Abstract
Human chromosomes terminate with specialized telomeric structures including the simple tandem repeat (TTAGGG)n and additional complex subtelomeric repeats1–3. Unique sequence DNA for each telomere is located 100–300 kilobases (kb) from the end of most chromosomes. A high concentration of genes4 and a number of candidate genes for recognizable syndromes5–8 are known to be present in telomeric regions. The human telomeric regions represent a major diagnostic challenge in clinical cytogenetics, because most of the terminal bands are G negative, and cryptic deletions and translocations in the telomeric regions are therefore difficult to detect by conventional cytogenetic methods. In fact, several submicroscopic chromosomal abnormalities in patients with undiagnosed mental retardation or multiple congenital anomalies have been identified by other molecular methods such as DNA polymorphism analysis9,10. To improve the sensitivity for deletion detection and to determine whether such cryptic rearrangements represent a significant source of human pathology that has not been previously appreciated, it would be valuable to have specific FISH probes for all human telomeres. We report here the isolation and characterization of a complete set of specific FISH probes representing each human telomere. As most of these clones are at a known distance of within 100–300 kb from the end of the chromosome arm, this provides a 10-fold improvement in deletion detection sensitivity compared with high-resolution cytogenetics (2–3 Mb resolution). While testing these probes, we serendipitously identified a family with multiple members carrying a cryptic 1q;11p rearrangement in the balanced or unbalanced state.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Moyzis, R.K. et al. A highly conserved repetitive DNA sequence (TTAGGG)n present at the telomeres of human chromosomes. Proc. Natl. Acad. Sci. USA 85, 6622–6626 (1988).
Brown, W.R.A. et al. Structure and polymorphism of human telomere-associated DNA. Cell 63, 119–132 (1990).
Cross, S., Lindsey, J., Fantes, J., McKay, S., McGill, N. & Cooke, H. The structure of a subterminal repeated sequence present on many human chromosomes. Nucl. Acids Res. 18, 6649–6657 (1990).
Saccone, S., De Sario, A., Della-Valle, G. & Bernardi, G. The highest gene concentrations in the human genome are in teiomeric bands of metaphase chromosomes. Proc. Natl. Acad. Sci. USA 89, 4913–4917 (1992).
Lamb, J. et al. Detection of breakpoints in submicroscopic chromosomal translocation, illustrating an important mechanism for genetic disease. Lancet 2, 819–824 (1989).
Overhauser, J. et al. Prenatal diagnosis and carrier detection of a cryptic translocation by using DNA markers from the short arm of chromosome 5. Am. J. Hum. Genet. 45, 296–303 (1989).
Altherr, M.R. et al. Molecular confirmation of Wolf-Hirschhorn syndrome with a subtle translocation of chromosome 4. Am. J. Hum. Genet. 49, 1235–1242 (1991).
Kuwano, A., Ledbetter, S.A., Dobyns, W.B., Emanuel, B.S. & Ledbetter, D.H. Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization. Am. J. Hum. Genet. 49, 707–714 (1991).
Flint, J. et al. The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nature Genet. 9, 132–140 (1995).
Biesecker, L.G. et al. Detection of a subtle rearrangement of chromosome 22 using molecular techniques. Am. J. Med. Genet. 58, 389–394 (1995).
Riethman, H.C., Moyzis, R.K., Meyne, J., Burke, D.T. and Olson, M.V. Cloning human telomeric DNA fragments into Saccharomyces cerevisiae using a yeast-artificial-chromosome vector. Proc. Natl. Acad. Sci. USA 86, 6240–6244 (1989).
Bates, G.P. et al. A yeast artificial chromosome telomere clone spanning a possible location of the Huntington disease gene. Am. J. Hum. Genet. 46, 762–775 (1990).
Martin-Gailardo, A. et al. Molecular analysis of a novel subtelomeric repeat with polymorphic chromosomal distribution. Cytogenet. Cell Genet. 71, 289–295 (1995).
Sternberg, N.L. Cloning high molecular weight DNA fragments by the bacteriophage P1 system. Trends Genet. 8, 11–16 (1992).
loannou, P.A. et al. A new bacteriophage P1-derived vector for the propagation of large human DNA fragments. Nature Genet. 6, 84–89 (1994).
Ning, Y., Rosenberg, M., Biesecker, L.G. & Ledbetter, D.H. Isolation of the human chromosome 22q telomere and its application to detection of cryptic chromosomal abnormalities. Hum. Genet. 97, 765–769 (1996).
Ferrin, L.J. & Camerini-Otero, R.D. Selective cleavage of human DNA: RecA-assisted restriction endonuclease (RARE) cleavage. Science 254, 1494–1497 (1991).
Ferrin, L.J. & Camerini-Otero, R.D. Long-range mapping of gaps and telomeres with RecA-assisted restriction endonuclease (RARE) cleavage. Nature Genet. 6, 379–383 (1994).
Collins, C., Kuo, W.L., Segraves, R., Fuscoe, J., Pinkel, D. & Gray, J.W. Construction and characterization of plasmid libraries enriched in sequences from single human chromosomes. Genomics 11, 997–1006 (1991).
Speicher, M.R., Ballard, S.G. & Ward, D.C. Karyotyping human chromosomes by combinatorial multi-fluor FISH. Nature Genet. 12, 368–375 (1996).
Schrock, E. et al. Multicolor spectral karyotyping of human chromosomes. Science 273, 494–497 (1996).
Riethman, H.C., Spais, C., Buckingham, J., Grady, D. & Moyzis, R.K. Physical analysis of the terminal 240 kb of DNA from human chromosome 1q. Genomics 17, 25–32 (1993).
Negorev, D.G., Macina, R.A., Spais, C., Ruthig, L.A., Hu, X.-L. & Riethman, H.C. Physical analysis of the terminal 270 kb of DNA from human chromosome 1q. Genomics 22, 569–578 (1994).
Macina, R.A., Negorev, D.G., Spais, C., Ruthig, L.A., Hu, X.-L. and Riethman, H.C. Sequence organization of the human chromosome 2q telomere. Hum. Mol. Genet. 3, 1847–1853 (1994).
Macina, R.A. & Riethman, H.C. Mapping vector-adjacent DNA from a 7q human telomeric YAC using RARE. Mamm. Genome 5, 596 (1994).
Browne, D.L., Smith, E.A., Dietz-Band, J., Riethman, H.C., Phromchotikul, T. & Litt, M. Dinucleotide repeat polymophism at the human chromosome 11p telomere (D11S2071). Genomics 25, 600–601 (1995).
Macina, R.A. et al. Molecular cloning and RARE cleavage mapping of human 2p, 6q, 8q, 12q, and 18q telomeres. Genome Res. 5, 225–232 (1995).
Reston, J.T., Hu, X.-L., Macina, R.A., Spais, C. & Riethman, H.C. Structure of the terminal 300 kb of DNA from human chromosome 21q. Genomics 26, 31–38 (1995).
Youngman, S. et al. The telomeric 60 kb of chromosome arm 4p is homologous to telomeric regions on 13p, 15p, 21 p and 22p. Genomics 14, 350–356 (1992).
Wright, T.J. et al. Fine mapping of the FSHD gene region orientates the rearranged fragment detected by the probe p13E-11. Hum. Mol. Genet. 2, 1673–1678 (1993).
Cooke, H.J., Brown, W.R. & Rappold, G.A. Hypervariable telomeric sequences from the human sex chromosomes are pseudoautosomal. Nature 317, 687–692 (1985).
Kvaloy, K., Galvagni, F. & Brown, W.R. The sequence organization of the long arm pseudoautosomal region of the human sex chromosomes. Hum. Mol. Genet. 3, 771–778 (1994).
Lehrach, H. et al. Hybridization fingerprinting in genome mapping and sequencing. in Genome Analysis Vol. 1: Genetic and Physical Mapping. (eds Davies, K.E. & Tilghman, S.M.) 39–81 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ning, Y., Roschke, A., Smith, A. et al. A complete set of human telomeric probes and their clinical application. Nat Genet 14, 86–89 (1996). https://doi.org/10.1038/ng0996-86
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0996-86
This article is cited by
-
An ethical analysis of divergent clinical approaches to the application of genetic testing for autism and schizophrenia
Human Genetics (2022)
-
One healthy live birth after preimplantation genetic testing of a cryptic balanced translocation (9;13) in a family with cerebral palsy and glaucoma: a case report
BMC Medical Genomics (2021)
-
Copy number variations and clinical cytogenetic diagnosis of constitutional disorders
Nature Genetics (2007)
-
A study of cryptic terminal chromosome rearrangements in recurrent miscarriage couples detects unsuspected acrocentric pericentromeric abnormalities
Human Genetics (2003)