Gene Repertoires by Whole-Genome Duplications in Early Vertebrates

Cell Reports Article On the Expansion of ‘‘Dangerous’’ Gene Repertoires by Whole-Genome Duplications in Early Vertebrates Param Priya Singh,1,3 Se´ verine Affeldt,1,3 Ilaria Cascone,2 Rasim Selimoglu,2 Jacques Camonis,2 and Herve´ Isambert1,* 1CNRS UMR168 2INSERM U830 UPMC, Institut Curie, Research Center, 26, rue d’Ulm, 75248 Paris, France 3These authors contributed equally to this work *Correspondence: [email protected] http://dx.doi.org/10.1016/j.celrep.2012.09.034 SUMMARY implicated in cancer and severe genetic diseases have also been greatly expanded by duplication in the course of vertebrate The emergence and evolutionary expansion of gene evolution. For example, the single orthologous locus, Ras85D in families implicated in cancers and other severe flies and Let-60 in nematodes, has been duplicated into three genetic diseases is an evolutionary oddity from RAS loci in typical vertebrates, KRAS, HRAS, and NRAS, that a natural selection perspective. Here, we show that present permanently activating mutations in 20%–25% of all HRAS NRAS gene families prone to deleterious mutations in the human tumors, even though and have also been human genome have been preferentially expanded shown to be dispensable for mouse growth and development (Ise et al., 2000; Esteban et al., 2001). by the retention of ‘‘ohnolog’’ genes from two rounds While the maintenance of essential genes is ensured by of whole-genome duplication (WGD) dating back their lethal null mutations, the expansion of dangerous gene from the onset of jawed vertebrates. We further families remains an evolutionary puzzle from a natural selection demonstrate that the retention of many ohnologs perspective. Indeed, considering that many vertebrate disease suspected to be dosage balanced is in fact indirectly genes are phylogenetically ancient (Domazet-Loso and Tautz, mediated by their susceptibility to deleterious muta- 2008; Cai et al., 2009; Dickerson and Robertson, 2012), and tions. This enhanced retention of ‘‘dangerous’’ ohno- that their orthologs also cause severe genetic disorders in extant logs, defined as prone to autosomal-dominant dele- invertebrates (Berry et al., 1997; Ciocan et al., 2006; Robert, terious mutations, is shown to be a consequence of 2010), it is surprising that dangerous gene families have been WGD-induced speciation and the ensuing purifying duplicated more than other vertebrate genes without known selection in post-WGD species. These findings high- dominant deleterious mutations. While gene duplicates can confer mutational robustness against loss-of-function muta- light the importance of WGD-induced nonadaptive tions, multiple copies of genes prone to gain-of-function muta- selection for the emergence of vertebrate complexity, tions are expected to lead to an overall aggravation of a species’ while rationalizing, from an evolutionary perspective, susceptibility to genetic diseases and thus be opposed by puri- the expansion of gene families frequently implicated fying selection. in genetic disorders and cancers. Two alternative hypotheses can be put forward to account for the surprising expansion of dangerous gene families. Either, the INTRODUCTION propensity of certain genes to acquire dominant deleterious mutations could be a mere by-product of their presumed advan- Just as some genes happen to be more ‘‘essential,’’ owing to tageous functions. In that case, only the overall benefit of gene their deleterious loss-of-function or null mutations, some genes family expansion should matter, irrespective of the mechanism can be classified as more ‘‘dangerous,’’ due to their propensity of gene duplication. Alternatively, gene susceptibility to domi- to acquire deleterious gain-of-function mutations. This is, in nant deleterious mutations could have played a driving role in particular, the case for oncogenes and genes with autoinhibitory the striking expansion of dangerous gene families. But what protein folds, whose mutations typically lead to constitutively could have been the selection mechanism? active mutants with dominant deleterious phenotypes (Pufall In this article, we report converging evidences supporting the and Graves, 2002). latter hypothesis and propose a simple evolutionary model to Dominant deleterious mutations, that are lethal or drastically explain the expansion of such dangerous gene families. It is reduce fitness over the lifespan of organisms, must have also based on the observation that the majority of human genes impacted their long term evolution on timescales relevant for prone to dominant deleterious mutations, such as oncogenes genome evolution (e.g., >10–100 million years [MY]). In fact, and genes with autoinhibitory protein folds, have not been dupli- dominant disease genes in humans have been shown to be cated through small scale duplication (SSD). Instead, the expan- under strong purifying selection (Furney et al., 2006; Blekhman sion of these dangerous gene families can be traced back to two et al., 2008; Cai et al., 2009). Yet, ‘‘dangerous’’ gene families rounds of whole-genome duplication (WGD), that occurred at the Cell Reports 2, 1387–1398, November 29, 2012 ª2012 The Authors 1387 A Reference B Susceptibility to Deleterious Mutations C Susceptibility to Dosage Balance Ratio: 0.53 0.92 (x1.7) 1.4 (x2.7) 1.5 (x2.9) 1.5 (x2.9) 3.2 (x6.0) 4.0 (x7.6) 10.1 (x19) 0.7 (x1.3) 1.2 (x2.2) 0.08 (x0.15) 91% 93% 80% 76% 65% 59% 61% 61% 59% 52% 54% 48% 46% 41% 41% 39% 39% 35% 24% 20% 9% 7% All Genes Cancer or Disease Dom. Disease Dominant Neg. Oncogenes Autoinhibition Autoinhibition Autoinhibition Complex Haploinsufficient Permanent Complex (20,506) Genes (8,095) Genes (440) (477) (813) (461) & cancer (369) & oncogene (114) (3,814) (330) (239) Figure 1. Prevalence of Retained Ohnologs in the Human Genome within Different Gene Classes (A and B) Prevalence of retained ohnologs either ‘‘w/ SSD or CNV’’ or ‘‘w/o SSD & CNV’’ for all 20,506 human protein-coding genes (A), and gene classes susceptible to deleterious mutations (B). Note that gene classes with higher susceptibility to deleterious mutations retained more ohnologs. (C) Ohnolog retention in gene classes susceptible to dosage balance constraints. Fold changes in ohnolog/nonohnolog ratios are given relative to the reference from all human genes in (A). See also Figure S1. onset of jawed vertebrates, some 500 MY ago (Ohno, 1970; Put- susceptibility to deleterious mutations, than their functional nam et al., 2008). importance or ‘‘essentiality.’’ We also demonstrate using These two rounds of WGD in the early vertebrate lineage are a causal inference analysis, that the retention of many ohnologs frequently credited with creating the conditions for the evolution suspected to be dosage balanced is in fact an indirect effect of of vertebrate complexity. Indeed, WGD-duplicated genes, so- their higher susceptibility to deleterious mutations. We argue called ‘‘ohnologs’’ in honor of Susumu Ohno (Ohno, 1970; Wolfe, that the enhanced retention of dangerous ohnologs is a some- 2000), have been preferentially retained in specific gene classes what counterintuitive yet simple consequence of the speciation associated with organismal complexity, such as signal transduc- event triggered by WGD and the ensuing purifying selection in tion pathways, transcription networks, and developmental post-WGD species. genes (Maere et al., 2005; Blomme et al., 2006; Freeling and These findings rationalize, from an evolutionary perspective, Thomas, 2006; Se´ mon and Wolfe, 2007; Makino and McLysaght, the WGD expansion of gene families frequently implicated in 2010; Huminiecki and Heldin, 2010). By contrast, gene dupli- genetic disorders, such as cancer, and highlight the importance cates coming from SSD are strongly biased toward different of nonadaptive selection on the emergence of vertebrate functional categories, such as antigen processing, immune complexity. response, and metabolism (Huminiecki and Heldin, 2010). SSD paralogs and WGD ohnologs also differ in their gene expression RESULTS and protein network properties (Hakes et al., 2007; Guan et al., 2007). Furthermore, recent genome-wide analysis have shown Genes Prone to Deleterious Mutations Retain More that ohnologs in the human genome have experienced fewer Ohnologs SSD than ‘‘nonohnolog’’ genes and tend to be refractory to We first analyzed a possible association between the suscepti- copy number variation (CNV) caused by polymorphism of small bility of human genes to deleterious mutations and their retention segmental duplications in human populations (Makino and of ohnologs, as proposed in Gibson and Spring (1998) for multi- McLysaght, 2010). These antagonist retention patterns of WGD domain proteins. To this end, we considered multiple classes of and SSD/CNV gene duplicates in the human genome have genes susceptible to deleterious mutations from experimentally been suggested to result from dosage balance constraints (Ma- verified databases and literature. These classes include cancer kino and McLysaght, 2010) on the relative expressions of genes (from multiple sources including COSMIC [Forbes et al., multiple protein partners (Veitia, 2002), as proposed earlier for 2011] and CancerGenes [Higgins et al., 2007]), genes mutated other organisms like yeast (Papp et al., 2003) and the parame- in other genetic disorders, dominant negative genes from cium (Aury et al., 2006). OMIM, and genes with autoinhibitory protein folds (Experimental In this article, we investigate the evolutionary causes respon- Procedures). We looked at the relative contributions

Load more