Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Mol Biol Evol. 2011 Jan;28(1):859-71. doi: 10.1093/molbev/msq257. Epub 2010 Oct 5.
The voltage-gated sodium channel (SCN) alpha subunits are large proteins with central roles in the generation of action potentials. They consist of approximately 2,000 amino acids encoded by 24-27 exons. Previous evolutionary studies have been unable to reconcile the proposed gene duplication schemes with the species distribution and molecular phylogeny of the genes. We have carefully annotated the complete SCN gene sequences, correcting numerous database errors, for a broad range of vertebrate species and analyzed their phylogenetic relationships. We have also compared the chromosomal positions of the SCN genes relative to adjacent gene families. Our studies show that the ancestor of the vertebrates probably had a single sodium channel gene with two characteristic AT-AC introns, the second of which is unique to vertebrate SCN genes. This ancestral gene, located close to a HOX gene cluster, was quadrupled along with HOX in the two rounds of basal vertebrate tetraploidizations to generate the ancestors of the four channels SCN1A, SCN4A, SCN5A, and SCN8A. The third tetraploidization in the teleost fish ancestor doubled this set of genes and all eight are still present in at least three of four investigated teleost fish genomes. In tetrapods, the gene family expanded by local duplications before the radiation of amniotes, generating the cluster SCN5A, SCN10A, and SCN11A on one chromosome and the cluster SCN1A, SCN2A, SCN3A, and SCN9A on a different chromosome. In eutherian mammals, a tenth gene, SCN7A, arose in a local duplication in the SCN1A gene cluster. The SCN7A gene has undergone rapid evolution and has lost the ability to cause action potentials-instead, it functions as a sodium sensor. The three genes in the SCN5A cluster were translocated from the HOX-bearing chromosome in a mammalian ancestor along with several adjacent genes. This evolutionary scenario is supported by the adjacent TGF-β receptor superfamily (comprised of five distinct families) and the cysteine-serine-rich nuclear protein gene family as well as the HOX clusters. The independent expansions of the SCN repertoires in tetrapods and teleosts suggest that the functional diversification may differ between the two lineages.
电压门控钠离子通道（SCN）α亚基是在产生动作电位中起核心作用的大型蛋白质。它们由大约 2000 个氨基酸组成，由 24-27 个外显子编码。以前的进化研究一直无法调和提议的基因复制方案与基因的物种分布和分子系统发生学。我们仔细注释了广泛的脊椎动物物种的完整 SCN 基因序列，纠正了许多数据库错误，并分析了它们的系统发生关系。我们还比较了 SCN 基因相对于相邻基因家族的染色体位置。我们的研究表明，脊椎动物的祖先可能有一个单一的钠离子通道基因，带有两个特征性的 AT-AC 内含子，第二个内含子是脊椎动物 SCN 基因所特有的。这个祖先基因位于靠近 HOX 基因簇的位置，在两轮基础脊椎动物四倍体化过程中与 HOX 一起被四倍化，产生了 SCN1A、SCN4A、SCN5A 和 SCN8A 这四个通道的祖先。在硬骨鱼祖先的第三次四倍体化过程中，这组基因又被加倍，在至少三个研究的硬骨鱼基因组中仍然存在这八个基因。在四足动物中，在羊膜动物辐射之前，通过局部复制使基因家族扩大，在一条染色体上产生了 SCN5A、SCN10A 和 SCN11A 基因簇，在另一条染色体上产生了 SCN1A、SCN2A、SCN3A 和 SCN9A 基因簇。在真兽类哺乳动物中，第十个基因 SCN7A 是在 SCN1A 基因簇中的局部复制中产生的。SCN7A 基因经历了快速进化，已经失去了产生动作电位的能力，而是作为钠离子传感器发挥作用。SCN5A 基因簇中的三个基因与几个相邻基因一起从哺乳动物祖先的含有 HOX 的染色体上易位。这种进化情景得到了相邻的 TGF-β 受体超家族（由五个不同的家族组成）和半胱氨酸-丝氨酸丰富的核蛋白基因家族以及 HOX 簇的支持。四足动物和硬骨鱼的 SCN 谱的独立扩张表明，这两个谱系之间的功能多样化可能不同。
