Key Points
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Human cytogenetics was launched 46 years ago with the discovery that human somatic cells contain 46 chromosomes.
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In the ensuing years, technological advances that have combined innovations in molecular biology, chemistry and instrumentation have repeatedly transformed human cytogenetics.
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The resolution and sensitivity of cytogenetic analysis have improved more than 10,000-fold in an astoundingly short time — first, using banding technology, and later, using fluorescence in situ hybridization (FISH) — such that subtle alterations in chromosome composition can now be detected and analysed for their association with disease.
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Using multicolour chromosome painting techniques, such as spectral karyotyping (SKY) and multicolour (M)-FISH, each chromosome can now be recognized easily by colour-coded labels, even in the highly rearranged karyotypes of tumour cells.
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The karyotype of non-dividing cells can be analysed using FISH and comparative genome hybridization (CGH).
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Other approaches, such as flow karyotyping, yield quantitative information on chromosomal content and structure and/or allow cytogeneticists to isolate specific chromosomes for molecular analyses.
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Array-CGH, the most recently developed technology, allows genome-wide screens for the loss or gain of chromosomal material to be conducted at unprecedented resolution.
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Most importantly, the cytogenetic map is cross-referenced to the human draft sequence at thousands of points. These connections greatly facilitate the translation of microscopically visible clues of the molecular basis of disease to the actual genes that are disrupted or altered in dosage.
Abstract
Human cytogenetics was born in 1956 with the fundamental, but empowering, discovery that normal human cells contain 46 chromosomes. Since then, this field and our understanding of the link between chromosomal defects and disease have grown in spurts that have been fuelled by advances in cytogenetic technology. As a mature enterprise, cytogenetics now informs human genomics, disease and cancer genetics, chromosome evolution and the relationship of nuclear structure to function.
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Acknowledgements
I would like to thank the National Institutes of Health, US Department of Energy and the Fred Hutchinson Cancer Research Center for their present and past support. B.J.T. has significant financial interest in Cytopeia and Dako Cytomation, which are companies that develop and market flow cytometers.
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Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Glossary
- KNUDSON'S TWO-HIT MODEL
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First proposed by Alfred Knudson in 1971, this model indicates that successive hits, such as deletion or mutation, in both alleles of a tumour-suppressor gene are required to turn a normal cell into a cancer cell.
- DUFFY BLOOD GROUP
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An antigenic variant of a chemokine receptor that is expressed on red blood cells.
- AMNIOCENTESIS
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A procedure in which a small sample of amniotic fluid is drawn out of the uterus through a needle inserted into the abdomen. The fluid is then analysed to detect genetic abnormalities in the fetus or to determine the sex of the fetus.
- G-BANDS/R-BANDS
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Chromosome banding pattern produced by Giemsa staining (G-bands); the reciprocal pattern (reverse or R-bands) can be produced with various other staining procedures.
- PEPTIDE NUCLEIC ACID
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(PNA). An analogue of DNA in which the backbone is a pseudopeptide rather than a sugar. PNA mimics the behaviour of DNA, but, because PNA has a neutral backbone, it binds complementary nucleic-acid strands more strongly and with greater specificity than an oligonucleotide.
- COD-FISH
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(Chromosome orientation and direction-fluorescence in situ hybridization). In this technique, single-stranded probes hybridize to one chromatid of a metaphase chromosome, because the most recently synthesized strand in each chromatid is specifically degraded before hybridization. A probe that recognizes the cytosine-rich strand of the telomeric repeat provides orientation by marking the 5′-end of each chromatid.
- BAC, PAC AND YAC
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Cloning vector system able to accomodate large genomic fragments. BACs and PACs are grown in bacteria; YACs are grown in yeast.
- PERICENTRIC INVERSION
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A structural alteration to a chromosome that results from breakage, inversion and reinsertion of a fragment that spans the centromere.
- IMPRINTING
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A genetic mechanism by which genes are selectively expressed from the maternal or paternal homologue of a chromosome.
- CHARCOT–MARIE–TOOTH SYNDROME
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An inherited degenerative peripheral nerve disorder that causes progressive muscle weakness and atrophy in the feet, legs, hands and forearms.
- SMITH–MAGENIS SYNDROME
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A rare condition that is associated with developmental delay, characteristic facial and other anatomical abnormalities, learning difficulties and behavioural problems, such as the tendency to harm oneself.
- DEGENERATE OLIGONUCLEOTIDE-PRIMED (DOP) PCR/LINKER–ADAPTOR PCR
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DOP-PCR uses partially degenerate primers to amplify sequences at dispersed sites in a sample. In linker-adaptor PCR, the DNA sample is digested with a restriction enzyme, the ends are ligated to an adaptor oligonucleotide, and the ligated fragments are amplified using PCR primers that are complementary to the linker-adaptor oligonucleotide. Both techniques generate large pools of fragments that almost completely represent the starting sample.
- INTERFEROMETER
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A device that uses an interference pattern to determine wave frequency, length or velocity.
- TYRAMIDE CHEMISTRY
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A labelling system that uses a hybridization probe that is directly or indirectly labelled with peroxidase. The peroxidase catalyses the localized deposition of a reactive tyramide-labelled tag (for example, biotin or fluorescent dyes).
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Trask, B. Human cytogenetics: 46 chromosomes, 46 years and counting. Nat Rev Genet 3, 769–778 (2002). https://doi.org/10.1038/nrg905
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DOI: https://doi.org/10.1038/nrg905
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