Abstract
DNA transposons are mobile elements with the ability to mobilize and transport genetic information between different chromosomal loci. Unfortunately, most transposons copies are currently inactivated, little is known about mariner elements in humans despite their role in the evolution of the human genome, even though the Hsmar2 transposon is associated to hotspots for homologous recombination involved in human genetic disorders as Charcot–Marie–Tooth, Prader-Willi/Angelman, and Williams syndromes. This manuscript describes the functional characterization of the human HSMAR2 transposase generated from fossil sequences and shows that the native HSMAR2 is active in human cells, but also in bacteria, with an efficiency similar to other mariner elements. We observe that the sub-cellular localization of HSMAR2 is dependent on the host cell type, and is cytotoxic when overexpressed in HeLa cells. Finally, we also demonstrate that the binding of HSMAR2 to its own ITRs is specific, and that the excision reaction leaves non-canonical footprints both in bacteria and eukaryotic cells.
Highlights
Transposons are small mobile genetic elements widely distributed in the genomes of bacteria, plants, invertebrates and vertebrates, that have the ability to migrate and carry genetic material between chromosomal loci [1]
Copies of Hsmar2 seem to be the remnants of an inactive functional mariner element of the primate lineage, the analysis of hotspot for homologous recombination in the human genome has revealed the presence of Hsmar2 copies near the hotspot for homologous recombination in, the PWS/AS region (15q13), the WAS region (7q11), and the CMT1A region (17p12), where large deletions, or repeated sequences are involved in the molecular mechanism of genetic disorders as Prader-Willi and Angelman syndromes (PWS/AS) [9], Williams syndrome (WAS) [10], and Charcot–Marie–Tooth [11] respectively
The three aspartic acid residues are located at positions D 160D254D289, and the first residue is part of the DETW motif conserved in the irritans subfamily. {Baba, 2005 #67}{Bell, 2007 #85} The secondary structure of the consensus HSMAR2 was predicted by Network Protein Sequence Analysis using the DSC [24] and PHD [25] methods and confirmed by the Predict Protein program [26] (Figure 1B)
Summary
Transposons are small mobile genetic elements widely distributed in the genomes of bacteria, plants, invertebrates and vertebrates, that have the ability to migrate and carry genetic material between chromosomal loci [1]. The low frequency of CpG suggests that Hsmar evolved in the genome of vertebrates, mutating into CA, TG or derivatives This pattern of molecular evolution fits the current model of neutral evolution for the mariner transposons in the human genome starting in a common ancestor of the initial suborders of primates [8]. Copies of Hsmar seem to be the remnants of an inactive functional mariner element of the primate lineage, the analysis of hotspot for homologous recombination in the human genome has revealed the presence of Hsmar copies near the hotspot for homologous recombination in, the PWS/AS region (15q13), the WAS region (7q11), and the CMT1A region (17p12), where large deletions, or repeated sequences are involved in the molecular mechanism of genetic disorders as Prader-Willi and Angelman syndromes (PWS/AS) [9], Williams syndrome (WAS) [10], and Charcot–Marie–Tooth [11] respectively. It has been described that of the 109 copies of Hsmar identified by PRINS [15], about 50% of them were in known fragile sites, suggesting that there may be a potential correlation between the localization of Hsmar copies and fragile sites in the human genome
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