Glycobiology Research and Training Center, University of California at San Diego, San Diego, CA, USA.
Mol Biol Evol. 2012 Aug;29(8):2073-86. doi: 10.1093/molbev/mss077. Epub 2012 Mar 1.
We previously reported a human-specific gene conversion of SIGLEC11 by an adjacent paralogous pseudogene (SIGLEC16P), generating a uniquely human form of the Siglec-11 protein, which is expressed in the human brain. Here, we show that Siglec-11 is expressed exclusively in microglia in all human brains studied-a finding of potential relevance to brain evolution, as microglia modulate neuronal survival, and Siglec-11 recruits SHP-1, a tyrosine phosphatase that modulates microglial biology. Following the recent finding of a functional SIGLEC16 allele in human populations, further analysis of the human SIGLEC11 and SIGLEC16/P sequences revealed an unusual series of gene conversion events between two loci. Two tandem and likely simultaneous gene conversions occurred from SIGLEC16P to SIGLEC11 with a potentially deleterious intervening short segment happening to be excluded. One of the conversion events also changed the 5' untranslated sequence, altering predicted transcription factor binding sites. Both of the gene conversions have been dated to ~1-1.2 Ma, after the emergence of the genus Homo, but prior to the emergence of the common ancestor of Denisovans and modern humans about 800,000 years ago, thus suggesting involvement in later stages of hominin brain evolution. In keeping with this, recombinant soluble Siglec-11 binds ligands in the human brain. We also address a second-round more recent gene conversion from SIGLEC11 to SIGLEC16, with the latter showing an allele frequency of ~0.1-0.3 in a worldwide population study. Initial pseudogenization of SIGLEC16 was estimated to occur at least 3 Ma, which thus preceded the gene conversion of SIGLEC11 by SIGLEC16P. As gene conversion usually disrupts the converted gene, the fact that ORFs of hSIGLEC11 and hSIGLEC16 have been maintained after an unusual series of very complex gene conversion events suggests that these events may have been subject to hominin-specific selection forces.
我们之前曾报道过一个由相邻的假基因（SIGLEC16P）对 SIGLEC11 进行的人类特异性基因转换，从而产生了一种独特的人类 Siglec-11 蛋白形式，该蛋白在人类大脑中表达。在这里，我们表明 Siglec-11 仅在所有研究的人脑中小胶质细胞中表达 - 这一发现可能与大脑进化有关，因为小胶质细胞调节神经元存活，而 Siglec-11 招募 SHP-1，一种调节小胶质细胞生物学的酪氨酸磷酸酶。在最近发现人类群体中存在功能性 SIGLEC16 等位基因后，对人类 SIGLEC11 和 SIGLEC16/P 序列的进一步分析揭示了两个基因座之间一系列不寻常的基因转换事件。两个串联且可能同时发生的基因转换从 SIGLEC16P 到 SIGLEC11 发生，其间发生了一个潜在的有害短片段缺失。其中一个转换事件还改变了 5'非翻译序列，改变了预测的转录因子结合位点。这两个基因转换都发生在约 1-1.2 万年前，即在人类属出现之后，但在约 80 万年前丹尼索瓦人和现代人类的共同祖先出现之前，这表明它们参与了人类大脑进化的后期阶段。与之相符的是，重组可溶性 Siglec-11 与人脑中的配体结合。我们还解决了来自 SIGLEC11 到 SIGLEC16 的第二轮更近的基因转换，后者在全球人群研究中显示出约 0.1-0.3 的等位基因频率。SIGLEC16 的初步假基因化估计至少发生在 3 Ma 之前，这先于 SIGLEC11 通过 SIGLEC16P 的基因转换。由于基因转换通常会破坏被转换的基因，因此 hSIGLEC11 和 hSIGLEC16 的 ORF 在一系列非常复杂的基因转换事件之后得以保留，这表明这些事件可能受到了人类特有的选择压力。
