Adaptive Evolution in Zinc Finger Transcription Factors

Emerson, Ryan; Thomas, James H.

doi:10.1371/journal.pgen.1000325

Cited by 263 publications

(337 citation statements)

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“…ZNF genes comprise a large family of transcription factors that underwent rapid evolution in primates and humans. Approximately 25% of ZNF genes in the human genome are primatespecific, and the majority of ZNF gene groups with primatespecific expansion were subject to strong positive selection according to nonsynonymous/synonymous substitution rate (dN/ dS) analysis (18). Moreover, over one-third of transcription factor genes differentially expressed between human and chimpanzee brains encode ZNF transcription factors (20).…”

Section: Discussionmentioning

confidence: 99%

“…Both GO terms refer to zinc finger (ZNF) transcription factors, a large family of transcription factors in the human genome. These transcription factors typically are characterized by an N-terminal protein interaction domain, most commonly the Kruppel-associated box (KRAB) domain and the C2H2 ZNF DNA-binding domain in the C-terminal region (18). Interestingly, ZNF genes underwent rapid expansion and adaptive evolution during primate and human evolution (18,19).…”

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confidence: 99%

“…These transcription factors typically are characterized by an N-terminal protein interaction domain, most commonly the Kruppel-associated box (KRAB) domain and the C2H2 ZNF DNA-binding domain in the C-terminal region (18). Interestingly, ZNF genes underwent rapid expansion and adaptive evolution during primate and human evolution (18,19). Therefore, they have been considered key contributors to lineage-specific transcriptome regulation in primates and humans (18,20).…”

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confidence: 99%

“…Interestingly, ZNF genes underwent rapid expansion and adaptive evolution during primate and human evolution (18,19). Therefore, they have been considered key contributors to lineage-specific transcriptome regulation in primates and humans (18,20).…”

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confidence: 99%

“…To avoid misinterpretation of RT-PCR results because of nonspecific amplification of paralogous ZNF genes, the identities of all PCR products were confirmed by sequencing. Although the specific biological functions of most ZNF genes remain obscure (18), some of the Alu-exon-containing ZNF genes have been implicated in disease or gene regulation. For example, ZNF445 has been shown to activate the transcriptional activity of activator protein 1 (AP1) (21).…”

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confidence: 99%

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Widespread establishment and regulatory impact of Alu exons in human genes

Shen¹,

Lin²,

Cai

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

123

118

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The Alu element has been a major source of new exons during primate evolution. Thousands of human genes contain spliced exons derived from Alu elements. However, identifying Alu exons that have acquired genuine biological functions remains a major challenge. We investigated the creation and establishment of Alu exons in human genes, using transcriptome profiles of human tissues generated by high-throughput RNA sequencing (RNA-Seq) combined with extensive RT-PCR analysis. More than 25% of Alu exons analyzed by RNASeq have estimated transcript inclusion levels of at least 50% in the human cerebellum, indicating widespread establishment of Alu exons in human genes. Genes encoding zinc finger transcription factors have significantly higher levels of Alu exonization. Importantly, Alu exons with high splicing activities are strongly enriched in the 5′-UTR, and two-thirds (10/15) of 5′-UTR Alu exons tested by luciferase reporter assays significantly alter mRNA translational efficiency. Mutational analysis reveals the specific molecular mechanisms by which newly created 5′-UTR Alu exons modulate translational efficiency, such as the creation or elongation of upstream ORFs that repress the translation of the primary ORFs. This study presents genomic evidence that a major functional consequence of Alu exonization is the lineagespecific evolution of translational regulation. Moreover, the preferential creation and establishment of Alu exons in zinc finger genes suggest that Alu exonization may have globally affected the evolution of primate and human transcriptomes by regulating the protein production of master transcriptional regulators in specific lineages. transcriptome evolution | transposable element | alternative splicing | deep sequencing | uORF

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Widespread establishment and regulatory impact of Alu exons in human genes

Shen¹,

Lin²,

Cai

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

123

118

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Evolution of C2H2 Zinc‐finger Gene Families in Mammals

Tadepally

Aubry

2010

Encyclopedia of Life Sciences

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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.

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Phenotypic and molecular characterization of 19q12q13.1 deletions: A report of five patients

Chowdhury

Bandholz

Parkash

et al. 2013

American J of Med Genetics Pt A

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A syndrome associated with 19q13.11 microdeletions has been proposed based on seven previous cases that displayed developmental delay, intellectual disability, speech disturbances, pre- and post-natal growth retardation, microcephaly, ectodermal dysplasia, and genital malformations in males. A 324-kb critical region was previously identified as the smallest region of overlap (SRO) for this syndrome. To further characterize this microdeletion syndrome, we present five patients with deletions within 19q12q13.12 identified using a whole-genome oligonucleotide microarray. Patients 1 and 2 possess deletions overlapping the SRO, and Patients 3-5 have deletions proximal to the SRO. Patients 1 and 2 share significant phenotypic overlap with previously reported cases, providing further definition of the 19q13.11 microdeletion syndrome phenotype, including the first presentation of ectrodactyly in the syndrome. Patients 3-5, whose features include developmental delay, growth retardation, and feeding problems, support the presence of dosage-sensitive genes outside the SRO that may contribute to the abnormal phenotypes observed in this syndrome. Multiple genotype-phenotype correlations outside the SRO are explored, including further validation of the deletion of WTIP as a candidate for male hypospadias observed in this syndrome. We postulate that unique patient-specific deletions within 19q12q13.1 may explain the phenotypic variability observed in this emerging contiguous gene deletion syndrome.

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Adaptive Evolution in Zinc Finger Transcription Factors

Cited by 263 publications

References 59 publications

Widespread establishment and regulatory impact of Alu exons in human genes

Widespread establishment and regulatory impact of Alu exons in human genes

Evolution of C2H2 Zinc‐finger Gene Families in Mammals

Phenotypic and molecular characterization of 19q12q13.1 deletions: A report of five patients

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