Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
PLoS One. 2010 Feb 23;5(2):e9369. doi: 10.1371/journal.pone.0009369.
The MS4A gene family in humans includes CD20 (MS4A1), FcRbeta (MS4A2), Htm4 (MS4A3), and at least 13 other syntenic genes encoding membrane proteins, most having characteristic tetraspanning topology. Expression of MS4A genes is variable in tissues throughout the body; however, several are limited to cells in the hematopoietic system where they have known roles in immune cell functions. Genes in the small TMEM176 group share significant sequence similarity with MS4A genes and there is evidence of immune function of at least one of the encoded proteins. In this study, we examined the evolutionary history of the MS4A/TMEM176 families as well as tissue expression of the phylogenetically earliest members, in order to investigate their possible origins in immune cells.
Orthologs of human MS4A genes were found only in mammals; however, MS4A gene homologs were found in most jawed vertebrates. TMEM176 genes were found only in mammals and bony fish. Several unusual MS4A genes having 2 or more tandem MS4A sequences were identified in the chicken (Gallus gallus) and early mammals (opossum, Monodelphis domestica and platypus, Ornithorhyncus anatinus). A large number of highly conserved MS4A and TMEM176 genes was found in zebrafish (Danio rerio). The most primitive organism identified to have MS4A genes was spiny dogfish (Squalus acanthus). Tissue expression of MS4A genes in S. acanthias and D. rerio showed no evidence of expression restricted to the hematopoietic system.
CONCLUSIONS/SIGNIFICANCE: Our findings suggest that MS4A genes first appeared in cartilaginous fish with expression outside of the immune system, and have since diversified in many species into their modern forms with expression and function in both immune and nonimmune cells.
人类 MS4A 基因家族包括 CD20（MS4A1）、FcRβ（MS4A2）、Htm4（MS4A3）和至少 13 个其他编码膜蛋白的直系同源基因，大多数具有特征性的四跨膜拓扑结构。MS4A 基因在全身组织中的表达具有可变性；然而，有几个基因仅限于造血系统中的细胞，在这些细胞中，它们在免疫细胞功能中具有已知的作用。TMEM176 小基因簇中的基因与 MS4A 基因具有显著的序列相似性，并且至少有一种编码蛋白具有免疫功能的证据。在这项研究中，我们研究了 MS4A/TMEM176 家族的进化历史以及进化上最早成员的组织表达，以研究它们在免疫细胞中的可能起源。
仅在哺乳动物中发现了人类 MS4A 基因的同源物；然而，在大多数有颚脊椎动物中发现了 MS4A 基因的同源物。TMEM176 基因仅在哺乳动物和硬骨鱼中发现。在鸡（Gallus gallus）和早期哺乳动物（负鼠，Monodelphis domestica 和鸭嘴兽，Ornithorhyncus anatinus）中鉴定出了几个具有 2 个或更多串联 MS4A 序列的异常 MS4A 基因。在斑马鱼（Danio rerio）中发现了大量高度保守的 MS4A 和 TMEM176 基因。鉴定出的具有 MS4A 基因的最原始生物是棘鲨（Squalus acanthus）。在 S. acanthias 和 D. rerio 中，MS4A 基因的组织表达没有证据表明其表达局限于造血系统。
结论/意义：我们的发现表明，MS4A 基因首先出现在软骨鱼类中，其表达不在免疫系统之外，此后，在许多物种中，它们多样化为具有免疫和非免疫细胞表达和功能的现代形式。
