Research into the evolution of genes has shown that the peptides they code for are of a finicky and precarious nature, both marginally stable and prone to aggregation. Protein folding happens to be a highly complex and synergistic process, involving a number of epistatic relationships among many residues. This phenomenon, compounded with the issue of interactions between protein molecules, can significantly complicate adaptive evolution such that in the majority of cases the overall effects on reproductive fitness are very slight. Many arguably "beneficial" mutations have been observed to incur some sort ofcost and so can be classified as a form of antagonistic pleiotropy.2<br style="font-family: arial, helvetica, sans, sans-serif, univers; font-size: 13px; "> Indeed, the place and extent of natural selection as a force for change in molecular biology have been questioned in recent years. Detecting the incidence of any beneficial substitutions in genes has so far relied on statistical inferences as empirical evidence is less readily available. In many instances, nonsynonymous changes and shifts in allelic diversity may be induced by factors that can serve to imitate selective effects—biased gene conversion, mutational and recombinational hotspots, hitchhiking, or even neutral drift being among them. Moreover, several well-known factors such as the linkage and the multilocus nature of important phenotypes tend to restrain the power of Darwinian evolution, and so represent natural limits to biological change. Selection, being an essentially negative filter, tends to act against variation including mutations previously believed to be innocuous.
The various postduplication mechanisms entailing random mutations and recombinations considered were observed to tweak, tinker, copy, cut, divide, and shuffle existing genetic information around,but fell short of generating genuinely distinct and entirely novel functionality. Contrary to Darwin's view of the plasticity of biological features, successive modification and selection in genes does indeed appear to have real and inherent limits: it can serve to alterthe sequence, size, and function of a gene to an extent, but this almost always amounts to a variation on the same theme—as with RNASE1B in colobine monkeys. The conservation of all-important motifs within gene families, such as the homeobox or the MADS-box motif, attests to the fact that gene duplication results in the copying and preservation of biological information, and not its transformation as something original.