part be byproducts of mechanisms to cope with DNA damage.
[37] However, the hypothesis that evolvability is an adaptation is often rejected in favor of alternative hypotheses, e.g. minimization of costs.
[38] In protein engineering, both rational design and directed evolution approaches aim to create changes rapidly through mutations with large effects.
[43] Proteins are also often studied as part of the basic science of evolvability, because the biophysical properties and chemical functions can be easily changed by a few mutations.
The study of evolvability has fundamental importance for understanding very long term evolution of protein superfamilies.
Viruses, bacteria, fungi and cancers evolve to be resistant to host immune defences, as well as pharmaceutical drugs.