Human Cytogenetics Help
Humans have a diploid chromosome number of 46 (23 pairs). When grouped as homologous pairs, the somatic chromosome complement is called a karyotype. Formerly, a chromosome could be distinguished only by its length and the position of its centromere at the time of maximum condensation in late prophase. No single autosome could be easily identified, but a chromosome could be assigned to one of seven groups (A–G) according to the "Denver system" of classification (Fig. 7.8).
Group A consists of large, metacentric chromosomes (1–3); group B contains submedian chromosomes (4, 5); group C has medium-sized chromosomes with submedian centromeres (pairs 6–12); group D consists of medium-sized chromosomes (pairs 13–15) with one very short arm (acrocentric); group E chromosomes (16–18) are a little shorter than those in group D and have median or submedian centromeres; group F (19, 20) contains short, metacentric chromosomes; and group Ghas the smallest acrocentric chromosomes (21, 22). The X and Y sex chromosomes are usually placed together in one part of the karyotype.
Special staining techniques (e.g., Giemsa, quinacrine) allowspecific banding patterns (G bands, Qbands, etc.) for each chromosome to be revealed (Fig. 7.9). Now, fluorescent probes are being used to "paint" chromosomes with different colors that correspond to a different gene or region sequence.
Prenatal screening of babies for gross chromosomal aberrations (polyploidy, aneuploidy, deletions, translocations, etc.), as well as sex prediction, is now possible. A fluid sample can be taken from the amniotic fluid that surrounds the fetus in utero, a process termed amniocentesis. The cells found in this fluid are of fetal origin. Such cells can be cultured in vitro in a highly nutritive solution and then treated with colchicine to stop division at metaphase. The cells are then placed into a hypotonic salt solution to cause the cells to swell and burst, resulting in release of their chromosomes. This preparation is placed on a slide, stained, and photographed under amicroscope. Individual chromosomes are then cut from the resulting photograph and matched as homologous pairs to form a karyotype.
The X chromosome can be identified in many non-dividing (interphase) cells of females as a dark-staining mass called sex chromatin or Barr body that is attached to the nuclear membrane. Barr bodies result from condensation [heterochromatinization] and inactivation of any X chromosomes in excess of one per cell. Sex-linked traits are not Expressed more intensely in females with two doses of X-linked genes than in males with only one X chromosome. At a particular stage early in development of females, one of the two X chromosomes in a cell becomes inactivated as a dosage compensation mechanism. Different cells inactivate one of the two chromosomes in an apparently random manner, but subsequently all derived cells retain the same functional chromosome. Females are thus a mixture of two kinds of cells; in some cells one X chromosome is active, and in different cells the other X chromosome is active. The same principle applies to mammals other than humans.
Mosaicism is the presence in an individual of two or more cell lineages of different chromosomal constitution, each cell lineage being derived from the same zygote. For example, a bilateral gynandromorph is a unique type of fruit fly that has had half its body develop as a male and the other half as a female; the different cell lineages are maleness and femaleness. In contrast, fusion of cell lines from different zygotes produces a chimera. Mosaicism results from abnormal postzygotic (mitotic) divisions of three kinds: (1) nondisjunction during the first cleavage division of the zygote, (2) nondisjunction during later mitotic divisions, and (3) anaphase lag, in which one member of a chromosome pair fails to segregate chomatids from the metaphase plate, and that chromatid fails to be included in the daughter cell nuclei (the entire chromosome is thus lost). Assuming that nondisjunction of chromatids affects only one member of a pair of chromosomes of the diploid set, the expected mosaic karyotype from nondisjunction during the first cleavage division of a zygote would be that half of the individual's cells are trisomic (2n + 1 = 47) and the other half are monosomic (2n – 1 = 45). If the first cleavage division is normal, but the second cleavage division involves a nondisjunctional event, three cell lineages would be established (45/46/47). Each line should "breed true," barring further mitotic abnormalities. In addition, XX/XO, sex-chromatin-positive Turner syndrome (Example 7.17) mosaics may result from anaphase lag of the sex chromosomes in females. A condition that may resemble Turner syndrome or be a hermaphrodite with physical characteristics of both sexes (XY/XO) may result from anaphase lag of the sex chromosomes in males.
EXAMPLE 7.17 Aneuploid females with only one X chromosome (XO) have a karyotype with 2n – 1 = 45. They are called Turner females, and they exhibit a group of characteristics that together define Turner syndrome: short stature, webbing of neck skin, underdeveloped gonads, shield like chest, and impaired intelligence. Non-mosaic Turner females are sex-chromatin-negative.
EXAMPLE 7.18 Abnormal males possessing an extra X chromosome (XXY) have a karyotype with 2n + 1 = 47. They are called Klinefelter males, and they exhibit Klinefelter syndrome: sterility, long limbs, breast development (gynecomastia), sparse body hair, and mental retardation. Klinefelter males are sex chromatin- positive. If some portion of the extra X chromosome is not inactivated, this could account for the phenotypic differences not only between XXY Klinefelter males and XY normal males, but also between XO Turner females and XX normal females.
EXAMPLE 7.19 XXX "superfemales" (metafemales) are karyotyped as 2n + 1 = 47 trisomics and exhibit two Barr bodies. These individuals may range phenotypically from normal fertile females to nearly like those with Turner syndrome. They have a high incidence of mental retardation.
EXAMPLE 7.20 Trisomic XYY males were first discovered in relatively high frequencies in penal and mental institutions. The presence of an extra Y chromosome was thought to predispose such a male to antisocial behavior, hence the name "tall-aggressive syndrome." Subsequently, more XYY males have been found among the non-institutionalized population, casting doubt upon the validity of the above hypothesis. XYY males do tend to have subnormal IQs, however, and this may contribute to impulsive behavior.
EXAMPLE 7.21 Down syndrome is usually associated with a trisomic condition for one of the smallest human autosomes (21). It is the most common chromosomal abnormality in live births (1/900 births). These individuals are mentally retarded, short, possess eye folds have stubby fingers and a swollen tongue. Women over age 35 have a greater chance of conceiving a child with Down syndrome: at 35, a woman has a 1 in 400 chance; while by age 40, this chance rises to 1 in 110; and at age 45, 1 in 35. Nondisjunction of chromosome pair 21 during spermatogenesis can also produce a child with Down syndrome, but paternal age does not seem to be associated with its incidence. In about 2–5% of the cases, the normal chromosome number is present (2n = 46), but the extra chromosome 21 is attached (translocated) to one of the larger autosomes.
EXAMPLE 7.22 Human autosomal monosomics are rarer than trisomics, possibly because harmful recessive mutations on the remaining homologue are hemizygous and can be expressed. Most cases of autosomal monosomy are mosaics of normal diploid (2n) and monosomic (2n – 1) cells resulting from mitotic nondisjunctions. Mosaics involving sex chromosomes are also known: e.g., XO: XX, XO:XY, XXY: XX, as well as autosomal mosaics such as 21-21 : 21-21-21, etc.
EXAMPLE 7.23 Deletion of part of the long arm of chromosome 22 produces an abnormality known as a Philadelphia chromosome (so named because it was discovered in that city). It is found only in the bone marrow (along with chromosomally normal cells) in approximately 90% of patients with chronic myelogenous leukemia (a kind of cancer). Usually, the missing piece of chromosome 22 can be found translocated to one of the larger autosomes (most frequently chromosome 9). See Example 11.11.
Practice problems for these concepts can be found at: