Tumor Immunology Laboratory, LIFE Center, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 23, 81377 Munich, Germany.
BMC Biol. 2010 Feb 4;8:12. doi: 10.1186/1741-7007-8-12.
Most rapidly evolving gene families are involved in immune responses and reproduction, two biological functions which have been assigned to the carcinoembryonic antigen (CEA) gene family. To gain insights into evolutionary forces shaping the CEA gene family we have analysed this gene family in 27 mammalian species including monotreme and marsupial lineages.
Phylogenetic analysis provided convincing evidence that the primordial CEA gene family in mammals consisted of five genes, including the immune inhibitory receptor-encoding CEACAM1 (CEA-related cell adhesion molecule) ancestor. Our analysis of the substitution rates within the nucleotide sequence which codes for the ligand binding domain of CEACAM1 indicates that the selection for diversification is, perhaps, a consequence of the exploitation of CEACAM1 by a variety of viral and bacterial pathogens as their cellular receptor. Depending on the extent of the amplification of an ancestral CEACAM1, the number of CEACAM1-related genes varies considerably between mammalian species from less than five in lagomorphs to more than 100 in bats. In most analysed species, ITAM (immunoreceptor tyrosine-based activation motifs) or ITAM-like motif-containing proteins exist which contain Ig-V-like, ligand binding domains closely related to that of CEACAM1. Human CEACAM3 is one such protein which can function as a CEACAM1 decoy receptor in granulocytes by mediating the uptake and destruction of specific bacterial pathogens via its ITAM-like motif. The close relationship between CEACAM1 and its ITAM-encoding relatives appears to be maintained by gene conversion and reciprocal recombination. Surprisingly, secreted CEACAMs resembling immunomodulatory CEACAM1-related trophoblast-specific pregnancy-specific glycoproteins (PSGs) found in humans and rodents evolved only in a limited set of mammals. The appearance of PSG-like genes correlates with invasive trophoblast growth in these species.
These phylogenetic studies provide evidence that pathogen/host coevolution and a possible participation in fetal-maternal conflict processes led to a highly species-specific diversity of mammalian CEA gene families.
大多数进化最快的基因家族参与免疫反应和生殖，这两种生物学功能被归因于癌胚抗原（CEA）基因家族。为了深入了解塑造 CEA 基因家族的进化力量，我们对包括单孔目和有袋目谱系在内的 27 种哺乳动物中的该基因家族进行了分析。
系统发育分析提供了令人信服的证据，表明哺乳动物中原始的 CEA 基因家族由五个基因组成，包括免疫抑制受体编码的 CEACAM1（CEA 相关细胞粘附分子）祖先。我们对编码 CEACAM1 配体结合域的核苷酸序列内的取代率进行的分析表明，多样化的选择可能是由于 CEACAM1 被各种病毒和细菌病原体作为其细胞受体而被利用的结果。根据祖先 CEACAM1 的扩增程度，CEACAM1 相关基因的数量在哺乳动物物种之间差异很大，从兔形目动物中的不到 5 个到蝙蝠中的超过 100 个。在大多数分析的物种中，存在包含 ITAM（免疫受体酪氨酸基激活基序）或 ITAM 样基序的蛋白质，这些蛋白质含有与 CEACAM1 密切相关的 Ig-V 样配体结合域。人 CEACAM3 就是这样一种蛋白质，它可以通过其 ITAM 样基序作为 CEACAM1 的诱饵受体，在粒细胞中发挥作用，介导特定细菌病原体的摄取和破坏。CEACAM1 与其 ITAM 编码相关物之间的密切关系似乎是通过基因转换和相互重组来维持的。令人惊讶的是，类似于免疫调节 CEACAM1 相关的胎盘特异性妊娠特异性糖蛋白（PSG）的分泌型 CEACAMs 仅在有限的一组哺乳动物中进化。PSG 样基因的出现与这些物种中侵袭性胎盘生长相关。
这些系统发育研究提供的证据表明，病原体/宿主的共同进化和可能参与胎儿-母体冲突过程导致了哺乳动物 CEA 基因家族的高度物种特异性多样性。
