Telomeres are specialized protein-DNA constructs present at the ends of eukaryotic chromosomes, which prevent them from degradation and end-to-end chromosomal fusion. Introductory biology courses often describe telomere as a type of chromosomal aglet. Most vertebrate telomeric DNA consists of long (TTAGGG)n repeats of variable length, often around 3-20kb.Subtelomeres are segments of DNA between telomeric caps and [chromatin]. Therefore, each chromosome has two subtelomere which are immediately adjacent to the long (TTAGGG)n repeats and also contain repetitive stretches of DNA. Subtelomeres are considered to be the most distal (farthest from the centromere) region of unique DNA on a chromosome. This is a complex and dynamic system which is not yet fully understood. From a structural approach, the constitutive elements of the subtelomeric region of a chromosome are nucleotide sequences of different nature, mostly repetitive stretches of DNA (Subtelomeric Repeats, Srpts) :
- segmental duplications
- (TTAGGG)n-like sequences
This structure with repeated sequences is responsible for frequent duplication events (which create new genes) and recombination events, at the origin of combination diversity. These peculiar properties are mechanisms that generate diversity at an individual scale and therefore contribute to adaptation of organisms to their environments.
Variations of subtelomere
Variation of subtelomeric regions are mostly variation on Srpts, due to recombination of large-scale stretches delimited by (TTAGGG)n-like repeated sequences, which play an important role in recombination and transcription process. Haplotype (or version of successive genes) and length differences are therefore observed from an individual to another.
The subtelomeric transcripts are pseudogenes (transcribed genes producing RNA sequences which are not translated in protein) and family genes. In human, those transcripts codes for olfactory receptors, globulin heavy chain and zinc-finger proteins. In other species, as parasitic species, the transcripts codes for virulence factor responsible for antigenic variation and immune system escape. For example, the genes belonging to var family in Plasmodium falciparum (agent of malaria) codes for the PfEMP1 (Plasmodium falciparum Erythrocytic Membrane Protein 1), a major virulence factor of erythrocytic stages, and are localized in subtelomere region. In Trypanosoma brucei, a major surface antigene, the VSG (Variable Surface Glycoprotein), is also located in subtelomeric region and is a key molecule for immune escape and parasitic success.
Loss of telomeric DNA through repeated cycles of cell division is associated with senescence or somatic cell aging. In contrast, germ line and cancer cells possess a telomerase enzyme which prevents this telomere degradation and maintains telomere integrity, causing these types of cells to be very long-lived. In human, the role of subtelomere disorder in pathology is demonstrated, as for FSHD which is a form of muscular dystrophy, Al-Zeihmer disease and peculiar syndromic diseases (malformation and mental retardation).
Analysis of subtelomere
The analysis of subtelomere, and more especially the profile establishment of the subtelomere of patients is difficult for the reasons of repeated sequences, length of stretches and lack of database on the topic. Those limits for specific molecular sequencing of subtelomere region of each chromosome is a challenge for molecular biology.
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