Gene redundancy and gene compensation: An updated view

Abstract

Gene knockdown approaches using antisense oligo nucleotides or analogs such as siRNAs and morpholinos have been widely adopted to study gene functions although the off-target issue has been always a concern in these studies. On the other hand, classic genetic analysis relies on the availability of loss-of-function or gain-of-function mutants. The fast development of genome editing technologies such as TALEN and CRISPR/Cas9 has greatly facilitated the generation of null mutants for the functional studies of target genes in a variety of organisms such as zebrafish. Surprisingly, an unexpected discrepancy was observed between morphant phenotype and mutant phenotype for many genes in zebrafish, i.e., while the morphant often displays an obvious phenotype, the corresponding null mutant appears relatively normal or only exhibits a mild phenotype due to gene compensation. Two recent reports have partially answered this intriguing question by showing that a pre-mature termination codon and homologous sequence are required to elicit the gene compensation and the histone modifying complex COMPASS is involved in activating the expression of the compensatory genes. Here, I summarize these exciting new progress and try to redefine the concept of genetic compensation and gene compensation.

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.