Evolution of C2H2 Zinc‐finger Gene Families in Mammals

Abstract 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.