Abstract
In the past few years, there has been an increasing neuroscientific interest in understanding the function of mammalian chromodomains helicase DNA-binding (CHD) proteins due to their association with severe developmental syndromes. Mammalian CHDs include nine members (CHD1 to CHD9), grouped into subfamilies according to the presence of specific functional domains, generally highly conserved in evolutionary terms. Mutations affecting these domains hold great potential to disrupt protein function, leading to meaningful pathogenic scenarios, such as embryonic defects incompatible with life. Here, we analysed the evolution of CHD proteins by performing a comparative study of the functional domains of CHD proteins between orthologous and paralogous protein sequences. Our findings show that the highest degree of inter-species conservation was observed at Group II (CHD3, CHD4, and CHD5) and that most of the pathological variations documented in humans involve amino acid residues that are conserved not only between species but also between paralogs. The parallel analysis of both orthologous and paralogous proteins, in cases where gene duplications have occurred, provided extra information showing patterns of flexibility as well as interchangeability between amino acid positions. This added complexity needs to be considered when the impact of novel mutations is assessed in terms of evolutionary conservation.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
The phylogenetic analysis of chromodomains helicase-DNA binding (CHD) proteins considering the six mammalian species under investigation (Figure 1) showed that CHDs cluster in three clades that match the three groups of proteins from the CHD family based on the types of functional domains: I (CHD1 and CHD2), II (CHD3, CHD4, and CHD5), and III (CHD6, CHD7, CHD8, and CHD9)
According to Flanagan and colleagues [51], each group of CHDs derived from one of three different ancestral proteins. In line with this and taking into account the position of the sequences from C. elegans, our analysis suggests that at least three ancestral CHDs existed before the divergence of vertebrates [6,51], an indication that the expansion of the CHD gene family by gene duplication events occurred after the divergence between invertebrates and vertebrates
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mammalian chromodomains helicase DNA-binding (CHDs) proteins represent a family of nine proteins involved in chromatin remodelling and transcription regulation during mammalian development [1–9]. All these proteins present two chromodomains and two helicase domains and yet other specific functional domains permit to distinguish three groups of CHDs: I (CHD1 and CHD2), II (CHD3, CHD4, and CHD5), and III (CHD6, CHD7, CHD8, and CHD9) [1]. Group II proteins possess two additional plant homeodomains (PHD), responsible for the physical binding of CHDs to the Nucleosome Remodelling
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