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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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Msx Domain Evolution Model. The Msx protein is represented here by a horizontal line overlain by boxes that represent the Msx Homology domains discussed in the text. Presumed loss of the MH1C domain is indicated by asterisks. Inferred ancestral chromosomal segments with homology to human chromosomal paralogons at 4p16, 5q35, 8p and 10q26 are indicated along internal branches. Abbreviations: MYA = Million Years Ago; HsChr p = Homo sapiens Chromosome paralogon [86]; MtHox = MetaHox; R1, R2 or R3 = Round 1, 2 or 3; WGD = whole genome duplication. Archeolog = ancestral sequence. Estimated divergence times are taken from the following sources:1 = R1 WGD, origin of craniates = 520 MYA; 687 +/- 156 MYA [85]; 2 = divergence of Chondrichthyes from Osteichthyes = 450 MYA[109,110]. The elephant shark has four Hox clusters, orthologous to known clusters in tetrapods, suggesting Chondrichthyes diverged after the second round of WGD but did not undergo an additional round of duplication as did the osteichthyes. R2 WGD, origin of jawed vertebrates, divergence from agnathans, 477 MYA [111]; 507 +/- 104 MYA, [85]; 3 = divergence of Actinopterygia and Sarcopterygia = 416 MYA [112]; 450 MYA [113]; 4 = R3 WGD within the Actinopterygia = 320 MYA [114]; 350 MYA [113]; 5 = evidence for a 4,5 and 8,10 paralogon split [85,86].
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Figure 8: Msx Domain Evolution Model. The Msx protein is represented here by a horizontal line overlain by boxes that represent the Msx Homology domains discussed in the text. Presumed loss of the MH1C domain is indicated by asterisks. Inferred ancestral chromosomal segments with homology to human chromosomal paralogons at 4p16, 5q35, 8p and 10q26 are indicated along internal branches. Abbreviations: MYA = Million Years Ago; HsChr p = Homo sapiens Chromosome paralogon [86]; MtHox = MetaHox; R1, R2 or R3 = Round 1, 2 or 3; WGD = whole genome duplication. Archeolog = ancestral sequence. Estimated divergence times are taken from the following sources:1 = R1 WGD, origin of craniates = 520 MYA; 687 +/- 156 MYA [85]; 2 = divergence of Chondrichthyes from Osteichthyes = 450 MYA[109,110]. The elephant shark has four Hox clusters, orthologous to known clusters in tetrapods, suggesting Chondrichthyes diverged after the second round of WGD but did not undergo an additional round of duplication as did the osteichthyes. R2 WGD, origin of jawed vertebrates, divergence from agnathans, 477 MYA [111]; 507 +/- 104 MYA, [85]; 3 = divergence of Actinopterygia and Sarcopterygia = 416 MYA [112]; 450 MYA [113]; 4 = R3 WGD within the Actinopterygia = 320 MYA [114]; 350 MYA [113]; 5 = evidence for a 4,5 and 8,10 paralogon split [85,86].

Mentions: Based on the conserved domain architecture within Msx and MetaHox proteins, the conserved synteny between diverse taxa, and a phylogenetic analysis of amino acid sequences, we can construct a more specific and detailed scenario for the evolution of the Msx family (Fig. 8). Combining all of the domain, phylogenetic, genomic and divergence data above suggests that: 1) Msx likely evolved from an ancestral MetaHox cluster gene, 2) seven ancient domains have been highly conserved over the course of Msx evolution, and 3) the vertebrate Msx paralogs evolved during the two rounds of whole genome duplication, with the MH1C domain either becoming lost or highly modified independently in both the Msx3/b/c and Msx2/d/a lineages.


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)

Msx Domain Evolution Model. The Msx protein is represented here by a horizontal line overlain by boxes that represent the Msx Homology domains discussed in the text. Presumed loss of the MH1C domain is indicated by asterisks. Inferred ancestral chromosomal segments with homology to human chromosomal paralogons at 4p16, 5q35, 8p and 10q26 are indicated along internal branches. Abbreviations: MYA = Million Years Ago; HsChr p = Homo sapiens Chromosome paralogon [86]; MtHox = MetaHox; R1, R2 or R3 = Round 1, 2 or 3; WGD = whole genome duplication. Archeolog = ancestral sequence. Estimated divergence times are taken from the following sources:1 = R1 WGD, origin of craniates = 520 MYA; 687 +/- 156 MYA [85]; 2 = divergence of Chondrichthyes from Osteichthyes = 450 MYA[109,110]. The elephant shark has four Hox clusters, orthologous to known clusters in tetrapods, suggesting Chondrichthyes diverged after the second round of WGD but did not undergo an additional round of duplication as did the osteichthyes. R2 WGD, origin of jawed vertebrates, divergence from agnathans, 477 MYA [111]; 507 +/- 104 MYA, [85]; 3 = divergence of Actinopterygia and Sarcopterygia = 416 MYA [112]; 450 MYA [113]; 4 = R3 WGD within the Actinopterygia = 320 MYA [114]; 350 MYA [113]; 5 = evidence for a 4,5 and 8,10 paralogon split [85,86].
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Figure 8: Msx Domain Evolution Model. The Msx protein is represented here by a horizontal line overlain by boxes that represent the Msx Homology domains discussed in the text. Presumed loss of the MH1C domain is indicated by asterisks. Inferred ancestral chromosomal segments with homology to human chromosomal paralogons at 4p16, 5q35, 8p and 10q26 are indicated along internal branches. Abbreviations: MYA = Million Years Ago; HsChr p = Homo sapiens Chromosome paralogon [86]; MtHox = MetaHox; R1, R2 or R3 = Round 1, 2 or 3; WGD = whole genome duplication. Archeolog = ancestral sequence. Estimated divergence times are taken from the following sources:1 = R1 WGD, origin of craniates = 520 MYA; 687 +/- 156 MYA [85]; 2 = divergence of Chondrichthyes from Osteichthyes = 450 MYA[109,110]. The elephant shark has four Hox clusters, orthologous to known clusters in tetrapods, suggesting Chondrichthyes diverged after the second round of WGD but did not undergo an additional round of duplication as did the osteichthyes. R2 WGD, origin of jawed vertebrates, divergence from agnathans, 477 MYA [111]; 507 +/- 104 MYA, [85]; 3 = divergence of Actinopterygia and Sarcopterygia = 416 MYA [112]; 450 MYA [113]; 4 = R3 WGD within the Actinopterygia = 320 MYA [114]; 350 MYA [113]; 5 = evidence for a 4,5 and 8,10 paralogon split [85,86].
Mentions: Based on the conserved domain architecture within Msx and MetaHox proteins, the conserved synteny between diverse taxa, and a phylogenetic analysis of amino acid sequences, we can construct a more specific and detailed scenario for the evolution of the Msx family (Fig. 8). Combining all of the domain, phylogenetic, genomic and divergence data above suggests that: 1) Msx likely evolved from an ancestral MetaHox cluster gene, 2) seven ancient domains have been highly conserved over the course of Msx evolution, and 3) the vertebrate Msx paralogs evolved during the two rounds of whole genome duplication, with the MH1C domain either becoming lost or highly modified independently in both the Msx3/b/c and Msx2/d/a lineages.

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