The complexity hypothesis  was proposed to explain the disparity in informational (those involved in transcription, translation, and related processes) and operational (those involved in housekeeping) gene transfer rates in bacteria. It states that because informational genes are generally involved in more complex interactions than operational genes, they are less likely to continue functioning well after horizontal transfer. The functional genes produced by shuffling three or more distinct sequences (i.e., 60%–85% identical) are usually derived predominantly from either one sequence or combinations of the most similar sequences [2,6,23,24].
The schema hypothesis proposes that these imbalances are due to the probability of recombinant protein-fold disruption increasing with increasing divergence of parental sequences [6,7]. The probability of the normal network of intragenome interactions being disrupted by recombination increases with increasing divergence of the exchanged fragments The successful inheritance of genomic fragments through recombination is expected to depend on the maintenance of important intragenome interactions. After all, the exchange of a genome fragment could be seen as a simultaneous introduction of multiple mutations. Negative or purifying selection should remove those recombinants that break the epistatic interactions that define the architecture of a particular genome, whereas genetic drift might permit the survival and spread of “neutral” recombinants. Alternatively, positive selection should favour the spread of rare recombinants with improved genomic interactions. The genomic interactions in the (natural) parental viruses used in these experiments have most likely been optimised through selection over long evolutionary periods. None of the recombinants generated from these viruses was more fit than the fitter of its parents, which is expected if negative selection is the dominant force that now maintains the integrity of these genomes.
The relative degree of modularity that we demonstrated experimentally for each genome component appears to be reflected in the recombination events detected within the same regions in natural viruses represented in GenBank. This correlation is surprising because the natural recombinants—unlike the recombinants we constructed in the laboratory—involve exchanges of fragments of genes or intergenic regions. Such exchanges may disrupt intraprotein or intra-intergenic region interactions as well as interaction networks amongst whole genes and intergenic regions. Survival of the natural viruses with detectable recombination events in coding regions presumably depended on their inheritance of sequences that did not overly disrupt either intraprotein or intergene/intergenic region interaction networks; survival of natural intergenic region recombinants and those we generated in the laboratory would have been subject only to the latter constraint. The correlation between our experimental results and the inferred natural recombinants may indicate that maintenance of intergenome component interactions is the principal determinant of recombination tolerance (at least for MSV and closely related viruses). Alternatively, a requirement for the preservation of both intergenome component, and intragene, interaction networks has a net effect that is difficult to distinguish from either constraint operating alone.
We have provided experimental support for the complexity hypothesis by demonstrating a relationship between the relative modularity of defined genomic regions and the complexity of interactions in which they are involved. The striking correlation between our experimental results and the types of recombination observed in nature lends credence to the notion that these detectable modularity differences are evolutionarily relevant. Our results also suggest that the degree of similarity between an inherited sequence and the sequence it replaces is an important additional determinant of recombinant fitness. Whereas recombination can substantially increase the evolutionary options of an organism, the obligatory maintenance of co-evolved interaction networks may severely restrict its evolutionary value."