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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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Phylogenetic support for alternate relationships among Msx1, Msx2, and Msx3. The three possible relationships among Msx1, Msx2, and Msx3 were directly compared using a dataset consisting of 11 taxa. Trees were generated using neighbor-joining and maximum-likelihood, with and without variation among sites (see methods). In all four instances, the favored topology grouped Msx1 with Msx2 to the exclusion of Msx3 (check marks).
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Figure 4: Phylogenetic support for alternate relationships among Msx1, Msx2, and Msx3. The three possible relationships among Msx1, Msx2, and Msx3 were directly compared using a dataset consisting of 11 taxa. Trees were generated using neighbor-joining and maximum-likelihood, with and without variation among sites (see methods). In all four instances, the favored topology grouped Msx1 with Msx2 to the exclusion of Msx3 (check marks).

Mentions: To compare the relative support for the three possible relationships among Msx1, Msx2, and Msx3 proteins, we conducted a battery of phylogenetic analyses on a subset of the taxa (see Methods). Both neighbor-joining and maximum-likelihood analyses of this smaller dataset, performed both with and without rate variation among sites, support the grouping of Msx1 with Msx2 (Fig. 4). Given the extremely low bootstrap support for the grouping of Msx2 and Msx3, this possibility can be confidently ruled out. However, the bootstrap analyses reveal some support in the data for the grouping of Msx1 with Msx3, and in one instance (a maximum-likelihood analysis assuming rate variation among sites), the bootstrap support for this hypothesis actually exceeds the support for an Msx1-Msx2 clade. Importantly, the grouping of Msx1 with either Msx2 or Msx3 would imply that the MH1C motif has been independently lost in Msx2 and Msx3.


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)

Phylogenetic support for alternate relationships among Msx1, Msx2, and Msx3. The three possible relationships among Msx1, Msx2, and Msx3 were directly compared using a dataset consisting of 11 taxa. Trees were generated using neighbor-joining and maximum-likelihood, with and without variation among sites (see methods). In all four instances, the favored topology grouped Msx1 with Msx2 to the exclusion of Msx3 (check marks).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Phylogenetic support for alternate relationships among Msx1, Msx2, and Msx3. The three possible relationships among Msx1, Msx2, and Msx3 were directly compared using a dataset consisting of 11 taxa. Trees were generated using neighbor-joining and maximum-likelihood, with and without variation among sites (see methods). In all four instances, the favored topology grouped Msx1 with Msx2 to the exclusion of Msx3 (check marks).
Mentions: To compare the relative support for the three possible relationships among Msx1, Msx2, and Msx3 proteins, we conducted a battery of phylogenetic analyses on a subset of the taxa (see Methods). Both neighbor-joining and maximum-likelihood analyses of this smaller dataset, performed both with and without rate variation among sites, support the grouping of Msx1 with Msx2 (Fig. 4). Given the extremely low bootstrap support for the grouping of Msx2 and Msx3, this possibility can be confidently ruled out. However, the bootstrap analyses reveal some support in the data for the grouping of Msx1 with Msx3, and in one instance (a maximum-likelihood analysis assuming rate variation among sites), the bootstrap support for this hypothesis actually exceeds the support for an Msx1-Msx2 clade. Importantly, the grouping of Msx1 with either Msx2 or Msx3 would imply that the MH1C motif has been independently lost in Msx2 and Msx3.

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