From “Junk” to Gene: Curriculum vitae of a Primate Receptor Isoform Gene

Singer, Silke S.; Männel, Daniela N.; Hehlgans, Thomas; Brosius, Jürgen; Schmitz, Jürgen

doi:10.1016/j.jmb.2004.06.070

Cited by 66 publications

(56 citation statements)

References 13 publications

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“…The precise steps needed for exonization and functiongaining in primate-specific, Alu-derived exonized sequences were further explored by Schmitz and colleagues (Singer et al 2004;Krull et al 2005). Their studies show that the transposon insertion in the genome and its actual exonization can be events separated millions of years apart, and depend both on the formation of active splice sites and, in some cases, the formation of an open reading frame (ORF).…”

Section: Molecular Mechanisms Leading To Exonizationmentioning

confidence: 99%

“…Their studies show that the transposon insertion in the genome and its actual exonization can be events separated millions of years apart, and depend both on the formation of active splice sites and, in some cases, the formation of an open reading frame (ORF). For example, by sequencing DNA from 13 different primates, Singer et al (2004) reconstructed the key events leading to the generation of an alternative 59 exon in the human tumor necrosis factor receptor gene (p75TNFR). Following the genomic integration of Alu z50 million years ago, an A/G substitution led to the creation of an alternative ATG start codon in this Alu.…”

Section: Molecular Mechanisms Leading To Exonizationmentioning

confidence: 99%

“…Following the genomic integration of Alu z50 million years ago, an A/G substitution led to the creation of an alternative ATG start codon in this Alu. However, the actual exonization was facilitated only 25 million years later, when a 7-base-pair (bp) deletion resulted in an uninterrupted ORF, and a C/T substitution created a functional 59 splice site (Singer et al 2004); thus, multiple, stepwise small changes enabled this functional exonization.…”

Section: Molecular Mechanisms Leading To Exonizationmentioning

confidence: 99%

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The birth of new exons: Mechanisms and evolutionary consequences

Sorek¹

2007

RNA

172

151

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A significant amount of literature was dedicated to hypotheses concerning the origin of ancient introns and exons, but accumulating evidence indicates that new exons are also constantly being added to evolving genomes. Several mechanisms contribute to the creation of novel exons in metazoan genomes, including whole gene and single exon duplications, but perhaps the most intriguing are events of exonization, where intronic sequences become exons de novo. Exonizations of intronic sequences, particularly those originating from repetitive elements, are now widely documented in many genomes including human, mouse, dog, and fish. Such de novo appearance of exons is very frequently associated with alternative splicing, with the new exon-containing variant typically being the rare one. This allows the new variant to be evolutionarily tested without compromising the original one, and provides an evolutionary strategy for generation of novel functions with minimum damage to the existing functional repertoire. This review discusses the molecular mechanisms leading to exonization, its extent in vertebrate genomes, and its evolutionary implications.

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Section: Molecular Mechanisms Leading To Exonizationmentioning

confidence: 99%

Section: Molecular Mechanisms Leading To Exonizationmentioning

confidence: 99%

Section: Molecular Mechanisms Leading To Exonizationmentioning

confidence: 99%

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The birth of new exons: Mechanisms and evolutionary consequences

Sorek¹

2007

RNA

172

151

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“…Although the vast majority of Alu exons are rarely incorporated into transcripts (7), the analyses of expressed sequence tags (ESTs) and exon array data recently have revealed a small number of Alu exons with high splicing activities or tissue-specific splicing profiles (8,9). In a few genes, the functional impact and evolutionary history of Alu exons have been characterized experimentally (9)(10)(11)(12). These data suggest that Alu exonization contributed to the adaptive evolution of primates and humans.…”

mentioning

confidence: 99%

Widespread establishment and regulatory impact of Alu exons in human genes

Shen¹,

Lin²,

Cai

et al. 2011

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

125

113

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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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“…68,69 In analyses of 13 primate individuals, Singer et al, mapped out the stepwise mutagenesis over millions of years that generated an alternative 5′ exon in the human tumor necrosis factor receptor gene. 70 Additionally, insertion of inverted Alu allows for a stretch of Us incorporating into pre-mRNA, together with desirable mutations, making it into a functional splice site for exon generation. Therefore, mutations over time contribute to the conversion of pseudosplice sites within Alus into functional ones.…”

mentioning

confidence: 99%