Morrison Gillian M, Semple Colin A M, Kilanowski Fiona M, Hill Robert E, Dorin Julia R
MRC Human Genetics Unit, Western General Hospital, Edinburgh, Scotland.
Mol Biol Evol. 2003 Mar;20(3):460-70. doi: 10.1093/molbev/msg060.
Beta-defensins are two exon genes which encode broad spectrum antimicrobial cationic peptides. We have analyzed the largest murine cluster of these genes which localizes to chromosome 8. Using hidden Markov models, we identified six beta-defensin exon 2-like sequences and subsequently found full-length expressed transcripts for these novel genes. Expression was high in brain and reproductive tissues. Eleven beta-defensins could be grouped into two clear subgroups by virtue of their position and high signal sequence (exon 1 encoded) identity. In contrast, however, there was a very low level of sequence conservation in the exon 2 region encoding the mature antimicrobial peptide. Examination of the gene sequences of orthologs in other rodents also revealed an excess of nucleotide changes that altered amino acids in the mature peptide region. Evolutionary analysis revealed strong evidence that following gene duplication, exon 1 and surrounding noncoding DNA show little divergence within subgroups. The focus for rapid sequence divergence is localized in the DNA encoding the mature peptide and this is driven by accelerated positive selection. This mechanism of evolution is consistent with the role of this gene family as defense against bacterial pathogens and the sequence changes have implications for novel antibiotic design.
β-防御素是编码广谱抗菌阳离子肽的双外显子基因。我们分析了定位于8号染色体的这些基因中最大的小鼠基因簇。利用隐马尔可夫模型，我们鉴定出6个β-防御素外显子2样序列，随后发现了这些新基因的全长表达转录本。在脑和生殖组织中表达水平很高。11种β-防御素可根据其位置和高信号序列（外显子1编码）同一性分为两个明显的亚组。然而，相比之下，编码成熟抗菌肽的外显子2区域的序列保守性非常低。对其他啮齿动物直系同源基因序列的研究也发现，成熟肽区域中改变氨基酸的核苷酸变化过多。进化分析显示有力证据表明，基因复制后，外显子1和周围的非编码DNA在亚组内几乎没有差异。快速序列分化的焦点定位于编码成熟肽的DNA中，这是由加速的正选择驱动的。这种进化机制与该基因家族作为抵御细菌病原体的作用相一致，并且序列变化对新型抗生素设计具有启示意义。
