Ohno's dilemma: evolution of new genes under continuous selection

Abstract

New genes with novel functions arise by duplication and divergence, but the process poses a problem. After duplication, an extra gene copy must rise to sufficiently high frequency in the population and remain free of common inactivating lesions long enough to acquire the rare mutations that provide a new selectable function. Maintaining a duplicated gene by selection for the original function would restrict the freedom to diverge. (We refer to this problem as Ohno's dilemma). A model is described by which selection continuously favors both maintenance of the duplicate copy and divergence of that copy from the parent gene. Before duplication, the original gene has a trace side activity (the innovation) in addition to its original function. When an altered ecological niche makes the minor innovation valuable, selection favors increases in its level (the amplification), which is most frequently conferred by increased dosage of the parent gene. Selection for the amplified minor function maintains the extra copies and raises the frequency of the amplification in the population. The same selection favors mutational improvement of any of the extra copies, which are not constrained to maintain their original function (the divergence). The rate of mutations (per genome) that improve the new function is increased by the multiplicity of target copies within a genome. Improvement of some copies relaxes selection on others and allows their loss by mutation (becoming pseudogenes). Ultimately one of the extra copies is able to provide all of the new activity.

Fig. 1.

Changes in the frequency of the extra (duplicate) allele (A²). According to the MDN model, the gene (A) duplicates at t = 0, and one copy (A¹) is maintained by selection for its original function. The extra allele (A²) is subject to loss from the population by drift and inactivation by common mutations. Frequent loss of A² will continue until a rare mutation provides a new selectable function.

Fig. 2.

Comparing rates at which an extra copy either is lost or acquires a new function. The magnitude of the several routes of loss will be different for various organisms. Given numbers are estimated as they might affect bacteria.

Fig. 3.

Innovation before duplication. It is proposed that the parent gene possesses a minor side activity that becomes selectively valuable before the parent allele is duplicated.

Fig. 4.

Amplification increases level of side-function. When selection favors a higher level of side-function “b,” a frequent response is amplification of gene A. This amplification leaves a source of the original function “A” and increases the level of the novel function “b.” Selection for increase in the novel function can selectively maintain multiple additional copies of the gene in the genome and increase the frequency of this amplification in the population.

Fig. 5.

Improvement of new function by mutation and recombination. The multiple copies of gene A that are held under selection can be improved for “b” by point mutations in any copy and reassortment of the improving mutations between copies. When any one allele becomes fully proficient at providing “B” function, selection to maintain the other extra copies is relaxed.