Scottish Oceans Institute, University of St Andrews, St Andrews, Fife, United Kingdom.
Mol Biol Evol. 2013 May;30(5):1060-76. doi: 10.1093/molbev/mst017. Epub 2013 Jan 29.
Whole-genome duplication (WGD) was experienced twice by the vertebrate ancestor (2 rounds; 2R), again by the teleost fish ancestor (3R) and most recently in certain teleost lineages (4R). Consequently, vertebrate gene families are often expanded in 3R and 4R genomes. Arguably, many types of "functional divergence" present across 2R gene families will exceed that between 3R/4R paralogs of genes comprising 2R families. Accordingly, 4R offers a form of replication of 2R. Examining whether this concept has implications for molecular evolutionary research, we studied insulin-like growth factor (IGF) binding proteins (IGFBPs), whose six 2R family members carry IGF hormones and regulate interactions between IGFs and IGF1-receptors (IGF1Rs). Using phylogenomic approaches, we resolved the complete IGFBP repertoire of 4R-derived salmonid fishes (19 genes; 13 more than human) and established evolutionary relationships/nomenclature with respect to WGDs. Traits central to IGFBP action were determined for all genes, including atomic interactions in IGFBP-IGF1/IGF2 complexes regulating IGF-IGF1R binding. Using statistical methods, we demonstrate that attributes of these protein interfaces are overwhelming a product of 2R IGFBP family membership, explain 49-68% of variation in IGFBP mRNA concentration in several different tissues, and strongly predict the strength and direction of IGFBP transcriptional regulation under differing nutritional states. The results support a model where vertebrate IGFBP family members evolved divergent structural attributes to provide distinct competition for IGFs with IGF1Rs, predisposing different functions in the regulation of IGF signaling. Evolution of gene expression then acted to ensure the appropriate physiological production of IGFBPs according to their structural specializations, leading to optimal IGF-signaling according to nutritional-status and the endocrine/local mode of action. This study demonstrates that relatively recent gene family expansion can facilitate inference of functional evolution within ancient genetic systems.
全基因组复制 (WGD) 经历了两次脊椎动物祖先 (2 轮；2R)，再次经历了硬骨鱼祖先 (3R)，最近又在某些硬骨鱼谱系中经历了 (4R)。因此，脊椎动物基因家族在 3R 和 4R 基因组中经常扩张。可以说，2R 基因家族中存在的许多类型的“功能分化”将超过由 2R 基因家族组成的 3R/4R 旁系同源物之间的分化。因此，4R 提供了一种复制 2R 的形式。我们研究了胰岛素样生长因子 (IGF) 结合蛋白 (IGFBPs)，以检验这一概念是否对分子进化研究有影响，这些蛋白的六个 2R 家族成员携带 IGF 激素，调节 IGF 与 IGF1 受体 (IGF1R) 之间的相互作用。我们使用系统发育基因组学方法解决了来自 4R 衍生的鲑鱼 (19 个基因；比人类多 13 个) 的完整 IGFBP 库，并建立了与 WGD 相关的进化关系/命名法。确定了所有基因的 IGFBP 作用的核心特征，包括调节 IGF-IGF1R 结合的 IGFBP-IGF1/IGF2 复合物中的原子相互作用。使用统计方法，我们证明了这些蛋白质界面的属性是 2R IGFBP 家族成员的产物的压倒性产物，解释了在几种不同组织中 IGFBP mRNA 浓度变化的 49-68%，并且强烈预测了在不同营养状态下 IGFBP 转录调控的强度和方向。结果支持了这样一种模型，即脊椎动物 IGFBP 家族成员进化出了不同的结构属性，以提供与 IGF1R 对 IGF 的不同竞争，从而在 IGF 信号转导的调节中赋予不同的功能。随后的基因表达进化作用确保了根据其结构特化适当地产生 IGFBPs，从而根据营养状况和内分泌/局部作用模式实现最佳的 IGF 信号转导。这项研究表明，相对较新的基因家族扩张可以促进对古老遗传系统中功能进化的推断。
