The complex structure and dynamic evolution of human subtelomeres

Key Points

  • Subtelomeres are dynamic and variable regions near the ends of chromosomes that form the transition between chromosome-specific DNA and the telomere. They are defined by their unusual structure: patchworks of blocks that are duplicated near the ends of multiple chromosomes.

  • The maps of human subtelomeres are still sketchy, owing to the complex and variable structure of these regions and their under-representation in the clone libraries used for sequencing.

  • Recurrent exchange of DNA among subtelomeric regions has effectively blurred the evolutionary history of these regions.

  • Relatively recent subtelomeric duplications have resulted in striking variation between individuals in subtelomeric content, including the number, location and sequence of subtelomerically located genes.

  • Subtelomeric plasticity might allow some organisms to rapidly adapt to new environmental conditions or, in the case of the malaria-causing parasite Plasmodium falciparum, to evade the host immune system.

  • Given their extensive homology, subtelomeres might also promote the recombinational processes that allow some tumour cells to maintain telomeres and replicate indefinitely in the absence of telomerase.

  • Anomalous pairing of subtelomeres might also lead to disease-causing rearrangements. Mental retardation and facioscapulohumeral muscular dystrophy are two disorders known to be associated with rearrangements that involve the tips of human chromosomes.

  • Further studies of the dynamic interactions among subtelomeres require techniques to clone large portions of these regions from many individuals, to reliably track sequence that is transferred from one chromosome to another and to select these newly rearranged cells for more detailed genomic analysis.

  • A better understanding of these exceptional genomic regions will continue to provide examples of exceptional biology and might help to further our understanding of other duplicated regions of the genome.

Abstract

Subtelomeres are extraordinarily dynamic and variable regions near the ends of chromosomes. They are defined by their unusual structure: patchworks of blocks that are duplicated near the ends of multiple chromosomes. Duplications among subtelomeres have spawned small gene families, making inter-individual variation in subtelomeres a potential source of phenotypic diversity. The ectopic recombination that occurs between subtelomeres might also have a role in reconstituting telomeres in the absence of telomerase. However, the propensity for subtelomeres to interchange is a double-edged sword, as extensive subtelomeric homology can mediate deleterious rearrangements of the ends of chromosomes to cause human disease.

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Figure 1: Subtelomeric structure.
Figure 2: Fluorescence in situ hybridization analysis of the chromosomal locations of a cloned subtelomeric segment.
Figure 3: Variability in copy number, chromosomal location and sequence of the subtelomeric block f7501.
Figure 4: Models of subtelomere evolution.
Figure 5: Telomere maintenance by recombination.
Figure 6: Subtelomeres and deleterious chromosomal rearrangements.

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Acknowledgements

The authors thank E. Linardopoulou, Y. Fan, C. Friedman, other present and past members of the Trask laboratory, and G. van den Engh for stimulating discussions about subtelomeric structure and evolution. This work was supported in part by the National Institutes of Health. H.C.M. was also supported by a Poncin fellowship.

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Correspondence to Barbara J. Trask.

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DATABASES

LocusLink

HBA1

HBA2

HeT-A element

IL9R

RABL2A

RABL2B

TART element

OMIM

α-thalassaemia

facioscapulohumeral muscular dystrophy

Saccharomyces Genome Database

MEL

RAD52

SUC

SUP11

URA3

FURTHER INFORMATION

Encyclopedia of Life Sciences

Telomeres

P. falciparum life cycle

Glossary

OLFACTORY RECEPTOR

A member of a large family of membrane-spanning receptors in the sensory neuroepithelium of the nose that bind volatile odorants. On being bound, the receptor initiates a signalling cascade that results in transmission of an electrical signal to the brain.

TELOMERASE

A ribonucleoprotein enzyme that maintains the ends of chromosomes by adding a characteristic series of nucleotides to telomeres.

RETROTRANSPOSITION

A class of transposition event, in which a mRNA intermediate is reverse transcribed and inserted at a new location in the genome.

MONOCHROMOSOMAL SOMATIC-CELL HYBRID LINE

A cell line that contains a single human chromosome in the genomic background of another species. A panel of these hybrids is used to assign DNA sequence to one of the 24 human chromosomes by PCR, Southern blot or functional assays.

FLUORESCENCE-ACTIVATED CELL/CHROMOSOME SORTING

(FACS). The separation of cells or chromosomes by their fluorescence and light-scattering properties, which are measured as the particles flow in a liquid stream past laser beams. The stream is then broken into droplets, and selected droplets are electrically charged and deflected into collection vessels as they pass through an electric field.

INTERSTITIAL

Situated in the body of a chromosome, not close to either end.

GENE CONVERSION

A specific type of recombination, which results in non-reciprocal genetic exchange, in which the sequence of one DNA strand is used to alter the sequence of the other. In ectopic gene conversion, the donor and recipient DNA strands are not allelic copies of the same locus.

ALU INSERTION

A dispersed, intermediately repetitive 300-bp DNA sequence, found in the human genome in 300,000 copies, that is named after the restriction endonuclease (AluI) that cleaves it.

PSEUDOGENE

A DNA sequence originally derived from a functional protein-coding gene that has lost its function through the presence of one or more inactivating mutations.

TELOMERE-POSITION EFFECT

The transcriptional silencing of genes by virtue of their close proximity to telomeres.

IDIOPATHIC

Arising spontaneously, or from an obscure or unknown cause.

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Mefford, H., Trask, B. The complex structure and dynamic evolution of human subtelomeres. Nat Rev Genet 3, 91–102 (2002). https://doi.org/10.1038/nrg727

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