Duplication, coclustering, and selection of human Alu retrotransposons

Abstract

Alu and L1 are families of non-LTR retrotransposons representing Ϸ30% of the human genome. Genomic distributions of young Alu and L1 elements are quite similar, but over time, Alu densities in GC-rich DNA increase in comparison with L1 densities. Here we analyze two processes that may contribute to this phenomenon. First, DNA duplications in the human genome occur more frequently in Alu-and GC-rich than in AT-rich chromosomal regions. Second, most Alu elements tend to be coclustered with each other, but recently retroposed elements are likely to be inserted outside the existing clusters. These ''stand-alone'' elements appear to be rapidly eliminated from the genome. We also report that over time, the densities of recently retroposed Alu families on chromosome Y decline rapidly, whereas Alu densities on chromosome X increase relative to autosomal densities. We propose that these changes in the chromosomal proportions of Alu densities and the elimination of stand-alone Alus represent the same process of paternal Alu selection. We also propose that long-term Alu accumulation in GC-rich DNA is associated with DNA duplication initiated by elevated recombinogenic activities in Alu clusters.A lu and L1 are families of non-LTR retrotransposons that have been actively retroposed throughout the evolutionary history of primates (1-3) and together contributed Ϸ30% of the DNA in the human genome (4). Both Alu and L1 elements are transcribed from a limited number of active source genes, reverse transcribed, and integrated to host DNA. The retroposed elements form subfamilies that share characteristic features with their source genes. The Alu source genes are Ϸ300 bp long and GC-rich, whereas L1 source genes are 6-7 kb long and AT-rich. Alu retrotransposition depends on reverse transcriptase encoded by active L1 retroelements (5-9), but the overall chromosomal distributions of Alu and L1 elements are quite different (10-12). L1s tend to be preserved in AT-rich DNA, whereas Alu are more abundant in GC-rich DNA. No standard biological mechanism has so far been able to explain this difference in the retroelement distribution (13,14).It has been shown recently that the chromosomal distributions of young Alu and L1 elements initially resemble each other but, unlike L1, the Alu distribution shifts toward GC-rich DNA over time (4). Based on this GC bias, it has been proposed that originally Alu elements are inserted relatively randomly throughout the genome but over time, they accumulate in GC-rich DNA (4, 15). The accumulation is particularly active for younger Alu, Ͻ5 million years (Myrs) old, but the mechanism of this process involving positive Alu selection in gene-rich regions appears to be controversial (4,16,17).In this paper, we discuss Alu-mediated DNA duplication and selection against young Alus as two basic processes that might have contributed to the postinsertional evolution of Alu distribution. DNA duplications, also known as segmental duplications or low copy repeats, represent Ϸ5% of the human genome and have been stu...

Regulation of mammalian gene expression by retroelements and non‐coding tandem repeats

“…(79,80) Specific prediction of this hypothesis is that all SINE subfamilies are amplified uniformly and their localization in chromosomes should correlate. Indeed, the local density of the mouse B1 elements along chromosomes (in 1 Mb windows) strongly correlates with that of the B2-B4 repeats (correlation coefficient r ¼ 0.9, p < 0.0000) consistent with co-amplification.…”

“…(19) Together, these data argue against the hypothesis that explains SINE clustering near genes by an excess of neutral segmental duplications over deletions in gene-rich regions. (79,80) Another hypothesis explaining asymmetry of SINE and LINE distributions in mammalian genomes is that positive selection for SINEs occurs in readily transcribed open chromatin, which is found near genes (19) and negative selection of LINE1 occurs in gene-rich segments. (16,82) This hypothesis can explain SINE clustering near genes not only in GC-rich segments but also in AT-rich regions.…”

“…(19,76) This indicates that the clustering of the major Alu subfamilies in gene-rich regions is unlikely to be a consequence of positive selection of their initial insertions (84) but it can arise through secondary genome rearrangements. (79) These rearrangements may have been fixed in populations through random genetic drift (80,81) or because of a population bottleneck (85) but it seems unlikely that similar neutral rearrangements were fixed in the human and mouse lineages. Negative selection of L1 elements in gene-rich segments is found to be a consequence of their ability to mediate ectopic recombination (82) and positive selection of SINEs may be caused by effects of SINE transcripts (86) or by SINE-associated transcription regulatory motifs (see above).…”

Repetitive sequence environment distinguishes housekeeping genes

“…Regardless of whether Alu elements are beneficial or merely tolerated, the increased abundance of Alu elements around housekeeping genes stood in stark contrast to the scarcity of longer (>400-bp) repeats and repeat tracts (LINE-1 elements and various other repeats) in these same regions Although, the lower abundance of the TT|AAAA target sequence near housekeeping genes may very well contribute to LINE-1 scarcity (Jurka, 1997;Cost and Boeke, 1998;Lander et al, 2001;Graham and Boissinot, 2006) despite their otherwise random insertion pattern (Smit, 1999;Boissinot et al, 2001;Lander et al, 2001;Ovchinnikov et al, 2001;Gilbert et al, 2002;Myers et al, 2002;Symer et al, 2002;Szak et al, 2002;Jurka et al, 2004;Gilbert et al, 2005), at least one additional explanation is needed since long repeats in general were scarce. One reason why long repeats might be selected against near housekeeping genes is that an abundance of these repeats might reduce gene expression via heterochromatin spread.…”

“…Alu transposons differ from other SINEs in that they are not derived from tRNA genes, but rather from the 7SL RNA gene (Ullu and Tschudi, 1984;Quentin, 1994;Smit, 1996;Okada and Hamada, 1997;Terai et al, 1998;Lander et al, 2001) which encodes the RNA component of the signal recognition particle that mediates the translocation of nascent secretory and membrane proteins (Wild et al, 2004). Aside from favoring TT|AAAA target sequences (Feng et al, 1996;Jurka, 1997;Cost and Boeke, 1998), human Alu and LINE-1 elements have been reported to insert at random positions in the genome (Smit, 1999;Boissinot et al, 2001;Lander et al, 2001;Ovchinnikov et al, 2001;Gilbert et al, 2002;Myers et al, 2002;Symer et al, 2002;Szak et al, 2002;Jurka et al, 2004;Gilbert et al, 2005). However, there is some evidence for insertional hot spots (Cost and Boeke, 1998;Myers et al, 2002;Graham and Boissinot, 2006).…”