Transposable Elements and Human Diseases: Mechanisms and Implication in the Response to Environmental Pollutants

Abstract

Transposable elements (TEs) are recognized as major players in genome plasticity and evolution. The high abundance of TEs in the human genome, especially the Alu and Long Interspersed Nuclear Element-1 (LINE-1) repeats, makes them responsible for the molecular origin of several diseases. This involves several molecular mechanisms that are presented in this review: insertional mutation, DNA recombination and chromosomal rearrangements, modification of gene expression, as well as alteration of epigenetic regulations. This literature review also presents some of the more recent and/or more classical examples of human diseases in which TEs are involved. Whether through insertion of LINE-1 or Alu elements that cause chromosomal rearrangements, or through epigenetic modifications, TEs are widely implicated in the origin of human cancers. Many other human diseases can have a molecular origin in TE-mediated chromosomal recombination or alteration of gene structure and/or expression. These diseases are very diverse and include hemoglobinopathies, metabolic and neurological diseases, and common diseases. Moreover, TEs can also have an impact on aging. Finally, the exposure of individuals to stresses and environmental contaminants seems to have a non-negligible impact on the epigenetic derepression and mobility of TEs, which can lead to the development of diseases. Thus, improving our knowledge of TEs may lead to new potential diagnostic markers of diseases.

Keywords: DNA methylation; DNA repair; aging; cancer; common disease; environmental pollutants; epigenetics; metabolic disease; neurologic disease; transposable element.

Figure 1

Proportions of transposable elements (TEs) in the human genome and their distribution in different families and subfamilies. Left panel: the percentage of each class or subclass of TEs is indicated with respect to the whole genome according to data from [1]. Right panel: the distribution of TEs in each category is given as a percentage of the total TEs present in the genome according to [1].

Figure 2

Schematic structure of the main human TEs of class I (retroelements). (a) The long terminal repeats (LTR)-less retrotransposon LINE-1 is commonly constituted of two open reading frames (ORF-1 and -2) with untranslated regions (UTR) on both sides and a 3′ end poly(A) tail. The sequence is flanked by target duplication sites (TSD). (b) The non-autonomous LTR-less retroelement Alu usually harbors two monomers separated by a A-rich linker. Alu also displays a poly(A) tail and TSDs. (c) SVA elements are non-autonomous composite TEs classically constituted of a C-rich repeat, inverted Alu-like sequence, VNTR-like repeats and SINE sequence. (d) The classical structure of the main human LTR-retrotransposons HERVs includes TSDs, 5′ and 3′LTR, the three retroviral ORFs (GAG, POL, ENV) and an additional ORF (Pr).

Figure 3

Insertion of Alu elements and recombination. Example of recombination between two AluYa5 insertions in the parental alleles of the UBE2T gene (a), leading to one recombination allele with deletion (b) and one recombination allele with duplication (c). The exons are represented by grey boxes and the AluYa5 insertions by blue boxes. Figure adapted from [14].

Figure 4

Example of SVA element insertion causing X-linked dystonia with parkinsonism in the TAF1 gene. TAF1 consists of 38 exons (vertical bars; red bars are exons flanking the insertion) with a SVA insertion in reverse orientation in intron 32 (orange triangle). This insertion leads to the retention of intron 32 in the mRNA and the variable number of repeats of the hexanucleotide (CCCTCT)n (see Figure 2c) affects the disease.

Figure 5

Insertion of a LINE-1 element into the APC gene. The insertion of a truncated and partially inverted LINE-1 element in the last exon of the APC gene results in a new polyadenylation site.

Figure 6

Example of the human endogenous retrovirus (HERV)-E element insertion causing X-linked Opitz syndrome. Schematic structure of the 5′ part of the MID1 gene, including the promoter (P, green box) and the first two introns (1N and 2, grey boxes). The insertion of the HERV-E element brings a new transcription start site (TATA) and a new intron 1 (1R, yellow box) leading to an alternative transcript (mRNA).