Evolution of networks and sequences in eukaryotic cell cycle control

Abstract

The molecular networks regulating the G1-S transition in budding yeast and mammals are strikingly similar in network structure. However, many of the individual proteins performing similar network roles appear to have unrelated amino acid sequences, suggesting either extremely rapid sequence evolution, or true polyphyly of proteins carrying out identical network roles. A yeast/mammal comparison suggests that network topology, and its associated dynamic properties, rather than regulatory proteins themselves may be the most important elements conserved through evolution. However, recent deep phylogenetic studies show that fungal and animal lineages are relatively closely related in the opisthokont branch of eukaryotes. The presence in plants of cell cycle regulators such as Rb, E2F and cyclins A and D, that appear lost in yeast, suggests cell cycle control in the last common ancestor of the eukaryotes was implemented with this set of regulatory proteins. Forward genetics in non-opisthokonts, such as plants or their green algal relatives, will provide direct information on cell cycle control in these organisms, and may elucidate the potentially more complex cell cycle control network of the last common eukaryotic ancestor.

Figure 1.

Schematic of (a) mammalian and (b) budding yeast G1–S control circuits indicates a common feedback-driven regulatory architecture. Shapes correspond to the type of protein (e.g. upward triangles denote cyclin-dependent kinases). Colour implies that the G1–S regulator has high sequence similarity (indicating homology, table 1) to the same regulator in another kingdom (animal, fungi, plant). The G1–S circuit in mammals is colourful (compared with budding yeast) because there are many identifiable sequence homologues between plants and animals.

Figure 2.

Schematic of possibilities for network evolution. (a) A simple network is conserved in two lineages, but along one or both lineages, highly accelerated sequence evolution results in loss of detectable homology in modern descendants (e.g. A′ and A are direct sequence descendants of A in the ancestor, and have carried out the same network role throughout evolution, but A and A′ are no longer sequence-alignable). In this case, both network and sequences are monophyletic: from a single origin, the network has retained the same topology, and all sequences have kept the same network role. (b) A simple network independently recruits new elements to elaborate the network (note that the ‘sense’ of the network remains the same, with A still activating the downstream C). In this case, the enhanced network is polyphyletic, as are the new sequences B and D. (c) Along one lineage, the network acquires an independent loop redundant with the B loop, allowing subsequent loss of B along this lineage, without losing network function at any step. In such a case, we consider the network monophyletic, even though the sequences are polyphyletic. Note that in the case of recruitment, B and D could be ancient relatives. Provided D did not carry out the indicated network role in precursor organisms, this still constitutes sequence polyphyly for this network.

Figure 3.

A current phylogeny of the eukaryotic supergroups, adapted from Rogozin et al. [69]. Branch lengths are not drawn to scale. Phylogenetic data support the idea that plants, fungi and animals are monophyletic (solid lines), that fungi and animals are part of a larger group known as the opisthokonts, and that plants diverged from the opisthokonts at an early point in eukaryotic evolution. However, the root of the eukaryotic tree and the relative placement of other supergroups (excavates, chromalveolata) with respect to each other, and the eukaryotic ancestor is still under debate.

Figure 4.

A sequence alignment of animal p27 from human (Homo sapiens) and C. elegans (nematode) [98], plant KRP1 [95] from Zea mays (maize) and P. patens (moss), along with a best-case alignment of Rum1 from fission yeast (Schizosaccharomyces pombe) and Sic1 from budding yeast (Saccharomyces cerevisiae) to the same region based on structural considerations and modelling [52,98,99]. The homology between the plant KRP1 and animal p27 is likely indicative of monophyly; it is not clear that the Sic1/Rum1 alignment to KRP1/p27 is any better than would be expected by chance.