DataSheet_1_Characterization of Human Dosage-Sensitive Transcription Factor Genes.xlsx

Copy number changes in protein-coding genes are detrimental if the consequent changes in protein concentrations disrupt essential cellular functions. The dosage sensitivity of transcription factor (TF) genes is particularly interesting because their products are essential in regulating the expression of genetic information. From four recently curated data sets of dosage-sensitive genes (genes with conserved copy numbers across mammals, ohnologs, and two data sets of haploinsufficient genes), we compiled a data set of the most reliable dosage-sensitive (MRDS) genes and a data set of the most reliable dosage-insensitive (MRDIS) genes. The MRDS genes were those present in all four data sets, while the MRDIS genes were those absent from any one of the four data sets and with the probability of being loss of function-intolerant (pLI) values < 0.5 in both of the haploinsufficient gene data sets. Enrichment analysis of TF genes among the MRDS and MRDIS gene data sets showed that TF genes are more likely to be dosage-sensitive than other genes in the human genome. The nuclear receptor family was the most enriched TF family among the dosage-sensitive genes. TF families with very few members were also deemed more likely to be dosage-sensitive than TF families with more members. In addition, we found a certain number of dosage-insensitive TFs. The most typical were the Krüppel-associated box domain-containing zinc-finger proteins (KZFPs). Gene ontology (GO) enrichment analysis showed that the MRDS TFs were enriched for many more terms than the MRDIS TFs; however, the proteins interacting with these two groups of TFs did not show such sharp differences. Furthermore, we found that the MRDIS KZFPs were not significantly enriched for any GO terms, whereas their interacting proteins were significantly enriched for thousands of GO terms. Further characterizations revealed significant differences between MRDS TFs and MRDIS TFs in the lengths and nucleotide compositions of DNA-binding sites as well as in expression level, protein size, and selective force.蛋白编码基因的拷贝数改变若导致蛋白质浓度变化并破坏必需细胞功能，则会产生有害影响。转录因子（transcription factor, TF）基因的剂量敏感性尤为值得关注，因为其编码产物在调控遗传信息表达过程中发挥必需作用。我们从4套近期整理的剂量敏感基因数据集（包括哺乳动物中保守拷贝数基因、ohnolog基因，以及2套单倍剂量不足基因数据集）中，汇编得到最可靠剂量敏感（most reliable dosage-sensitive, MRDS）基因数据集与最可靠剂量不敏感（most reliable dosage-insensitive, MRDIS）基因数据集。其中MRDS基因指同时存在于全部4套数据集中的基因，而MRDIS基因则指未出现在任意1套上述4套数据集、且在两套单倍剂量不足基因数据集中的功能丧失不耐受概率（probability of being loss of function-intolerant, pLI）值均小于0.5的基因。对MRDS与MRDIS基因数据集中的TF基因开展富集分析，结果显示TF基因相较于人类基因组中的其他基因，更易呈现剂量敏感性。在剂量敏感基因中，核受体家族是富集程度最高的TF家族。成员数量极少的TF家族，相较于成员更多的TF家族，也被认为更易呈现剂量敏感性。此外，我们还发现了一定数量的剂量不敏感TF，其中最具代表性的是含Krüppel相关盒结构域的锌指蛋白（Krüppel-associated box domain-containing zinc-finger proteins, KZFPs）。基因本体（Gene Ontology, GO）富集分析结果显示，MRDS TFs富集的GO条目数量远多于MRDIS TFs；但与这两组TF相互作用的蛋白质并未呈现如此显著的差异。进一步分析发现，MRDIS KZFPs未显著富集任何GO条目，而其相互作用蛋白质却显著富集了数千个GO条目。进一步的特征分析显示，MRDS TFs与MRDIS TFs在DNA结合位点的长度、核苷酸组成，以及表达水平、蛋白质大小与选择压力等方面均存在显著差异。