The Birth of an Alternatively Spliced Exon: 3' Splice-Site Selection in
            <i>Alu</i>
            Exons

Lev-Maor, Galit; Sorek, Rotem; Shomron, Noam; Ast, Gil

doi:10.1126/science.1082588

Cited by 394 publications

(422 citation statements)

References 23 publications

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“…The mutation corresponds to a nucleotide substitution at position 279 of an Alu consensus sequence. 34 Interestingly, it has been shown that mutating this specific guanine nucleotide to any other nucleotide, as is the case in patient 2, results in exonization of the Alu sequence. 34 The Artemis gene has a higher transposable element content (45%) than the average of the human genome (37%).…”

Section: Discussionmentioning

confidence: 91%

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

IJspeert

Lankester

et al. 2011

Genes Immun

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Artemis deficiency is known to result in classical TÀBÀ severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical TÀBÀ SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5 0 splice-site or an intronic point mutation creating a novel 3 0 splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3 0 splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.

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Section: Discussionmentioning

confidence: 91%

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

IJspeert

Lankester

et al. 2011

Genes Immun

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“…As recently shown, many retrotransposons have 'exapted' to become exons, genes or promoters, or to acquire other novel functions [1][2][3][4][5][6][7][8][9] . To attain a new function, a retrotransposon must undergo a rare series of fortuitous mutations.…”

mentioning

confidence: 99%

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

2011

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Retrotransposons had an important role in genome evolution, including the formation of new genes and promoters and the rewiring of gene networks. However, it is unclear how such a repertoire of functions emerged from a relatively limited number of source sequences. Here we show that DnA editing, an antiviral mechanism, accelerated the evolution of mammalian genomes by large-scale modification of their retrotransposon sequences. We find numerous pairs of retrotransposons containing long clusters of G-to-A mutations that cannot be attributed to random mutagenesis. These clusters, which we find across different mammalian genomes and retrotransposon families, are the hallmark of APoBEC3 activity, a potent antiretroviral protein family with cytidine deamination function. As DnA editing simultaneously generates a large number of mutations, each affected element begins its evolutionary trajectory from a unique starting point, thereby increasing the probability of developing a novel function. our findings thus suggest a potential mechanism for retrotransposon domestication.

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“…Exonization of intronic sequences is a mechanism that not only enriches the transcriptome and enhances the coding capacity of human genome for a diversity of biological activities [24,25], but also provides genetic sources for evolution. Exonization of intronic sequences of human DMRT1 was generated by alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional diversity of DMRT1 (dsx- and mab3-related transcription factor 1) in human testis

et al. 2006

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Recent advances in the evolutionary genetics of sex determination indicate that the only molecular similarity in sex determination found so far among phyla is between the fly doublesex, worm mab-3 and vertebrate DMRT1(dsx-and mab3-related transcription factor 1) /DMY genes. Each of these factors encodes a zinc-finger-like DNA-binding motif, DM domain. Insights into the evolution and functions of human DMRT1 gene could reveal evolutionary mechanisms of sexual development. Here we report the identification and characterization of multiple isoforms of human DMRT1 in the testis. These transcripts encode predicted proteins with 373, 275 and 175 amino acids and they were generated by alternative splicing at 3′ region. Expression level of DMRT1a is higher than those of both DMRT1b and c, and the DMRT1c expression was the lowest in testis, based on comparisons of mean values from real-time fluorescent quantitative RT-PCR analysis. Both DMRT1b and c result from exonization of intronic sequences, including the exonization of an Alu element. A further search for Alu elements within the DMRT1 gene demonstrated that all 99 Alu elements are non-randomly distributed among the non-coding regions on both directions. These new characteristics of DMRT1 would have an important impact on the evolution of sexual development mechanisms.

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The Birth of an Alternatively Spliced Exon: 3' Splice-Site Selection in Alu Exons

Cited by 394 publications

References 23 publications

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

Transcriptional diversity of DMRT1 (dsx- and mab3-related transcription factor 1) in human testis

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