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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.01208

Characterization of Human Dosage-Sensitive Transcription Factor Genes

 Zhihua Ni1, 2, Xiao-Yu Zhou1,  Sidra Aslam1 and  Deng-Ke Niu1*
  • 1College of Life Sciences, Beijing Normal University, China
  • 2College of Life Sciences, Hebei University, China

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 datasets of dosage-sensitive genes (genes with conserved copy numbers across mammals, ohnologs, and two datasets of haploinsufficient genes), we compiled a dataset of the most reliable dosage-sensitive (MRDS) genes and a dataset of the most reliable dosage-insensitive (MRDIS) genes. The MRDS genes were those present in all four datasets, while the MRDIS genes were those absent from any one of the four datasets and with the probability of being loss of function-intolerant (pLI) values < 0.5 in both of the haploinsufficient gene datasets. Enrichment analysis of TF genes among the MRDS and MRDIS gene datasets 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.

Keywords: transcription factor, dosage-sensitive, Ohnolog, conserved copy number, Haploinsufficiency, Disease, nuclear receptor, C2H2-ZF

Received: 19 Sep 2019; Accepted: 01 Nov 2019.

Copyright: © 2019 Ni, Zhou, Aslam and Niu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Deng-Ke Niu, College of Life Sciences, Beijing Normal University, Beijing, 100875, China, dkniu@bnu.edu.cn