Investigating Different Duplication Pattern of Essential Genes in Mouse and Human

March Investigating Different Duplication Pattern of Essential Genes in Mouse and Human Debarun Acharya 0 Dola Mukherjee 0 Soumita Podder 0 Tapash C. Ghosh 0 0 Bioinformatics Centre, Bose Institute , Kolkata, West Bengal , India Gene duplication is one of the major driving forces shaping genome and organism evolution and thought to be itself regulated by some intrinsic properties of the gene. Comparing the essential genes among mouse and human, we observed that the essential genes avoid duplication in mouse while prefer to remain duplicated in humans. In this study, we wanted to explore the reasons behind such differences in gene essentiality by cross-species comparison of human and mouse. Moreover, we examined essential genes that are duplicated in humans are functionally more redundant than that in mouse. The proportion of paralog pseudogenization of essential genes is higher in mouse than that of humans. These duplicates of essential genes are under stringent dosage regulation in human than in mouse. We also observed slower evolutionary rate in the paralogs of human essential genes than the mouse counterpart. Together, these results clearly indicate that human essential genes are retained as duplicates to serve as backed up copies that may shield themselves from harmful mutations. - Data Availability Statement: All the data used in the experiments are freely available in the paper, the supplemental files, and in well-recognized public repositories. All "gene essentiality, gene duplication, developmental genes and phyletic age data of mouse and human" are available from the Online Gene Essentiality Database (URL- http://ogeedb.embl.de). The dataset is also provided as a supplemental file S1_Dataset.xlsx. The duplicate pairs of mouse and human genes under study is provided in supplemental file S2_Dataset.xlsx. All Gene Ontology Annotation for mouse and human are available from the Ensembl biomart interface (Release 71) (URLhttp://www.ensembl.org/biomart/martview). Gene biotype data for Pseudogenization for mouse and human are available from the Ensembl biomart interface (Release 71) (URL-http://www.ensembl.org/ Gene duplication was thought to be one of the major driving factors stimulating genome and organism evolution [14], as it provides raw genetic materials for structural and functional modification and at the same time conserves the parental function. Although, gene duplication is not always beneficial, and most duplicates become subsequently inactivated or pseudogenized in the genome [4], it may have many implications in an organisms life. For example, the duplicates may be maintained in the genome for its immediate benefit to the organism, like increased gene dosage [5] or serve as backup copies to restore the function if the original one becomes deleted [6,7]. Apart from this, the duplicates may undergo modifications to take up novel functions, i.e. neofunctionalization [4], or they may share their function after complementary degenerative mutations, i.e. subfunctionalization [8,9]. The pattern of gene duplication may vary between species and also across different groups of genes within the same species. Several factors contributing gene duplication has been observed till date in diverse organisms like protein connectivity and protein interaction network [1012], protein complexity [13,14], gene retention and sequence divergence [15], dosage balance [16] and nevertheless, gene essentiality [1719]. biomart/martview). Nonsynonymous nucleotide substitution per nonsynonymous sites (dN) and synonymous nucleotide substitution per synonymous sites (dS) for mouse and human with corresponding one-to-one rat orthologs are available from the Ensembl biomart interface (Release 71) (URL-http:// www.ensembl.org/biomart/martview). All micro-RNA target sites for mouse and human were obtained from TargetScan Release 6.2 (http://www.targetscan.org). In the case of any query, the readers may contact Mr. Debarun Acharya (e-mail: ). Competing Interests: The authors have declared that no competing interests exist. Essential genes are indispensable to an organism and cause severe reduction in its fitness like sterility or lethality upon deletion [20]. These genes are mainly associated with important biological functions. However, many expressed genes performing such functions are considered to be nonessential, as their deletion can be compensated by other genes having similar or identical functions and expression [21]. Gene duplication is an important mechanism for such functional redundancy to occur [4]. Now, there may be two kinds of possibilities for essential genes to prefer or avoid the course of gene duplication. First, essential genes are required to become duplicated for providing backup copies that could shield themselves from any harmful mutations; secondly from evolutionary standpoint, essential genes may prefer to stay away from gene duplication since ectopic recombination and replication driven gene duplication may increase the chances of mutational load which is not at all acceptable for essential genes for being the most conserved gene-group [22,23]. Gene essentiality was widely studied across model organisms and shown to bear a complex relationship with gene duplication [19]. In lower eukaryotes like yeast, a higher proportion of essential genes were observed in singletons than in duplicates [7]. However, studies with mouse showed that the proportion of essential genes in duplicates are comparable to that in singletons [10,18]. Additionally, two follow-up studies with mouse also report that the proportion of essential genes is higher in singletons than in duplicates [21,24]. Till date, all the studies regarding essential genes were carried in yeast and mouse due to unavailability of human gene essentiality data. In a previous study, researchers attempted to explore the properties of human orthologs of mouse essential genes [25]. However, considering such human orthologs as essential may not be accurate [26]. Taking advantage of the Online Gene Essentiality (OGEE) database that represents a valuable resource of human and mouse essential genes, we performed a comprehensive analysis comparing duplication pattern of essential genes in human and mouse. We noticed that in mouse, the essential genes prefer to remain as singleton whereas the trend is reverse for human, which is unexplored so far. We have also explored the underlying reasons and the benefits of maintaining essential genes as duplicates in humans. Materials and Methods Gene Essentiality and Gene Duplication Gene essentiality and duplication of human (Homo sapiens) and mouse (Mus musculus) were obtained from the Online Gene Essentiality (OGEE) database (http://ogeedb.embl.de) [27] (S1 Dataset). The paralog lists for human and mouse essential genes were provided by the authors of OGEE database [27] (S2 Dataset). The developmental genes for mouse and human were obtained from Online Gene Essentialit (...truncated)