Pairing and anti-pairing: a balancing act in the diploid genome

Abstract

The presence of maternal and paternal homologs appears to be much more than just a doubling of genetic material. We know this because genomes have evolved elaborate mechanisms that permit homologous regions to sense and then respond to each other. One way in which homologs communicate is to come into contact and, in fact, Dipteran insects such as Drosophila excel at this task, aligning all pairs of maternal and paternal chromosomes, end-to-end, in essentially all somatic tissues throughout development. Here, we reexamine the widely held tenet that extensive somatic pairing of homologous sequences cannot occur in mammals and suggest, instead, that pairing may be a widespread and significant potential that has gone unnoticed in mammals because they expend considerable effort to prevent it. We then extend this discussion to interchromosomal interactions, in general, and speculate about the potential of nuclear organization and pairing to impact inheritance.

Figure 1

A) In the conventional model, Drosophila pairs homologs because it supports a pairing activity that evolved specifically in the Dipteran lineage. In this viewpoint, both pairing and anti-pairing activity would be absent in human cells. An alternative explanation posits that all organisms support both pairing and anti-pairing activities, the relative strengths of which differ between Drosophila and humans. Importantly, this model predicts that disruption of anti-pairing in humans will induce ectopic pairing and potentially predispose individuals to disease, a notion that is consistent with the pairing of chromosome 19q in renal oncocytomas by Koeman et al. [84]. B) Two models of Drosophila transvection are shown. On the left, the enhancer of a promoter-less gene acts in trans on the promoter of a paired, enhancer-less homolog [39, 102]. Deficiencies are denoted as (). On the right, the gain-of-function zeste¹ mutation (denoted at Z¹) is required to repress paired white genes. Vertical lines represent homolog pairing interactions [103].

Figure 2

Three evolutionary models to explain the singular ability of Dipterans to support genome-wide somatic pairing. The leftmost figure suggests that Dipterans evolved de novo a genome-wide mechanism for somatic pairing, while the middle figure suggests that a capacity for pairing had been pre-existing in the common ancestor of Dipterans and other organisms but was lost in all but the Dipteran lineage. The rightmost figure depicts an explanation wherein the paired state reflects a balance of antagonistic activities, one that promotes pairing and another that prevents pairing (anti-pairing), both of which were present in the common ancestor. A shift in balance toward pairing and anti-pairing activity would be favored in the Dipteran and human lineages, respectively.

Figure 3

Model for how intrachromosomal (cis) interactions (e.g. compaction, looping, CT formation) might influence the potential for interchromosomal interactions (trans) (e.g. pairing, recombination, translocations). We note that this antagonistic relationship between intra- and interchromosomal interactions might also be observed at the gene- or chromosome-specific level.

Figure 4

A) As is the case with other genetic material, genome organization might be subject to alteration and then inheritance in its altered state, such as through cell division (top row). Furthermore, alterations transferred to the germline from the soma or occurring de novo in the germline would have the potential to be inherited by subsequent generations. Alterations might arise via error, mutation, stress, stochastic processes, and/or even developmentally directed cues. B) Pairing may enable cells to assess and respond to the degree of heterogeneity between parental genomes. Depending on whether it occurs in the germline or soma, this process would have the potential to alter genomic diversity in the next generation or in a population of somatic cells.