Evolution of C2H2 Zinc‐finger Gene Families in Mammals


The C2H2 zinc‐finger encode the largest class of transcription factors and second largest gene family in the human genome. Based on the presence or absence of an N‐terminal effector domain, they are grouped into different subfamilies. The KRAB (Kruppel‐associated box) C2H2‐ZNF subfamily, found specifically in tetrapods, constitutes about half of these genes in human and mouse. Often found in clusters, the C2H2‐ZNF genes have evolved independently in various species at the level of genes, effector motifs and the zinc‐finger region. More specifically, in recent times there has been an unprecedented expansion of these genes in mammalian genomes. Cross‐species comparisons reveal a series of dynamic duplications and gene loss events that led to rapid and lineage‐specific evolution of these genes in different vertebrate genomes. Both lineage‐specific variation in the number, sequence and subfamilies of C2H2‐ZNF genes and differential expansion in genomes may be determinant for functions related to speciation.

Key Concepts:

  • C2H2‐ZNF genes are ubiquitously present in all organisms ranging from bacteria to human and are often arranged in a clustered organisation.

  • A massive expansion in the number of C2H2‐ZNF genes occurred from yeast to primates.

  • Besides gene duplication, loss and to a certain extent pseudogenisation are contributing factors in the evolution of the C2H2‐ZNF gene family.

  • C2H2‐ZNF genes follow the ‘Birth and Death’ model of evolution contributing to differential and independent evolution of the C2H2‐ZNF genes in different genomes.

  • C2H2‐ZNF genes encode DNA‐ and RNA‐binding proteins presumably involved in gene expression as transcription factors or possibly RNA regulators.

  • Members of the C2H2‐ZNF family are characterised by tandemly repeated zinc‐finger motifs involved in nucleic acid binding and are grouped into different subfamilies based on their N‐terminal regulatory domains which include SCAN, KRAB, BTB, HOMEO and SET domains.

  • Because of their tandemly repeated zinc‐finger motifs, members of the C2H2‐ZNF family are named multifingered C2H2‐ZNF genes. These motifs are prone to be duplicated, lost or to degenerate during evolution.

  • The KRAB and SCAN domains are solely confined to vertebrates. In all vertebrates, the KRAB domain is found within C2H2‐ZNF proteins.

  • The KRAB domain‐encoding C2H2‐ZNF genes define the largest and a rapidly evolving C2H2‐ZNF subfamily in vertebrates and particularly in mammals.

  • The study of the evolution of the C2H2‐ZNF genes in various genomes may help to elucidate their possible role in functions associated with speciation.

Keywords: C2H2 zinc‐finger genes; evolution; mammals; duplication; KRAB; SCAN

Figure 1.

The different C2H2‐ZNF subfamilies. (a) The three‐dimensional structure of the C2H2‐ZNF protein is shown. The two cysteine residues on the β strand in green can be seen interacting with the two histidine residues in orange on the α helix. The interacting zinc ion is shown in red in the centre. (b) The different effector domains found associated with the C2H2‐ZNF proteins are shown. These proteins comprise of three regions: The N‐terminal effector domain, the Spacer region and the C‐terminal zinc‐finger region. The blue circles represent the individual zinc‐finger domains of the zinc‐finger region. As schematised, SCAN and KRAB C2H2‐ZNF proteins contain a higher number of zinc‐finger domains than the BTB, SET and HOMEO C2H2‐ZNF. The consensus sequences of the KRAB (A, B, b and C), SCAN, BTB, SET and HOMEO domains are also shown.

Figure 2.

Distribution of the C2H2‐ZNF genes in different genomes. The total number of C2H2‐ZNF genes in different genomes is shown. There has been a massive expansion in the number of C2H2‐ZNF genes over the course of evolution. Humans (Homo sapiens) (Tadepally et al., ; Ding et al., ) have the highest number of genes as compared to the other species like Mouse (Mus musculus) (Ding et al., ), Chicken (Gallus gallus) (Thomas and Emerson, ), Fly (Drosophila melanogaster), Worm (Caenorhabditis elegans), Yeast (Saccharomyces cerevisiae) and Plant (Arabidopsis thaliana) (Looman et al., ).

Figure 3.

Distribution of the various effector domains associated with C2H2‐ZNF proteins in various species over the course of evolution. The presence or absence of the various effector domains associated at the N‐terminal of the zinc‐finger region from C2H2‐ZNF proteins in various species is shown here. C2H2‐ZNF proteins are found throughout evolution in prokaryotes (bacteria) and eukaryotes (including metazoan and nonmetazoan such as plant). As illustrated, while the BTB domain is found in all species except bacteria, the SCAN and KRAB domains are found in vertebrates. The KRAB domain is more specifically confined to tetrapods. Chicken lost the SCAN domain during evolution. * indicates that in lower vertebrates like frog and fish, the SCAN domain is present but is not associated with C2H2‐ZNF proteins. The blue circles represent the individual zinc‐finger domains of the zinc‐finger region.

Figure 4.

Distribution of the C2H2‐ZNF genes in the different subfamilies from the human genome. (a) The distribution of human C2H2‐ZNF genes in the different subfamilies defined by the effector motifs is shown. The KRAB C2H2‐ZNF subfamily constitutes nearly half of all the C2H2‐ZNF genes in human. None represents the C2H2‐ZNF genes not associated with any typical effector motif. (b) The distribution of C2H2‐ZNF genes from the different subfamilies that are present in clusters is shown here. Almost 90% of the KRAB and SCAN motif‐containing C2H2‐ZNF genes are present in clusters as opposed to the genes associated with the other effector motifs which have a higher tendency to be present as singletons.



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Further Reading

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Dhwani Tadepally, Hamsa, and Aubry, Muriel(May 2010) Evolution of C2H2 Zinc‐finger Gene Families in Mammals. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021738]