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Jocelyn E. Krebs received a B.A. in Biology from Bard College, Annandale-on-Hudson, New York, and a Ph.D. in Molecular and Cell Biology from the University of California, Berkeley. For her Ph.D. thesis, she studied the roles of DNA topology and insulator elements in transcriptional regulation. She performed her postdoctoral training as an American Cancer Society Fellow at the University of Massachusetts Medical School in the laboratory of Dr. Craig Peterson, where she focused on the roles of histone acetylation and chromatin remodeling in transcription. In 2000, Dr. Krebs joined the faculty in the Department of Biological Sciences at the University of Alaska, Anchorage, where she is now a Full Professor. Her most recent research focus has been on the role of the Williams syndrome transcription factor (one of the genes lost in the human neurodevelopmental syndrome Williams syndrome) in early embryonic development in the frog Xenopus. She teaches courses in introductory biology, genetics, and molecular biology for undergraduates, graduate students, and first-year medical students. She also teaches courses on the molecular biology of cancer and epigenetics. Although working in Anchorage, she lives in Portland, Oregon, with her wife and two sons, a dog, and three cats. Her nonwork passions include hiking, gardening, and fused glass work.


Elliott S. Goldstein earned his B.S. in Biology from the University of Hartford in Connecticut and his Ph.D. in Genetics from the University of Minnesota, Department of Genetics and Cell Biology. Following this, he was awarded an NIH Postdoctoral Fellowship to work with Dr. Sheldon Penman at the Massachusetts Institute of Technology. After leaving Boston, he joined the faculty at Arizona State University in Tempe, Arizona, where he is an Associate Professor, Emeritus, in the Cellular, Molecular, and Biosciences program in the School of Life Sciences and in the Honors Disciplinary Program. His research interests are in the area of molecular and developmental genetics of early embryogenesis in Drosophila melanogaster. In recent years, he has focused on the Drosophila counterparts of the human protooncogenes jun and fos. His primary teaching responsibilities are in the undergraduate general genetics course as well as the graduate-level molecular genetics course. Dr. Goldstein lives in Tempe with his wife, his high school sweetheart. They have three children and two grandchildren. He is a bookworm who loves reading as well as underwater photography. His pictures can be found at elliotg/.

This review focuses heavily on studies generated as a result of the advent of high-throughput genomics providing huge datasets of genome sequences, and data on gene expression and epigenetics. These data provide tremendous insight into the role of Alu elements in genetic instability and genome evolution, as well as their many impacts on expression of the genes in their vicinity. These roles then influence normal cellular health and function, as well as having a broad array of impacts on human health.

Alu elements have an even larger impact than that provided by their insertional mutagenesis through their influence on genome instability by providing the most common source of homology for non-allelic homologous recombination events leading to disease [23, 46]. The bioinformatics required to analyze these types of rearrangements from comparative genomic data is technically more difficult than characterizing insertions. However, studies of the human and chimpanzee genomes show that approximately 500 deletion events have occurred in both genomes (Figure 3) [47, 48]. It has not been possible to assess the duplication events that are also caused by this type of recombination, but it is likely that there is approximately the same number of events, and these events have also been suggested to contribute to genomic inversions [49] and segmental duplications [50]. The lower number of apparent non-allelic Alu/Alu recombination events between human and chimpanzee relative to the number of Alu insertion events (Figure 3) suggests that the recombination events cause a stronger negative selection because there are many more Alu recombination events than insertions causing disease [23]. Thus, they contribute more to disease, but are less well fixed in the population. This is consistent with the relatively short length of the fixed deletions relative to the longer deletions commonly found associated with disease [46].

Alu elements are preferentially enriched in regions that are generally gene rich, whereas L1 elements are enriched in the gene-poor regions [1]. This also correlates with Alu elements being enriched in reverse G bands [51], as well as in G+C-rich genomic isochores [52]. However, younger Alu and L1 elements do not show much disparity in their locations, making it most likely that the differences in location are the result of losses of L1 and Alu elements in different genomic regions. It is easy to understand why the much larger L1 elements might have more negative selection when located in genes, making Alu elements much more stably maintained within the genes. It is more difficult to understand why Alu elements seem to be preferentially lost between genes over evolutionary time compared with L1. It is most likely that the tendency of Alu elements to participate in non-allelic homologous recombination events might allow loss of these elements when not under selection [53, 54].

Alu insertions contribute to disease by either disrupting a coding region or a splice signal [23, 56] (Table 1). Although Alu element insertions causing disease are broadly spread throughout the genome, some genes seem more prone to disease-causing insertions of this type, particularly on the X chromosome. Fourteen new Alu insertions inactivating the NF1 gene have been reported [57], representing 0.4% of known mutations in this gene. Similarly, many diseases caused by non-allelic homologous recombination between Alu elements have been discussed previously [23, 57]. Although these events are also broadly spread throughout the genome, some regions, such as the MSH2, VHL and BRCA1 genes, are much more subject to this instability than others [58]. Most Alu-related genomic instability events will either have no major functional consequence, and over many generations simply be lost from the human population gene pool through random fixation, or be deleterious and therefore lost through negative selection. Thus, the events described above represent only a tiny proportion of the overall genetic instability in the human population caused by such elements.

Alu elements are relatively rich in CpG residues, which appear to be widely subject to methylation and therefore are responsible for approximately 25% of all of the methylation in the genome [71]. Because methylated CpGs readily mutate to TpG, the higher density of methylation occurs in the younger elements. Methylation of Alu elements does vary in different tissues and appears to decrease in many tumors. It is likely that demethylation of an Alu increases expression from that Alu locus. It has also been proposed that Alu elements might be a source of new CpG islands that could influence the regulation of nearby genes. However, studies to date do not make a clear case for Alu methylation being the driving force for nearby gene expression changes rather than the alternative, that Alu methylation is influenced by other nearby genome features.

Alternative splicing involving Alu elements is referred to as Alu 'exonization' [80] (Figure 5). This phenomenon is widespread, certainly affecting hundreds, if not thousands, of human genes. In some cases the exonized Alu RNA may make up a relatively minor portion of the transcripts from a gene, although in a study of human brain transcripts, hundreds of genes were found to have Alu exonization in the majority of their transcripts [5]. In general, the use of Alu sequences to generate alternative splicing seems to cause only decreased expression of the appropriate transcript. However, it appears that those alternative splices that survive over evolutionarily long periods of time become dominant and are more likely to represent those transcripts that serve functionally [81]. Alu elements have only relatively weak, cryptic splice sites upon insertion. However, as elements accumulate more mutations, these sites can be further activated. There are also a number of cases where the evolution of a cryptic Alu splice site to a more functional form disrupts gene expression sufficiently to lead to disease [7]. A wide range of diseases are caused by this mechanism, and they include Alport syndrome, Leigh syndrome, chorioretinal degeneration and mucopolysaccharidosis VII. There are also two cases of Duchenne muscular dystrophy, probably because the DMD gene is so large and requires many splicing events. There are also examples of Alu exonization, where the Alu sequences require ADAR editing to become functional [6]. These are particularly prevalent in the brain, where ADAR activity is particularly high.

Alu elements and post-transcriptional processing of transcripts. (a) The majority of primary transcripts from genes contain Alu elements, both sense and antisense, within their introns. These Alu elements gradually accumulate mutations that can activate cryptic splice sites, or polyadenylation sites, within the Alu. This can lead to alternative splicing of RNAs that can either include a portion of an Alu in the coding region or result in premature termination of translation. Similarly, Alu elements may cause premature termination and polyadenylation resulting in truncated genes. (b) Alu elements in introns located in opposite orientations can fold into secondary structures that are then a major substrate for ADAR (adenosine deaminase that acts on RNA) activity. The edited RNAs may then have cryptic splice sites activated or may also result in retention of the RNA in the nucleus.


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