Maxeiner Stephan, Benseler Fritz, Brose Nils, Krasteva-Christ Gabriela
Anatomy and Cell Biology, Saarland University, Homburg, Germany.
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
Front Mol Neurosci. 2022 Mar 30;15:838262. doi: 10.3389/fnmol.2022.838262. eCollection 2022.
The neural cell adhesion protein neuroligin-4 has puzzled neuroscientists and geneticist alike for almost two decades. Its clinical association with autism spectrum disorders (ASD) is well established, however, its diversification into sex chromosome-specific copies, and , remains uncharted territory. Just recently, the presence of substantial neuroligin-4 sequence differences between humans and laboratory mice, in which is a pseudoautosomal gene, could be explained as a consequence of dramatic changes affecting the pseudoautosomal region on both sex chromosomes in a subset of rodents, the clade eumuroida. In this study, we describe the presence of sex chromosome-specific copies of neuroligin-4 genes in the Mongolian gerbil () marking the first encounter of its kind in rodents. Gerbils are members of the family Muridae and are closely related to mice and rats. Our results have been incorporated into an extended evolutionary analysis covering primates, rodents, lagomorphs, treeshrews and culogos comprising together the mammalian superorder euarchontoglires. We gathered evidence that substantial changes in neuroligin-4 genes have also occurred outside eumuroida in other rodent species as well as in lagomorphs. These changes feature, e.g., a general reduction of its gene size, an increase in its average GC-content as well as in the third position (GC3) of synonymous codons, and the accumulation of repetitive sequences in line with previous observations. We further show conclusively that the diversification of neuroligin-4 in sex chromosome-specific copies has happened multiple times independently during mammal evolution proving that Y-chromosomal genes do not originate from a single common ancestor.
近二十年来，神经细胞粘附蛋白神经连接蛋白4一直困扰着神经科学家和遗传学家。它与自闭症谱系障碍（ASD）的临床关联已得到充分证实，然而，其分化为性染色体特异性拷贝的情况仍未可知。就在最近，人类和实验室小鼠之间存在显著的神经连接蛋白4序列差异，其中在小鼠中该基因是一个假常染色体基因，这一差异可以解释为在啮齿动物的一个亚类——真鼠总科的一部分啮齿动物中，影响两条性染色体上假常染色体区域的剧烈变化的结果。在这项研究中，我们描述了在蒙古沙鼠（Meriones unguiculatus）中存在神经连接蛋白4基因的性染色体特异性拷贝，这在啮齿动物中尚属首次发现。沙鼠是鼠科动物，与小鼠和大鼠亲缘关系密切。我们的研究结果已纳入一项扩展的进化分析，该分析涵盖了灵长类动物、啮齿动物、兔形目动物、树鼩和象鼩，它们共同构成了真灵长大目哺乳动物。我们收集的证据表明，神经连接蛋白4基因在真鼠总科之外的其他啮齿动物物种以及兔形目动物中也发生了显著变化。这些变化包括，例如，其基因大小普遍减小，平均GC含量以及同义密码子第三位（GC3）的含量增加，以及重复序列的积累，这与之前的观察结果一致。我们进一步确凿地表明，神经连接蛋白4在性染色体特异性拷贝中的多样化在哺乳动物进化过程中多次独立发生，证明Y染色体上的神经连接蛋白4基因并非起源于单一的共同祖先。
