Abstract
The reasons why certain domains evolve much slower than others is unclear. The notion that functionally more important genes evolve more slowly than less important genes is one of the few commonly believed principles of molecular evolution. The macro-domain (also known as the X domain) is an ancient, slowly evolving and highly conserved structural domain found in proteins throughout all of the kingdoms and was first discovered nearly two decades ago with the isolation and cloning of macroH2A1. Macrodomains, which are functionally promiscuous, have been studied intensively for the past decade due to their importance in the regulation of cellular responses to DNA damage, chromatin remodeling, transcription and tumorigenesis. Recent structural, phylogenetic and biological analyses, however, suggest the need for some reconsideration of the evolutionary advantage of concentrating such a plethora of diverse functions into the macrodomain and of how macrodomains could perform so many functions. In this article, we focus on macrodomains that are evolving slowly and broadly discuss the potential relationship between the biological evolution and functional diversity of macrodomains.
Highlights
The highly evolutionarily conserved macrodomains were first discovered nearly two decades ago with the isolation and cloning of macroH2A1 [1], which has since been shown to have alternatively spliced forms [2]
MacroH2A is highly conserved in all vertebrates; macrodomains can be found in all of the phylogenetic kingdoms, and these domains have evolved common and fundamental roles in the control of biological processes, indicating that many of these related proteins have existed since the beginning of evolution
Most of the members of the macrodomain family are conserved throughout evolution (Figure 1(a) and (b)), with homologs identified in viruses
Summary
According to the general understanding, evolution is a process of the gradual change of a system, from a simpler to a more complex state Macrodomains are one such system, and one of the challenges for modern protein domain science is to outline those earlier stages that, presumably, preceded the modern state. Most of the macrodomain proteins contain a plethora of diverse additional domains, allowing them to interact with specific target proteins or nucleic acid regions [3]. In the future, animals with reduced macrodomain dosages can be used to test whether the different macrodomain modules could functionally compensate for each other It is these types of animal model systems that will allow us to determine the precise role of macrodomains during development. An interesting and possible answer to this query is that, during evolution, a role for macrodomains in the regulation of cell apoptosis occurs in response to biological, chemical or physical stimuli; upon exposure to different stimuli, organisms could depend on non-mutually exclusive mechanisms via the different macrodomains to inhibit apoptosis
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