Telomeres

A telomere is a stretch of repeating six-base units (TTAGGG in humans) at the end of every chromosome. At the very tip sits a single-stranded overhang loop that hides the chromosome end from repair mechanisms, which would otherwise interpret a free DNA end as damage. Without telomeres, chromosome ends would degrade or fuse with other chromosomes, leading to cell death or chromosomal instability.

When a cell divides, its entire genome must be copied. The DNA polymerase that does this always needs a starter (a primer) and can only synthesise in one direction. At the very end of the chromosome, after the last primer is removed, there is no room for a new one, so a piece of telomeric DNA is lost with each division. This is called the end-replication problem. In culture, a normal cell divides about 40 to 60 times before the telomeres are so short that division stops (the Hayflick limit).

Telomerase is an enzyme with a built-in RNA template complementary to the telomere sequence. It attaches to the chromosome end, reads the template and adds new TTAGGG repeats. In germ cells and stem cells telomerase is active, which is why these cells can maintain their telomeres. In most differentiated body cells the gene for the telomerase subunit (TERT) is silenced. About 90 percent of cancer cells reactivate telomerase to remain dividing indefinitely.

Telomeres are highly repetitive and a prime example of regions that short read lengths struggle with. Short-read sequencing (Illumina, 150 bases) cannot resolve them, because every read falls within the repeat and no unique anchor exists. Long-read technologies (PacBio, Nanopore) can capture telomeres and subtelomeric regions but are not part of the standard WGS pipeline. Tools like ExpansionHunter, which estimates repeat regions in genome analysis, focus on disease-relevant repeat expansions within genes, not on telomeres.