Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers.
Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers.
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DOI：
10.1186/1471-2148-9-18
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发表时间：
2009-01-20
影响因子：
3.4
通讯作者：
Jezewski PA
中科院分区：
文献类型：
--
作者：
Finnerty JR;Mazza ME;Jezewski PA
Msx起源于动物进化的早期，与人类遗传疾病有关。为了重建Msx的功能进化并为人类突变的研究提供信息，我们分析了46种后生动物Msx蛋白的同源性和同线性，并跟踪了保守基序的重复，多样化和丢失。脊椎动物Msx序列分为不同的Msx 1，Msx 2和Msx 3进化枝。MSX 1和MSX 2之间的姐妹群关系反映了它们来自4p/5 q染色体旁系同源物，这是原始“MetaHox”簇的衍生物。我们证明了在刺胞动物中Msx和其他MetaHox基因（Hmx，NK 1，Emx）之间的物理联系。七个保守的结构域，包括两个Groucho抑制结构域（N-和C-末端），存在于祖先Msx。在刺胞动物中，Groucho域是高度相似的。在脊椎动物Msx 1中，N-末端Groucho结构域是保守的，而C-末端结构域则发生了很大的差异，这意味着一种新的功能。在脊椎动物Msx 2和Msx 3中，C-末端结构域丢失。与外胚层发育不良或口面裂畸形相关的MSX 1突变以非随机方式映射到保守结构域。Msx起源于MetaHox祖先，其也产生Tlx、Demox、NK，并且可能产生EHGbox、Hox和ParaHox基因。结构域的重复、分歧或丢失在Msx的功能进化中起着核心作用。重复的结构域允许多效性表达的蛋白质在不破坏现有相互作用网络的情况下进化出新的功能。人类错义序列变体存在于进化上保守的结构域中，可能破坏蛋白质功能。候选疾病标志物的基因组评估将为临床和功能研究提供信息。
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. 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. 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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