Predicting the Proportion of Essential Genes in Mouse Duplicates Based on Biased Mouse Knockout Genes

Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Journal of Molecular Evolution (Impact Factor: 1.68). 12/2008; 67(6):705-9. DOI: 10.1007/s00239-008-9170-9
Source: PubMed


In the yeast or nematode, the proportion of essential genes in duplicates is lower than in singletons (single-copy genes), due to the functional redundancy. One may expect that it should be the same in the mouse genome. However, based on the publicly available mouse knockout data, it was observed that the proportion of essential genes in duplicates is similar to that in singletons. The most straightforward interpretation, as claimed in a recent study, is that duplicate genes may have a negligible role in the mouse genetic robustness. Here we show that in the current mouse knockout dataset, recently duplicated genes have been highly underrepresented, leading to an overestimation of the proportion of essential genes in duplicates. After estimating the duplication time of mouse duplication events, we have developed a simple bias-correcting procedure and shown that the bias-corrected proportion of essential genes in mouse duplicates is significantly lower than that in singletons.

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    • "Thus, genes that have not been duplicated are more likely to be essential than those that have duplicated [17], [21], [22]. However, this is not true in mammals [21], [23]–[25], probably due to the complexity of development of higher organisms [26], [27]. "
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    ABSTRACT: Genes are characterized as essential if their knockout is associated with a lethal phenotype, and these "essential genes" play a central role in biological function. In addition, some genes are only essential when deleted in pairs, a phenomenon known as synthetic lethality. Here we consider genes displaying synthetic lethality as "essential pairs" of genes, and analyze the properties of yeast essential genes and synthetic lethal pairs together. As gene duplication initially produces an identical pair or sets of genes, it is often invoked as an explanation for synthetic lethality. However, we find that duplication explains only a minority of cases of synthetic lethality. Similarly, disruption of metabolic pathways leads to relatively few examples of synthetic lethality. By contrast, the vast majority of synthetic lethal gene pairs code for proteins with related functions that share interaction partners. We also find that essential genes and synthetic lethal pairs cluster in the protein-protein interaction network. These results suggest that synthetic lethality is strongly dependent on the formation of protein-protein interactions. Compensation by duplicates does not usually occur mainly because the genes involved are recent duplicates, but is more commonly due to functional similarity that permits preservation of essential protein complexes. This unified view, combining genes that are individually essential with those that form essential pairs, suggests that essentiality is a feature of physical interactions between proteins protein-protein interactions, rather than being inherent in gene and protein products themselves.
    PLoS ONE 04/2013; 8(4):e62866. DOI:10.1371/journal.pone.0062866 · 3.23 Impact Factor
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    • "The ENCyclopedia Of DNA Elements (ENCODE) project, designed to analyse 30 megabases (Mb) of DNA from 44 genomic regions (thereby sampling 1% of the genome) in order to characterize the functional elements present, has identified complex patterns of regulation and 'pervasive transcription' of the human genome [ENCODE Project Consortium, 2007]. Whilst >90% of the human genome appears to be represented in nuclear primary transcripts, it has become clear that only 35-50% of processed transcripts have so far been annotated as genes, implying that many genes may not yet have been recognized as such [ENCODE Project Consortium, 2007; Gingeras, 2007; Rozowsky et al., 2007; Sultan et al., 2008]. Thus, large numbers of hitherto unannotated transcripts may well yet turn out to be of functional significance "
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    ABSTRACT: The number of reported germline mutations in human nuclear genes, either underlying or associated with inherited disease, has now exceeded 100,000 in more than 3,700 different genes. The availability of these data has both revolutionized the study of the morbid anatomy of the human genome and facilitated "personalized genomics." With approximately 300 new "inherited disease genes" (and approximately 10,000 new mutations) being identified annually, it is pertinent to ask how many "inherited disease genes" there are in the human genome, how many mutations reside within them, and where such lesions are likely to be located? To address these questions, it is necessary not only to reconsider how we define human genes but also to explore notions of gene "essentiality" and "dispensability."Answers to these questions are now emerging from recent novel insights into genome structure and function and through complete genome sequence information derived from multiple individual human genomes. However, a change in focus toward screening functional genomic elements as opposed to genes sensu stricto will be required if we are to capitalize fully on recent technical and conceptual advances and identify new types of disease-associated mutation within noncoding regions remote from the genes whose function they disrupt.
    Human Mutation 06/2010; 31(6):631-55. DOI:10.1002/humu.21260 · 5.14 Impact Factor
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    • "This is indeed the case in the yeast and in the nematode (Gu et al. 2003; Conant and Wagner 2004) but not in the mouse (Liang and Li 2007; Liao and Zhang 2007). Although recent reports pointed out that the mouse knockout data were biased in both duplication age and function (Su and Gu 2008; Makino et al. 2009), the relationship between phenotypic effect and gene duplication in the mouse appears to be weaker than those in the yeast and the nematode (Hannay et al. 2008). It was proposed that because mouse is more complex than nematode and yeast in terms of the number of different cell types, duplicate genes in mouse tend to undergo functional diversification instead of preserving functional compensation (Zhang 2003; Liao and Zhang 2007). "
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    ABSTRACT: Knocking out a gene from a genome often causes no phenotypic effect. This phenomenon has been explained in part by the existence of duplicate genes. However, it was found that in mouse knockout data duplicate genes are as essential as singleton genes. Here, we study whether it is also true for the knockout data in Arabidopsis. From the knockout data in Arabidopsis thaliana obtained in our study and in the literature, we find that duplicate genes show a significantly lower proportion of knockout effects than singleton genes. Because the persistence of duplicate genes in evolution tends to be dependent on their phenotypic effect, we compared the ages of duplicate genes whose knockout mutants showed less severe phenotypic effects with those with more severe effects. Interestingly, the latter group of genes tends to be more anciently duplicated than the former group of genes. Moreover, using multiple-gene knockout data, we find that functional compensation by duplicate genes for a more severe phenotypic effect tends to be preserved by natural selection for a longer time than that for a less severe effect. Taken together, we conclude that duplicate genes contribute to genetic robustness mainly by preserving compensation for severe phenotypic effects in A. thaliana.
    Genome Biology and Evolution 10/2009; 1:409-14. DOI:10.1093/gbe/evp043 · 4.23 Impact Factor
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