Mobile genetic elements, or transposons, are powerful modulators of genome variation and the biological implications of their activity are considerable, ranging from genomic instability in cancers to regulation of gene expression during development to speciation (Jurka et al. 2005
; Comeaux et al. 2009
; Perez-Stable et al. 1984
). In mammalian genomes, all transposons belong to the group of retrotransposons which generate new copies and multiply by reverse-transcription of their RNA and integration of this cDNA into new genomic locations. Among the many types of retrotransposons present in humans, the short interspersed nuclear elements (SINEs) of the Alu
class, originally derived from a signal recognition particle, 7SL RNA, have a high mutagenic potential in humans, and represent the largest group of repetitive sequences, accounting for approximately 20% of the human genome (Lander et al. 2001
). Alu elements have propagated to an estimated 1–2×106
copies in primate genomes, and have generally achieved a balance between detrimental consequences for the individual and beneficial outcomes for genetic variation and speciation.
transpositions affect the genome in several ways, such as causing insertion mutations, recombination between elements, gene adaptation, and alterations in gene expression. Throughout 65 million years of primate evolution, these elements have spread over the entire genome by retrotransposition, contributing significantly to the size of the genome. Over the evolutionary timescale, most Alu subfamilies have lost their ability for retrotransposition and reside within the genomes as phenotypically neutral elements that are located in the intergenic, intronic, and untranslated regions, but rarely in the coding regions of genes and genomes (Batzer and Deininger 2002
). However, some have preserved their retrotransposition capability, and have been shown to be the causative alteration in some diseases (Callinan and Batzer 2006
; Claverie-Martín et al.,2003
The Alu element identified in these patients belongs to the still-active Ya5 family, and thus features of the insertion suggest a very recent retrotransposition event. Interestingly, this is one of very few examples for an Alu element causing a direct disruption of an open reading frame by insertion in a coding exon.
The mutagenic potential of these retrotransposons has led to the development of host genome defense mechanisms aimed to suppress “retrotransposons life cycle”, mainly at the stage of transcription via DNA methylation of their promoters (Yoder et al. 1997
). At the molecular level, Alu
-mediated recombination can lead to deletion of genomic loci flanked by identical Alu
repeats and is common in some hereditary cancers (Moolhuijzen et al
.; Konkel and Batzer 2010
). Another phenomenon, exon skipping, occurs when Alu
insertions interfere with the assembly of the splicing machinery upon premRNA. Finally and infrequently, as in the case reported here, de novo Alu
insertions may disrupt a coding exon of an essential gene, leading to an inheritable disease in people homozygous for the disrupted allele.
In summary a novel mutation was identified to be caused by a recent Alu insertion in the coding sequence of human ALMS1 in a Turkish family with Alström Syndrome. The large insertion leads to a disruption of the open reading frame and thus represents a unique disease-causing variant among ALMS1 mutations and extends the spectrum of mutations causative for Alström Syndrome. Additionally, this new observation provides valuable evidence for the devastating mutagenic potential of transposition-competent Alu elements.