Cloning, mapping, and collaborative DNA sequencing efforts culminated in reference sequences for each of the 41 genetically distinct human subtelomeric regions (Riethman et al. 2001, 2004). Sequence gaps that remain on the reference telomeres are generally small, well-defined, and for the most part restricted to regions directly adjacent to the terminal (TTAGGG)n tract. Distal subtelomere regions are highly enriched in recently-duplicated chromosome segments relative the rest of the human genome. Our recent analysis of the substructure of this duplicated DNA has shown that (1) some duplicon blocks comprising the mosaic patchwork are very highly similar (98 to 99.5% identical), whereas others are less so; (2) Internal islands of (TTAGGG)n-like sequences, which are involved in controlling DNA replication and in enhanced recombination in model organisms, are enriched > 25-fold in subtelomeric DNA relative to the rest of the genome and are almost always located at duplicon boundaries; (3) While most duplicon blocks have copies in both internal and in subtelomeric regions, a subset localizes exclusively to subtelomeres – these subtelomere-specific blocks may provide an opportunity to develop probes for tracking particular subtelomeric CNPs; (4) subterminal duplicon blocks, which are immediately adjacent to terminal (TTAGGG)n tracts and are potentially involved in cis-regulation of allele-specific (TTAGGG)n tract length, group into just 6 families of sequences, the detailed characterization of which may permit development of subterminal genotyping assays.
Telomeric and subtelomeric DNA regions exhibit a very high level of structural variation that is likely to impact telomere function but has yet to be characterized in detail. A new resource of clone libraries and associated paired-end reads constructed as part of the Human Structural Variation initiative is being used along with a combination of computational and wet-lab mapping methods to identify and characterize structural variants in distal human subtelomere regions. Appropriately regulated (TTAGGG)n tracts are critical for normal cell function; individual (TTAGGG)n tract lengths in humans are allele-specific and regulated in part by cis-acting subtelomeric elements. The sequence information on new subterminal alleles and allelic variants is opening new avenues of telomere research, especially relating to telomeric transcription of non-coding RNAs and epigenetic mechanisms active at human telomeres. In addition, it is providing novel opportunities for developing PCR-based methods to track subterminal genotypes in populations and measure allele-specific telomere lengths.
Trainees in the lab have participated in many aspects of this work over the years. Currently, Mr. Donahue is using a combined microarray analysis and telomere structure analysis of human endothelial cells subjected to oxidative stress in order to investigate mechanisms of senescence and aging in the human cardiovascular system.
Selected Publications
Riethman H: Human Telomere Structure and Biology. Annu Rev Genomics Hum Genet. May 2008.
Ambrosini A, Paul S, Hu S, and Riethman H. : Human Subtelomeric Duplicon Structure and Organization. Genome Biology Page: 8:R151, July 2007.
Riethman, H., Ambrosini, A. and Paul, S. : Human subtelomere structure and variation. Chromosome Research 13: 505-515, 2005.
Riethman, H., Ambrosini, A., Castaneda, C., Finklestein, J., Hu, X-L., Mudunuri, U., Paul, S., and Wei, J. : Mapping and initial analysis of human subtelomeric sequence assemblies. Genome Research 14: 18-28, 2004.
Ning, Y., Xu, J-F., Li, Y., Chavez, L., Riethman, H., Lansdorp, P., and Weng, N-P. : Telomere length and the expression of natural telomeric genes in human fibroblasts. Human Mol Genet. 12: 1329-36, 2003.
Riethman, H.: Cloning, Mapping, and Sequencing Telomeres. Genomic Mapping and Sequencing. Horizon Press, Wymondham, UK, I: 257-277, 2003.
Riethman, H., Ambrosini, A., Castaneda, C., Finklestein, J., Hu, X-L., Paul, S., and Wei, J. : Human Subtelomeric DNA The Genome of Homo Sapiens: The 68th Cold Spring Harbor Laboratory Symposium on Quantitative Biology Cold Spring Harbor Laboratory Press, Cold Spring Harbor Page: 39-47, 2003.
Xiang, Z., Morse, E., Hu, X-L., Flint, J., Chi, H, Grady, D., Moyzis, R., Riethman, H. : A sequence-ready map of the human chromosome 1q telomere Genomics 72: 105-107, 2001.
Riethman, H., Xiang, Z., Paul, S., Morse, E., Hu, X.-L., Flint., J., Grady, D., Chi, H., Moyzis, R.K. : Integration of telomere sequences with the draft human genome sequence. Nature 409: 948-51, 2001.
Knight SJL, Lese CM, Precht KP, Kuc J, Ning Y, Lucas S, Regan R, Brenan M, Nicod A, Martin Lawrie N, Cardy DLN, Nguyen H, Hudson TJ, Riethman, H, Ledbetter DH., Flint J: An optimized set of human telomere clones for studying telomere integrity and architecture. Am. J. Hum Genet. 67: 320-32, 2000.
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Last updated: 07/30/2008
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