ReviewGene redundancy and gene compensation: An updated view
Introduction
Gene redundancy is a term that describes a gene which has one or more homologues playing same/similar biochemical function in the genome. From the evolution point of view, gene redundancy is beneficial for an organism to survive when one copy of the homologues becomes non-functional/malfunctional. However, it is disfavored by geneticists or developmental biologists who rely on the forward genetic approach to screen phenotypic mutants or on the reverse genetics to generate null alleles for target genes because the redundant genes might obscure the phenotypic screening or analysis. To overcome this problem, geneticists and developmental biologists prefer to use model organisms, such as yeast, Drosophila, Caenorhabditis elegan, Arabidpsis, rice and zebrafish, owing to their presumable small and simple genome (Goffeau et al., 1996; C. elegans Sequencing Consortium, 1998; Adams et al., 2000; Arabidopsis Genome Initiative, 2000; Howe et al., 2013), with the hope that it will minimize the potential disadvantage brought by the redundant genes. With these model systems, scientists have made achievements which have greatly advanced our understanding of many fundamental biological processes. However, even with model systems, it is not unusual to find that loss-of-function of a gene does not show any phenotype or an obvious phenotype (Peng et al., 1997; Lee et al., 2002). Before genome sequencing era, it was a routine approach to use a radio-labelled probe in screening a genomic or cDNA library to clone the corresponding gene. Often, such screening obtained the perfect match gene but meanwhile its homologues as well (Peng et al., 1997). With that, functional compensation for the mutated gene by its homologue(s) became a logical interpretation to this phenomenon. The fast advancing of genome sequencing has opened a completely new avenue for gene function study; however, it also brought a dismay to geneticists and developmental biologists because now we know that the genomes of our genetic model organisms are not as simple as we originally imagined, and gene redundancy is a prevailing phenomenon (Goffeau et al., 1996; C. elegans Sequencing Consortium, 1998;; Adams et al., 2000; Arabidopsis Genome Initiative, 2000; Howe et al., 2013). To overcome this problem, researchers have to generate a mutant harboring mutations in most if not all of the homologous genes (Cheng et al., 2004). However, whether the gene function compensation by the homologues of the mutated gene is a passive or active process had not been seriously investigated before 2015.
Section snippets
Morpholino-mediated gene knockdown
Zebrafish was formally accepted as a model system for the study of vertebrate development by the community of developmental biologists in 1990s (Driever et al., 1996; Peng et al., 2012). Several large scale mutagenesis was carried out which identified several hundreds of phenotypic mutants affecting a variety of developmental processes, demonstrating the power of this new genetic model system (Driever et al., 1996; Haffter et al., 1996). However, to get a genome-wide saturated mutagenized
Phenotypic discrepancy between morphants and null mutants
The fast development of techniques in genome editing, especially the TALEN and CRISPR/Cas9 techniques, has turned the study of a gene function to a new page (Huang et al., 2012; Chang et al., 2013; Hwang et al., 2013). Researches quickly started to adopt these techniques to generate loss-of-function mutants of their target genes. However, the community was astonished to find that numerous apparent loss-of-function alleles of some important genes failed to display the expected phenotype or only
Discovery of gene compensation induced by deleterious mutation
The episode suddenly turned around in August 2015. Rossi and colleagues reported their finding that deleterious mutation rather gene knockdown induced gene compensation (GC) by activating the expression of genes harboring homologous sequences (Rossi et al., 2015). The authors generated two mutant alleles for the EGF-like-domain, multiple 7 (egfl7) gene, one with 3-bp deletion (thus resulting in one amino acid deletion in the protein product) in the non-conserved region while the other with 4-bp
Gene compensation relies on PTC-bearing mRNA, sequence homology, NMD pathway and COMPASS components
The myth behind GC by deleterious mutation was recently partly unraveled by two publications in the same issue of Nature. El-Brolosy and colleagues analyzed six zebrafish gene mutants including hbegfa, vcla, hif1ab, vegfaa, egfl7 and alcama mutants and found that their corresponding family members were up-regulated in homozygous mutants (El-Brolosy et al., 2019). Interestingly, the wild-type transcripts in hbegfa, hif1ab, vegfaa and alcama heterozygous embryos were also up-regulated, suggesting
Remaining issues and therapeutic application potentials
Both work summarized in the above proved the necessarity of the homologous sequence and COMPASS complex for eliciting a GC. While Ma and colleagues showed that a PTC is required to trigger the GC, El-Brolosy and colleagues believed that mRNA degradation products are sufficient and the PTC-bearing mRNA may just serve as a substrate of the NMD pathway to produce the degradation products. This might explain the finding of the importance of Upf1 in the GC by El-Brolosy and colleagues (El-Brolosy
Updated view of genetic compensation and gene compensation
Based on the new discoveries summarized in the above, here I am trying to refine the concept for genetic compensation and GC (Fig. 1). Genetic compensation is a more general concept to describe genetic robustness which ensures a living organism to maintain its viability and fitness when it encounters genetic variations. Genetic compensation can be achieved by gene redundancy, alternative splicing of the transcripts containing PTC-bearing mutations (Anderson et al., 2017; Lalonde et al., 2017),
Acknowledgments
This research was supported by National Key R&D Program of China (2018YFA0800501), National Natural Science Foundation of China (Nos.31571495, 31830113 and 31330050). I sincerely thank Drs. Jun Chen and Zhipeng Ma and other members in my lab and Dr. Jun Chen's lab for their excellent research work that has inspired me to write this review.
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2023, Genes and DiseasesCitation Excerpt :The upregulating genes which could be triggered in genetic compensation (genetic robustness) might be gained from the redundancy of gene function, when a gene has one or more homologous gene(s) which play the same or similar biochemical function in the genome. For those respective organisms, genetic robustness has a beneficial role to help organisms survive when one copy of the homologous genes becomes non/mal-function due to mutation.2 In the most recent study, the phenomenon of genetic compensation response has been widely studied and observed in the zebrafish model especially for the concept in which several mutant zebrafish for different genes performed normal phenotype.6,8–14