Insertional Mutagenesis

Alu elements create an approx 300-bp insertion mutation at any new genomic insertion site. If Alu insertion occurs in a coding exon, or near a splice junction, they are likely to disrupt the appropriate expression of a gene (2). Table 1 shows a collection of most of the known cases

35 mya

5 mya

25 mya

1 5 mya

5 mya

25 mya

1 5 mya

100,000 Y

ZOO.000 All! 200,000 Monomer 200.000 Type II

45 mya

850,000 J and 5

55 mya

Fig. 3. Insertion history ofAlu elements in the primate lineage. The times and approximate copy numbers of some of the major subfamilies of Alu elements are listed on a primate tree to illustrate the approximate times of formation of Alu elements, primarily for the human lineage, but also including several SINEs identified in prosimians.

of human diseases, caused fairly equally by these two types of insertions. Although these represent a number of different diseases, reflecting the broad distribution of Alu elements throughout the human genome, there are multiple independent cases in four different loci. This is probably largely a case of ascertainment bias because those genes have been very heavily studied. However, there is also a strong preference seen for diseases associated with the X chromosome (10/23 cases). There is much less of a bias for the X chromosome than has been seen for L1 element insertions, and probably also largely represents an ascertainment bias in favor of sex-linked diseases.

In a few rare cases, Alu elements have inserted into an exon coding for the carboxy-terminus of a protein and has not destroyed the function of the protein (15,16). In these cases, the Alu element has incorporated a portion of its sequence into the coding region of the protein, likely because that portion of the protein was not critical for function, but novel proteins can evolve this way.

Insertions in the middle of introns or between genes appear to be well-tolerated and to have minimal effects on genes. Many genes have introns that include dozens of Alu elements that make up more than half of their DNA. However, as discussed next, many of these initially harmless Alu insertions can become deleterious by contributing to recombination events, or through further mutation altering their properties.

As illustrated in Fig. 2C, it is possible that Alu elements sometimes begin the insertion process, but that cellular repair processes remove the initial primed element. This would result in a nicked DNA that could serve as a free end in a recombination event (Fig. 2D), as well as

Table 1

Alu Insertions Causing Human Disease

Table 1

Alu Insertions Causing Human Disease

Locus

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