In the last two decades, great advances have been made in the identification of human chromosomes in the karyotype and in the localization of genes. Such studies have had important biological and medical implications in light of the discovery that many congenital diseases and syndromes are related to chromosomal aberrations. Today, human cytogenetics has become a specialized science in itself, the wide-ranging interests of which far exceed the limits of this article.
The first step in this field was made by Tjio and Levan in 1956, with the final demonstration that the correct diploid number of human chromosomes is 46 (44 autosomes + XY in the male and 44 + XX in the female). The field of human cytogenetics, however, started to receive great attention three years later with the discovery by Lejeune and coworkers of a trisomy (i.e., an extra chromosome) in patients affected by mongolism or Down's syndrome. This finding led to rapid advances, with the identification in the same year of a series of aberrations of the sex chromosomes, such as Klinefelter's syndrome with XXY and Turner's syndrome with XO (i.e., without Y), and later on a series of autosomal aberrations was discovered.
After 1968, a new era was initiated with the demonstration by Caspersson and coworkers of chromosome banding using a fluorescent dye (quinacrine mustard). This was followed by the development of a number of banding techniques which, by demonstrating a substructure in chromosomes, have permitted a more precise identification not only of individual chromosomes but also of their parts. These methods have increased the precision of cytogenetics diagnosis by allowing the study of finer chromosomal aberrations, such as deletions, translocations, inversions, and so forth, of individual chromosomes. The impact of such technical advances has been so great that from the point of view of clinical application, the field can be divided historically into two major periods: one before the discovery of the banding techniques and the other after. These advances have permitted the observation of new chromosomal defects involving almost every chromosome of the human karyotype.
In recent years, considerable progress has been made in the study of the genetic map of human chromosomes, thanks to modern methods of molecular biology. These include somatic cell genetics, gene transfer and nucleic acid hybridization.
The Normal Human Karyotype
The human karyotype has been studied in tissue cultures of fibroblasts, bone marrow, skin, and peripheral blood; colchicines and hypotonic solutions are used to block mitosis at metaphase and to separate the chromosomes. An important technical advance has been the introduction of phytohaemagglutinin, which induces lymphocytes to transform into lymphoblast-like cells that start to divide 48 to 72 hours after exposure. The strong mitogenic properties of this substance have allowed the development of microtechniques that employ small amounts of blood. Spreading the cells on a slide causes them to burst and to display all the chromosomes, which are usually studied in metaphase.
A karyotype of the human metaphase chromosomes is usually obtained from microphotographs. The individual chromosomes are cut out of the microphotograph and then lined up by size with their respective partners. The technique can be improved by determining the so called centromeric index, which is the ratio of the lengths of the long and short arms of the chromosome. More recently, a system has been introduced that involves a computer-controlled microscope and several accessories that permit
1) Scanning of slides,
2) Location of cells in metaphase,
3) Counting chromosomes, and
4) transmission of digitally expressed images for computation and storage.
All these steps, which can be carried out automatically, may help in making karyotypes more rapidly and in determining chromosomal aberrations.
Classification of human chromosomes
The 23 pairs are disposed in seven groups (A through G) with differing morphology (i.e., metacentric, submetacentric, acrocentric with satellites, and others) and decreasing in size. For example,
Group A consists of pairs 1,2, and 3, large almost metacentric chromosomes;
Group B comprises pairs 4 and 5, large submetacentric chromosomes, and so forth.
Group C comprises X chromosome (pairs 6 through 12), medium sized submetacentric chromosomes
Group G comprises Y chromosome together with pairs 21 and 22, small acrocentric chromosomes.
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