Transposons are mobile DNA elements which inserted themselves into the human genome during the evolution. So it is common to refer to them as transposon insertions. Transposons arise from RNA-based or DNA-based mechanisms and are therefore categorized in two classes: retrotransposons and DNA transposons.
Retrotransposons are fragments of cDNA which are transcribed from RNA and then inserted in a permissive sequence of the genome (splicesosomal introns, for instance, are permissive regions). The transcription mechanism requires the activity of an inverse transcriptase. Three types of transposons belong to this class: LINE (also known as LINE-1 or L1), SINE and LTR transposons.
DNA transposons are fragments of DNA which are not copied, but simply transposed. They code for a transposase which regulate their transposition process. Since these sequences are not active anymore, they are considered transposon fossils. Transposon fossils are the fourth type of transposons.
So there are four two classes (retrotransposons and DNA transposons) and four types of transposons: LINE (o LINE-1 o L1), SINE, LTR, and transposon fossils.
Up to 40% of human genome
Transposons insertions usually generate repetitive units. Transposons insertions are estimated to constitute up to 40% of the human genome (only LINEs represent 17%). Transposon insertions may be pathogenic, as they can impact gene expression. It is actually estimated that up to 5% of pathogenic mutations in humans are caused by transposons insertions.
Retrotransposons, for instance, may activate alternative gene promoters or generate non-coding RNAs (i.e. antisense RNAs or regulatory RNAs). Alu repetitions (which occur every 3 kb in the human genome) are SINE with an internal promoter. Such promoter is usually inactive, unless its sequence become interspersed in a region that allows for its activation. Alu repetitions are typically GC rich. An example of pathogenic mutation caused by an Alu element is the insertion in intron 14 of the FERMT1 gene, which causes Kindler syndrome. Another example is given by the insertion of an Alu element in the factor VIII gene (F8), which causes hemophilia A.
Retrotransposons may also alter the splicing process, causing the inclusion of introns or the exclusion of exons through the activation of cryptic splice sites. In other cases, the retrotransposon-mediated pathogenicity is due to NHAR – Non Homologous Allelic Recombination (see also unequal crossing-over), which usually lead to large deletions or duplications (also referred to as CNVs – Copy Number Variations). Some examples of NHAR-mediated CNVs are the PDHX gene deletion, caused by the retrotransposition of LINE elements, and the LINE-mediated insertions in the CFTR gene.
Transposons and multifactorial diseases
Finally, it is possible that transposon insertions play a role in the susceptibility to multifactorial diseases such as tumors. Apart from traditional, fully pathogenic mutations, transposons can also generate hypomorphic alleles. Hypomorphic alleles aren’t full mutations with a totally disruptive pathogenic effect, they are simply allele with reduced functionality. A such, they may worsen the phenotype of a disease when they are found together with a classic fully pathogenic mutation. It is thought that hypomorphic alleles may play a role in the susceptibility to multifactorial diseases.
Breda Genetics srl
Breda Genetics can proceed to the screening of transposon-mediated pathogenic mutations, such as large deletions and duplications. Such analyses can be done in collaboration with our partner laboratories and include all the following methodologies: algorithmic CNV detection on exome/genome sequencing data, MLPA, qPCR, FISH, array-CGH and karyotyping (KÁRION-500).