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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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Related in: MedlinePlus

Human MSX1 domain and mutation map. A) The positions of disease-associated human mutations are indicated by vertical arrowheads above the domain structure for human MSX1. Missense mutations (e.g., V114G) are described by the wild-type amino acid (e.g., V), the position within the human MSX1 protein (e.g., 114), and the mutation at each site (e.g., G). Nonsense mutations are indicated by horizontal arrows that terminate over the position of the introduced stop codon. Frameshift mutations are indicated by horizontal arrows terminating at the location of the mutation followed by a series of dots. Pink arrowheads denote mutations (M61K, Q187X, S202X, A219T) found in individuals that exhibit an ectodermal dysplasia phenotype. Red arrowheads denote mutations (E78V, G91D, G98E, V114G, G116E, P147Q, R151S, G267C, P278S) found in individuals that exhibit an orofacial cleft phenotype. B) The graph displays pairwise distances between MSX1, MSX2, and two outgroup sequences (Branchiostoma Msx and Lamprey MsxA). The lamprey MsxA was compared to MSX1 (small boxes) or MSX2 (large boxes) for each of the domain comparisons. In a similar fashion, Branchiostoma Msx was compared to MSX1 (down slanting lines) and MSX2 (up slanting lines).
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Figure 6: Human MSX1 domain and mutation map. A) The positions of disease-associated human mutations are indicated by vertical arrowheads above the domain structure for human MSX1. Missense mutations (e.g., V114G) are described by the wild-type amino acid (e.g., V), the position within the human MSX1 protein (e.g., 114), and the mutation at each site (e.g., G). Nonsense mutations are indicated by horizontal arrows that terminate over the position of the introduced stop codon. Frameshift mutations are indicated by horizontal arrows terminating at the location of the mutation followed by a series of dots. Pink arrowheads denote mutations (M61K, Q187X, S202X, A219T) found in individuals that exhibit an ectodermal dysplasia phenotype. Red arrowheads denote mutations (E78V, G91D, G98E, V114G, G116E, P147Q, R151S, G267C, P278S) found in individuals that exhibit an orofacial cleft phenotype. B) The graph displays pairwise distances between MSX1, MSX2, and two outgroup sequences (Branchiostoma Msx and Lamprey MsxA). The lamprey MsxA was compared to MSX1 (small boxes) or MSX2 (large boxes) for each of the domain comparisons. In a similar fashion, Branchiostoma Msx was compared to MSX1 (down slanting lines) and MSX2 (up slanting lines).

Mentions: When all known disease-associated coding mutations previously identified within the human MSX1 gene are mapped onto the protein, the mutations causing orofacial clefting (OFC) and the mutations causing ectodermal dysplasias (ED) map to the domain architecture in a non-overlapping fashion (Fig. 6A). OFC mutations, (shown in dark red), [32,38] are found in and around the MH1C, MH3 and MH6 domains, while ED mutations, (shown in light pink), [36,37,82,83] are found within or upstream of MH1N and within MH4 domains.


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)

Human MSX1 domain and mutation map. A) The positions of disease-associated human mutations are indicated by vertical arrowheads above the domain structure for human MSX1. Missense mutations (e.g., V114G) are described by the wild-type amino acid (e.g., V), the position within the human MSX1 protein (e.g., 114), and the mutation at each site (e.g., G). Nonsense mutations are indicated by horizontal arrows that terminate over the position of the introduced stop codon. Frameshift mutations are indicated by horizontal arrows terminating at the location of the mutation followed by a series of dots. Pink arrowheads denote mutations (M61K, Q187X, S202X, A219T) found in individuals that exhibit an ectodermal dysplasia phenotype. Red arrowheads denote mutations (E78V, G91D, G98E, V114G, G116E, P147Q, R151S, G267C, P278S) found in individuals that exhibit an orofacial cleft phenotype. B) The graph displays pairwise distances between MSX1, MSX2, and two outgroup sequences (Branchiostoma Msx and Lamprey MsxA). The lamprey MsxA was compared to MSX1 (small boxes) or MSX2 (large boxes) for each of the domain comparisons. In a similar fashion, Branchiostoma Msx was compared to MSX1 (down slanting lines) and MSX2 (up slanting lines).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Human MSX1 domain and mutation map. A) The positions of disease-associated human mutations are indicated by vertical arrowheads above the domain structure for human MSX1. Missense mutations (e.g., V114G) are described by the wild-type amino acid (e.g., V), the position within the human MSX1 protein (e.g., 114), and the mutation at each site (e.g., G). Nonsense mutations are indicated by horizontal arrows that terminate over the position of the introduced stop codon. Frameshift mutations are indicated by horizontal arrows terminating at the location of the mutation followed by a series of dots. Pink arrowheads denote mutations (M61K, Q187X, S202X, A219T) found in individuals that exhibit an ectodermal dysplasia phenotype. Red arrowheads denote mutations (E78V, G91D, G98E, V114G, G116E, P147Q, R151S, G267C, P278S) found in individuals that exhibit an orofacial cleft phenotype. B) The graph displays pairwise distances between MSX1, MSX2, and two outgroup sequences (Branchiostoma Msx and Lamprey MsxA). The lamprey MsxA was compared to MSX1 (small boxes) or MSX2 (large boxes) for each of the domain comparisons. In a similar fashion, Branchiostoma Msx was compared to MSX1 (down slanting lines) and MSX2 (up slanting lines).
Mentions: When all known disease-associated coding mutations previously identified within the human MSX1 gene are mapped onto the protein, the mutations causing orofacial clefting (OFC) and the mutations causing ectodermal dysplasias (ED) map to the domain architecture in a non-overlapping fashion (Fig. 6A). OFC mutations, (shown in dark red), [32,38] are found in and around the MH1C, MH3 and MH6 domains, while ED mutations, (shown in light pink), [36,37,82,83] are found within or upstream of MH1N and within MH4 domains.

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