Trends in Genetics
Volume 20, Issue 1, January 2004, Pages 1-4
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The origins and implications of Aluternative splicing

https://doi.org/10.1016/j.tig.2003.11.001Get rights and content

Abstract

Ten percent of the human genome is composed of highly repetitive DNA sequences called Alu elements. It has recently been found that at least 5% of all human alternative exons are derived from Alu elements. Moreover, single nucleotide mutations can convert either alternative or otherwise silent Alu elements into constitutive exons and this can lead to the development of human disease. These results provide new insights into the function and dangers of ‘junk DNA’ in the human genome.

Section snippets

Of mice and men

Humans and mice last shared a common ancestor ∼75 million years ago. Thus, it is not surprising that humans 3, 4 and mice [11] each contain ∼30 000 protein-coding genes, and most of these genes are shared between both species. What then accounts for the phenotypic differences between mice and humans? As discussed in this article, part of the difference might be because of species-specific alternative splicing.

There are two types of exons: constitutive and alternative. Constitutive exons are

Exonization of Alu elements

There are several repetitive DNA elements in eukaryotes that fall into one of two major classes: blocks of tandem arrays (satellite DNA) and those with single units scattered throughout the genome. The latter group includes LINEs (long interspersed elements) and SINEs (short interspersed elements). The most abundant variety of SINEs in primates are the Alu elements, which first appeared ∼65 million years ago, either coincident with or immediately after the radiation of primates [16]. Alu

Converting an alternative Alu exon into a constitutive exon

What prevents Alu exons from being constitutively spliced? One of the most intriguing aspects of the work by Lev-Maor and colleagues is their investigation of the sequences required to maintain Alu exons as alternative exons, and the realization of how little it takes to constitutively activate Alu exons [10].

After examining all exonized Alu elements, Lev-Maor and colleagues immediately realized that in the majority of cases only two of the twelve potential 3′ splice sites on the minus strand

Alu elements and disease

The first proof that the constitutive inclusion of an Alu exon could be deleterious was provided by Mitchell et al. over a decade ago [22]. These researchers found that a point mutation that creates a new 5′ splice site in an Alu element residing in the third intron of the ornithine aminotransferase gene (OAT), resulted in the constitutive inclusion of part of the Alu element. This Alu exon contains an in-frame stop codon that truncates the encoded protein and results in ornithine

Alu elements and evolution

The results of Lev-Maor and colleagues clearly demonstrates that exonization of Alu elements can have two distinct and important effects. First, if an Alu exon is constitutively spliced, it might disrupt protein function and lead to a genetic disease. More commonly, however, Alu exons are alternatively spliced. As a result, the normal version of the encoded protein might still be synthesized at a level sufficient to maintain its function. This would enable the Alu exon to diversify in such a

Acknowledgements

We thank members of the Graveley laboratory for critical comments and discussions. Work in our laboratory is supported by NIH grants GM-62516, GM-67842 and AR-46026 to B.R.G.

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      Importantly, Alu elements are only conserved among primates, contributing to the genomic diversity of the human genome through multiple recombination events [55]. Recent evidence highlights Alu elements as critical regulators of gene expression [56], as Alu insertions or deletions can induce alternative splice sites [57], polyadenylation signals [58] or ARE-mediated stability [59], ultimately affecting the fate of RNA molecules. Several studies have now evidenced that 8 out of 10 lncRNAs contain at least one repetitive element [60–62].

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