Swiss Institute of Allergy and Asthma Research, Davos, Switzerland.
Genome Res. 2012 Jun;22(6):1050-8. doi: 10.1101/gr.134098.111. Epub 2012 Mar 14.
The LRRC37 gene family maps to a complex region of the human genome and has been subjected to multiple rounds of segmental duplication. We investigate the expression and regulation of this gene family in multiple tissues and organisms and show a testis-specific expression of this gene family in mouse but a more ubiquitous pattern of expression among primates. Evolutionary and phylogenetic analyses support a model in which new alternative promoters have been acquired during primate evolution. We identify two promoters, Cl8 and particularly Cl3, both of which are highly active in the cerebellum and fetal brain in human and have been duplicated from a promoter region of two unrelated genes, BPTF and DND1, respectively. Two of these more broadly expressed gene family members, LRRC37A1 and A4, define the boundary of a common human inversion polymorphism mapping to chromosome 17q21.31 (the MAPT locus)-a region associated with risk for frontal temporal dementia, Parkinsonism, and intellectual disability. We propose that the regulation of the LRRC37 family occurred in a stepwise manner, acquiring foreign promoters from BPTF and DND1 via segmental duplication. This unusual evolutionary trajectory altered the regulation of the LRRC37 family, leading to increased expression in the fetal brain and cerebellum.
LRRC37 基因家族定位于人类基因组的一个复杂区域，经历了多轮片段重复。我们研究了这个基因家族在多种组织和生物体中的表达和调控情况，发现该基因家族在小鼠的睾丸中具有特异性表达，而在灵长类动物中则具有更为普遍的表达模式。进化和系统发育分析支持了这样一种模型，即在灵长类动物进化过程中获得了新的替代启动子。我们鉴定了两个启动子，Cl8 和特别是 Cl3，它们在人类的小脑和胎儿脑中都具有高度活性，并且分别来自两个不相关基因 BPTF 和 DND1 的启动子区域。这些更广泛表达的基因家族成员中的两个，LRRC37A1 和 A4，定义了一个常见的人类倒位多态性的边界，该多态性位于 17q21.31 号染色体上（MAPT 基因座）-一个与额颞痴呆、帕金森病和智力障碍风险相关的区域。我们提出，LRRC37 家族的调控是逐步发生的，通过片段重复从 BPTF 和 DND1 获得了外源启动子。这种不寻常的进化轨迹改变了 LRRC37 家族的调控，导致在胎儿大脑和小脑中的表达增加。
