TBC1D3 is a primate-specific gene family that has expanded in the human lineage and has been implicated in neuronal progenitor proliferation and expansion of the frontal cortex. The gene family and its expression have been challenging to investigate because it is embedded in high-identity and highly variable segmental duplications. We sequenced and assembled the gene family using long-read sequencing data from 34 humans and 11 nonhuman primate species. Our analysis shows that this particular gene family has independently duplicated in at least five primate lineages, and the duplicated loci are enriched at sites of large-scale chromosomal rearrangements on Chromosome 17. We find that all human copy-number variation maps to two distinct clusters located at Chromosome 17q12 and that humans are highly structurally variable at this locus, differing by as many as 20 copies and ∼1 Mbp in length depending on haplotypes. We also show evidence of positive selection, as well as a significant change in the predicted human TBC1D3 protein sequence. Last, we find that, despite multiple duplications, human TBC1D3 expression is limited to a subset of copies and, most notably, from a single paralog group: TBC1D3-CDKL. These observations may help explain why a gene potentially important in cortical development can be so variable in the human population.

中文翻译：

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人类 TBC1D3 基因家族的独立扩增、选择和高变异性


TBC1D3 是一个灵长类动物特异性基因家族，已在人类谱系中扩增，与神经元祖细胞增殖和额叶皮层扩张有关。基因家族及其表达一直难以研究，因为它嵌入在高同一性和高度可变的节段重复中。我们使用来自 34 种人类和 11 种非人类灵长类动物的长读长测序数据对基因家族进行了测序和组装。我们的分析表明，这个特定的基因家族在至少 5 个灵长类动物谱系中独立复制，并且重复的基因座在 17 号染色体上大规模染色体重排的位点富集。我们发现所有人类拷贝数变异都映射到位于染色体 17q12 的两个不同簇，并且人类在该基因座的结构上高度可变，根据单倍型，差异多达 20 个拷贝和 ∼1 Mbp。我们还显示了阳性选择的证据，以及预测的人类 TBC1D3 蛋白序列的显着变化。最后，我们发现，尽管存在多个重复，但人类 TBC1D3 表达仅限于拷贝的子集，并且最值得注意的是，来自单个旁系同源组：TBC1D3-CDKL。这些观察可能有助于解释为什么在皮层发育中可能重要的基因在人类群体中如此可变。