Graduate School of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan.
Mol Biol Evol. 2010 Nov;27(11):2522-33. doi: 10.1093/molbev/msq138. Epub 2010 Jun 4.
Domain shuffling has provided extraordinarily diverse functions to proteins. Nevertheless, how newly combined domains are coordinated to create novel functions remains a fundamental question of genetic and phenotypic evolution. Previously, we reported a unique mechanism of gene creation, whereby new combinations of functional domains are assembled from distinct genes at the RNA level, reverse transcribed, and integrated into the genome by the L1 retrotransposon. The novel gene PIPSL, created by the fusion of phosphatidylinositol-4-phosphate 5-kinase (PIP5K1A) and 26S proteasome subunit (S5a/PSMD4) genes, is specifically transcribed in human and chimpanzee testes. We present the first evidence for the translation of PIPSL in humans. The human PIPSL locus showed a low nucleotide diversity within 11 populations (125 individuals) compared with other genomic regions such as introns and overall chromosomes. It was equivalent to the average for coding sequences or exons from other genes, suggesting that human PIPSL has some function and is conserved among modern populations. Two linked amino acid-altering single-nucleotide polymorphisms were found in the PIPSL kinase domain of non-African populations. They are positioned in the vicinity of the substrate-binding cavity of the parental PIP5K1A protein and change the charge of both residues. The relatively rapid expansion of this haplotype might indicate a selective advantage for it in modern humans. We determined the evolutionary fate of PIPSL domains created by domain shuffling. During hominoid diversification, the S5a-derived domain was retained in all lineages, whereas the ubiquitin-interacting motif (UIM) 1 in the domain experienced critical amino acid replacements at an early stage, being conserved under subsequent high levels of nonsynonymous substitutions to UIM2 and other domains, suggesting that adaptive evolution diversified these functional compartments. Conversely, the PIP5K1A-derived domain is degenerated in gibbons and gorillas. These observations provide a possible scheme of domain shuffling in which the combined parental domains are not tightly linked in the novel chimeric protein, allowing for changes in their functional roles, leading to their fine-tuning. Selective pressure toward a novel function initially acted on one domain, whereas the other experienced a nearly neutral state. Over time, the latter also gained a new function or was degenerated.
结构域改组为蛋白质提供了极其多样的功能。然而，新组合的结构域如何协调以产生新的功能仍然是遗传和表型进化的基本问题。此前，我们报道了一种独特的基因产生机制，即通过 RNA 水平的不同基因组合、逆转录和 L1 反转录转座子整合到基因组中，将功能结构域的新组合装配在一起。新型基因 PIPSL 是由磷脂酰肌醇-4-磷酸 5-激酶（PIP5K1A）和 26S 蛋白酶体亚基（S5a/PSMD4）基因融合而成，仅在人类和黑猩猩睾丸中特异性转录。我们首次提供了 PIPSL 在人类中翻译的证据。与其他基因组区域（如内含子和整条染色体）相比，人类 PIPSL 基因座在 11 个人群（125 个人）中的核苷酸多样性较低。它与其他基因的编码序列或外显子的平均水平相当，表明人类 PIPSL 具有某些功能，并在现代人群中保守。在非非洲人群的 PIPSL 激酶结构域中发现了两个连锁的氨基酸改变单核苷酸多态性。它们位于亲本 PIP5K1A 蛋白的底物结合腔附近，并改变了两个残基的电荷。该单倍型的相对快速扩张可能表明其在现代人类中具有选择优势。我们确定了结构域改组产生的 PIPSL 结构域的进化命运。在人科动物多样化过程中，所有谱系都保留了 S5a 衍生的结构域，而该结构域中的泛素相互作用基序（UIM）1 在早期经历了关键的氨基酸替换，在随后的高水平非同义替换下被保守到 UIM2 和其他结构域，表明适应性进化使这些功能区多样化。相反，PIP5K1A 衍生的结构域在长臂猿和大猩猩中退化。这些观察结果提供了一种可能的结构域改组方案，其中新嵌合蛋白中组合的亲本结构域没有紧密连接，允许其功能角色发生变化，从而对其进行微调。最初对一种新功能施加选择压力，而另一种结构域则处于近中性状态。随着时间的推移，后者也获得了新的功能或退化。
