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Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers.

Finnerty JR, Mazza ME, Jezewski PA - BMC Evol. Biol. (2009)

Bottom Line: MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion.Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function.This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA. jrf3@bu.edu

ABSTRACT

Background: Msx originated early in animal evolution and is implicated in human genetic disorders. To reconstruct the functional evolution of Msx and inform the study of human mutations, we analyzed the phylogeny and synteny of 46 metazoan Msx proteins and tracked the duplication, diversification and loss of conserved motifs.

Results: Vertebrate Msx sequences sort into distinct Msx1, Msx2 and Msx3 clades. The sister-group relationship between MSX1 and MSX2 reflects their derivation from the 4p/5q chromosomal paralogon, a derivative of the original "MetaHox" cluster. We demonstrate physical linkage between Msx and other MetaHox genes (Hmx, NK1, Emx) in a cnidarian. Seven conserved domains, including two Groucho repression domains (N- and C-terminal), were present in the ancestral Msx. In cnidarians, the Groucho domains are highly similar. In vertebrate Msx1, the N-terminal Groucho domain is conserved, while the C-terminal domain diverged substantially, implying a novel function. In vertebrate Msx2 and Msx3, the C-terminal domain was lost. MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion.

Conclusion: Msx originated from a MetaHox ancestor that also gave rise to Tlx, Demox, NK, and possibly EHGbox, Hox and ParaHox genes. Duplication, divergence or loss of domains played a central role in the functional evolution of Msx. Duplicated domains allow pleiotropically expressed proteins to evolve new functions without disrupting existing interaction networks. Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function. This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.

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MEME Domain Identification in the Msx Family. A) Conserved domains identified by MEME in a comparison of human MSX1 (Msx1_Hos) and the Msx proteins of cephalochordate, hemichordate, sea urchin, polychaete, and coral. The domains are named consecutively from the N-terminal to the C-terminal ends of the protein as Msx Homology (MH) domains 1–5. B) Conserved domains identified by MEME in a comparison of vertebrate Msx paralogs plus single Msx proteins from cephalochordate, tunicate, sea urchin, polychaete, and coral. The MH2 and MH5 domains include more amino acids (see Fig. 2) due to the increased sequence similarity within the vertebrate clade. These slightly larger domains are indicated by a "+". Taxon/gene abbreviations are listed in the methods.
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Figure 1: MEME Domain Identification in the Msx Family. A) Conserved domains identified by MEME in a comparison of human MSX1 (Msx1_Hos) and the Msx proteins of cephalochordate, hemichordate, sea urchin, polychaete, and coral. The domains are named consecutively from the N-terminal to the C-terminal ends of the protein as Msx Homology (MH) domains 1–5. B) Conserved domains identified by MEME in a comparison of vertebrate Msx paralogs plus single Msx proteins from cephalochordate, tunicate, sea urchin, polychaete, and coral. The MH2 and MH5 domains include more amino acids (see Fig. 2) due to the increased sequence similarity within the vertebrate clade. These slightly larger domains are indicated by a "+". Taxon/gene abbreviations are listed in the methods.

Mentions: To look for common coding domains relevant to the evolution of the Msx family, comparisons were deliberately made between Msx sequences from taxa more ancient than that utilized in the engrailed comparisons, since current evidence suggests that the Msx family is more ancient than the engrailed family [61]. First, to look for ancient sequence homologies relevant to deuterostome taxa, human MSX1 was compared with Msx proteins from a cephalochordate, a urochordate, an echinoderm, and two non-deuterostomes that served as outgroups, a nereid annelid [62] and a cnidarian. Five conserved domain-types were identified in this initial analysis that closely resemble those from the Engrailed family. These domains may actually be a plesiomorphic character relative to the origin of the Engrailed family. Thus these domains were designated as Msx Homology domains 1 to 5, or MH1-5 (Fig. 1A, 2), in parallel to the nomenclature for the Engrailed domains. All five of these Msx proteins were found to harbor two MH1 domains, labeled as MH1N and MH1C, (named for their respective positions within the protein nearer the amino (N) or carboxy (C) terminus of the protein).


Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers.

Finnerty JR, Mazza ME, Jezewski PA - BMC Evol. Biol. (2009)

MEME Domain Identification in the Msx Family. A) Conserved domains identified by MEME in a comparison of human MSX1 (Msx1_Hos) and the Msx proteins of cephalochordate, hemichordate, sea urchin, polychaete, and coral. The domains are named consecutively from the N-terminal to the C-terminal ends of the protein as Msx Homology (MH) domains 1–5. B) Conserved domains identified by MEME in a comparison of vertebrate Msx paralogs plus single Msx proteins from cephalochordate, tunicate, sea urchin, polychaete, and coral. The MH2 and MH5 domains include more amino acids (see Fig. 2) due to the increased sequence similarity within the vertebrate clade. These slightly larger domains are indicated by a "+". Taxon/gene abbreviations are listed in the methods.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2655272&req=5

Figure 1: MEME Domain Identification in the Msx Family. A) Conserved domains identified by MEME in a comparison of human MSX1 (Msx1_Hos) and the Msx proteins of cephalochordate, hemichordate, sea urchin, polychaete, and coral. The domains are named consecutively from the N-terminal to the C-terminal ends of the protein as Msx Homology (MH) domains 1–5. B) Conserved domains identified by MEME in a comparison of vertebrate Msx paralogs plus single Msx proteins from cephalochordate, tunicate, sea urchin, polychaete, and coral. The MH2 and MH5 domains include more amino acids (see Fig. 2) due to the increased sequence similarity within the vertebrate clade. These slightly larger domains are indicated by a "+". Taxon/gene abbreviations are listed in the methods.
Mentions: To look for common coding domains relevant to the evolution of the Msx family, comparisons were deliberately made between Msx sequences from taxa more ancient than that utilized in the engrailed comparisons, since current evidence suggests that the Msx family is more ancient than the engrailed family [61]. First, to look for ancient sequence homologies relevant to deuterostome taxa, human MSX1 was compared with Msx proteins from a cephalochordate, a urochordate, an echinoderm, and two non-deuterostomes that served as outgroups, a nereid annelid [62] and a cnidarian. Five conserved domain-types were identified in this initial analysis that closely resemble those from the Engrailed family. These domains may actually be a plesiomorphic character relative to the origin of the Engrailed family. Thus these domains were designated as Msx Homology domains 1 to 5, or MH1-5 (Fig. 1A, 2), in parallel to the nomenclature for the Engrailed domains. All five of these Msx proteins were found to harbor two MH1 domains, labeled as MH1N and MH1C, (named for their respective positions within the protein nearer the amino (N) or carboxy (C) terminus of the protein).

Bottom Line: MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion.Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function.This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA. jrf3@bu.edu

ABSTRACT

Background: Msx originated early in animal evolution and is implicated in human genetic disorders. To reconstruct the functional evolution of Msx and inform the study of human mutations, we analyzed the phylogeny and synteny of 46 metazoan Msx proteins and tracked the duplication, diversification and loss of conserved motifs.

Results: Vertebrate Msx sequences sort into distinct Msx1, Msx2 and Msx3 clades. The sister-group relationship between MSX1 and MSX2 reflects their derivation from the 4p/5q chromosomal paralogon, a derivative of the original "MetaHox" cluster. We demonstrate physical linkage between Msx and other MetaHox genes (Hmx, NK1, Emx) in a cnidarian. Seven conserved domains, including two Groucho repression domains (N- and C-terminal), were present in the ancestral Msx. In cnidarians, the Groucho domains are highly similar. In vertebrate Msx1, the N-terminal Groucho domain is conserved, while the C-terminal domain diverged substantially, implying a novel function. In vertebrate Msx2 and Msx3, the C-terminal domain was lost. MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion.

Conclusion: Msx originated from a MetaHox ancestor that also gave rise to Tlx, Demox, NK, and possibly EHGbox, Hox and ParaHox genes. Duplication, divergence or loss of domains played a central role in the functional evolution of Msx. Duplicated domains allow pleiotropically expressed proteins to evolve new functions without disrupting existing interaction networks. Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function. This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.

Show MeSH
Related in: MedlinePlus