Nekrutenko Anton, Wadhawan Samir, Goetting-Minesky Paula, Makova Kateryna D
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
PLoS Genet. 2005 Aug;1(2):e18. doi: 10.1371/journal.pgen.0010018. Epub 2005 Aug 12.
XLalphas and ALEX are structurally unrelated mammalian proteins translated from alternative overlapping reading frames of a single transcript. Not only are they encoded by the same locus, but a specific XLalphas/ALEX interaction is essential for G-protein signaling in neuroendocrine cells. A disruption of this interaction leads to abnormal human phenotypes, including mental retardation and growth deficiency. The region of overlap between the two reading frames evolves at a remarkable speed: the divergence between human and mouse ALEX polypeptides makes them virtually unalignable. To trace the evolution of this puzzling locus, we sequenced it in apes, Old World monkeys, and a New World monkey. We show that the overlap between the two reading frames and the physical interaction between the two proteins force the locus to evolve in an unprecedented way. Namely, to maintain two overlapping protein-coding regions the locus is forced to have high GC content, which significantly elevates its intrinsic evolutionary rate. However, the two encoded proteins cannot afford to change too quickly relative to each other as this may impair their interaction and lead to severe physiological consequences. As a result XLalphas and ALEX evolve in an oscillating fashion constantly balancing the rates of amino acid replacements. This is the first example of a rapidly evolving locus encoding interacting proteins via overlapping reading frames, with a possible link to the origin of species-specific neurological differences.
XLalphas和ALEX是由单个转录本的可变重叠阅读框翻译而来的结构不相关的哺乳动物蛋白质。它们不仅由同一基因座编码，而且特定的XLalphas/ALEX相互作用对于神经内分泌细胞中的G蛋白信号传导至关重要。这种相互作用的破坏会导致异常的人类表型，包括智力迟钝和生长发育迟缓。两个阅读框之间的重叠区域以惊人的速度进化：人类和小鼠ALEX多肽之间的差异使得它们几乎无法比对。为了追踪这个令人困惑的基因座的进化，我们对猿类、旧世界猴和新世界猴的该基因座进行了测序。我们发现，两个阅读框之间的重叠以及两种蛋白质之间的物理相互作用迫使该基因座以前所未有的方式进化。也就是说，为了维持两个重叠的蛋白质编码区域，该基因座被迫具有高GC含量，这显著提高了其内在进化速率。然而，两种编码的蛋白质彼此之间不能变化太快，因为这可能会损害它们的相互作用并导致严重的生理后果。结果，XLalphas和ALEX以振荡的方式进化，不断平衡氨基酸替换的速率。这是通过重叠阅读框编码相互作用蛋白质的快速进化基因座的第一个例子，可能与物种特异性神经差异的起源有关。
