Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains

<p>Abstract</p> <p>Background</p> <p>C2H2 zinc finger genes (C2H2-ZNF) constitute the largest class of transcription factors in humans and one of the largest gene families in mammals. Often arranged in clusters in the genome, these genes are thought to have undergone a massive expansion in vertebrates, primarily by tandem duplication. However, this view is based on limited datasets restricted to a single chromosome or a specific subset of genes belonging to the large KRAB domain-containing C2H2-ZNF subfamily.</p> <p>Results</p> <p>Here, we present the first comprehensive study of the evolution of the C2H2-ZNF family in mammals. We assembled the complete repertoire of human C2H2-ZNF genes (718 in total), about 70% of which are organized into 81 clusters across all chromosomes. Based on an analysis of their N-terminal effector domains, we identified two new C2H2-ZNF subfamilies encoding genes with a SET or a HOMEO domain. We searched for the syntenic counterparts of the human clusters in other mammals for which complete gene data are available: chimpanzee, mouse, rat and dog. Cross-species comparisons show a large variation in the numbers of C2H2-ZNF genes within homologous mammalian clusters, suggesting differential patterns of evolution. Phylogenetic analysis of selected clusters reveals that the disparity in C2H2-ZNF gene repertoires across mammals not only originates from differential gene duplication but also from gene loss. Further, we discovered variations among orthologs in the number of zinc finger motifs and association of the effector domains, the latter often undergoing sequence degeneration. Combined with phylogenetic studies, physical maps and an analysis of the exon-intron organization of genes from the SCAN and KRAB domains-containing subfamilies, this result suggests that the SCAN subfamily emerged first, followed by the SCAN-KRAB and finally by the KRAB subfamily.</p> <p>Conclusion</p> <p>Our results are in agreement with the "birth and death hypothesis" for the evolution of C2H2-ZNF genes, but also show that this hypothesis alone cannot explain the considerable evolutionary variation within the subfamilies of these genes in mammals. We, therefore, propose a new model involving the interdependent evolution of C2H2-ZNF gene subfamilies.</p

Overview of the interactive task in BioCreative V

Fully automated text mining (TM) systems promote efficient literature searching, retrieval, and review but are not sufficient to produce ready-to-consume curated documents. These systems are not meant to replace biocurators, but instead to assist them in one or more literature curation steps. To do so, the user interface is an important aspect that needs to be considered for tool adoption. The BioCreative Interactive task (IAT) is a track designed for exploring user-system interactions, promoting development of useful TM tools, and providing a communication channel between the biocuration and the TM communities. In BioCreative V, the IAT track followed a format similar to previous interactive tracks, where the utility and usability of TM tools, as well as the generation of use cases, have been the focal points. The proposed curation tasks are user-centric and formally evaluated by biocurators. In BioCreative V IAT, seven TM systems and 43 biocurators participated. Two levels of user participation were offered to broaden curator involvement and obtain more feedback on usability aspects. The full level participation involved training on the system, curation of a set of documents with and without TM assistance, tracking of time-on-task, and completion of a user survey. The partial level participation was designed to focus on usability aspects of the interface and not the performance per se. In this case, biocurators navigated the system by performing pre-designed tasks and then were asked whether they were able to achieve the task and the level of difficulty in completing the task. In this manuscript, we describe the development of the interactive task, from planning to execution and discuss major findings for the systems tested

The mammalian gene function resource: the International Knockout Mouse Consortium.

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research

The mammalian gene function resource: The International Knockout Mouse Consortium

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed highthroughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research

Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains-6

Ng syntenically homologous clusters in the other mammals. For each species, the average number of zinc finger motifs for the total C2H2-ZNF genes (All) and for members of the various C2H2-ZNF sub-families is presented. For each category, the number of genes in each species is listed above the bars in the following order (human, chimpanzee, mouse, rat and dog). For the human C2H2-ZNF cluster 6.2 (chromosome 6p22.1) and its syntenically homologous counterparts in chimpanzee, mouse, rat and dog, each C2H2-ZNF genes is represented by an open arrow which indicates its orientation on the chromosome strands; this excludes the pseudogenes whose names appear in parenthesis. For these clusters which contain C2H2-ZNF genes that are from the KRAB or SCAN subfamily or that do not encode any conserved N-terminal domain, the presence of a conserved N-terminal is indicated by as square for a KRAB domain or an open circle for a SCAN domain both being positioned in front of the open arrow representing the gene. Genes identified as orthologs, based on the phylogenetic tree and physical maps, are aligned vertically on their respective chromosomes. Cases where orthologs from the different mammals do not consistently share the same effector domain (s) are marked by a grey box. C) Exon-Intron organization of most human C2H2-ZNF genes from the SCAN-KRAB and SCAN subfamilies. 80% of SCAN-KRAB (11/14) and 55% of the SCAN (16/29) C2H2-ZNF genes found in clusters in human have the presented exon-intron structures shown. The exons encoding the SCAN, KRAB (A box) and ZNF are indicated.<p><b>Copyright information:</b></p><p>Taken from "Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains"</p><p>http://www.biomedcentral.com/1471-2148/8/176</p><p>BMC Evolutionary Biology 2008;8():176-176.</p><p>Published online 18 Jun 2008</p><p>PMCID:PMC2443715.</p><p></p

Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains-9

Of clusters. C2H2-ZNF genes associated with KRAB and SCAN domains are more often found to be clustered. S-K = C2H2-ZNF containing both a SCAN and a KRAB domain. NONE = C2H2-ZNF without any conserved domain associated. The percentage distribution is mentioned on top of each bar for each sub-family. The number of C2H2-ZNF clusters is shown with respect to the number of genes present in each cluster. The proportion of clusters composed solely of C2H2-ZNF without any intervening gene or with intervening genes other than C2H2-ZNF (Non-C2H2-ZNF) is also represented. An asterisk identifies large clusters present on human chromosome 19.<p><b>Copyright information:</b></p><p>Taken from "Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains"</p><p>http://www.biomedcentral.com/1471-2148/8/176</p><p>BMC Evolutionary Biology 2008;8():176-176.</p><p>Published online 18 Jun 2008</p><p>PMCID:PMC2443715.</p><p></p

Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains-2

Nd in these clusters are mentioned on the species tree. Since and C2H2-ZNF genes are used as an outgroup in phylogenetic studies, these species are also positioned on the tree. A graphical representation of different scenarios seen in the evolution of human C2H2-ZNF clusters and their syntenically homologous C2H2-ZNF clusters in chimpanzee, mouse, rat and dog. The human clusters selected and named on the graph as well as their syntenic counterparts were 1) present in all species, 2) primate-specific, 3) lost in rodents or 4) absent in dog. For each human C2H2-ZNF cluster named on the graph and described in Additional File , the first number indicates the chromosome number and the second is the number attributed to that cluster on the chromosome. Additional File provides a more comprehensive graphical representation including the 40 human clusters that contain at least 3 C2H2-ZNF genes and their syntenic counterparts in the four other mammals.<p><b>Copyright information:</b></p><p>Taken from "Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains"</p><p>http://www.biomedcentral.com/1471-2148/8/176</p><p>BMC Evolutionary Biology 2008;8():176-176.</p><p>Published online 18 Jun 2008</p><p>PMCID:PMC2443715.</p><p></p

Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains-1

Of clusters. C2H2-ZNF genes associated with KRAB and SCAN domains are more often found to be clustered. S-K = C2H2-ZNF containing both a SCAN and a KRAB domain. NONE = C2H2-ZNF without any conserved domain associated. The percentage distribution is mentioned on top of each bar for each sub-family. The number of C2H2-ZNF clusters is shown with respect to the number of genes present in each cluster. The proportion of clusters composed solely of C2H2-ZNF without any intervening gene or with intervening genes other than C2H2-ZNF (Non-C2H2-ZNF) is also represented. An asterisk identifies large clusters present on human chromosome 19.<p><b>Copyright information:</b></p><p>Taken from "Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains"</p><p>http://www.biomedcentral.com/1471-2148/8/176</p><p>BMC Evolutionary Biology 2008;8():176-176.</p><p>Published online 18 Jun 2008</p><p>PMCID:PMC2443715.</p><p></p

Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains-3

the species, 1, 2, 3 and 4. A species-specific gain of genes appears as a clade including a single homolog from one species and multiple homologs from the other. Phylogeny between genes from species 1, 2, 3 and 4, respectively is shown. Gene gain in species 4 is observed. Species-specific gene loss appears as the absence of a corresponding ortholog for one species on the tree and is deduced from the evolutionary relationships of the species considered with the other species. Gene loss occurred in species 3.<p><b>Copyright information:</b></p><p>Taken from "Evolution of C2H2-zinc finger genes and subfamilies in mammals: Species-specific duplication and loss of clusters, genes and effector domains"</p><p>http://www.biomedcentral.com/1471-2148/8/176</p><p>BMC Evolutionary Biology 2008;8():176-176.</p><p>Published online 18 Jun 2008</p><p>PMCID:PMC2443715.</p><p></p