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KARYOTYPES Normal female cells contain 46 chromosomes, 23 received from the mother via the egg and 23 from the father via the sperm. The 46 chromosomes consist of 22 homologous pairs of autosomes (chromosomes that do not determine the sex of the organism ) and 2 Xchromosomes that are sex-determining . Normal male cells also contain 46 chromosomes; the 22 pairs of autosomes and two dissimilar chromosomes - an X-chromosome and a much smaller Y-chromosome. The possession of a Y-chromosome determines a human to be a male. These facts about human chromosomes were discovered relatively recently in scientific history - until the mid 1950s, humans were thought to possess only 44 chromosomes. The development of techniques for karyotyping, or chromosome analysis, in humans became available at that time. These techniques allow for the detection of normal vs. abnormal chromosome content in tested cells. Thus, karyotyping has become an important process in studying actual or potential birth defects due to chromosome abnormalities. White blood cells or fetal cells in the amniotic fluid are commonly used for chromosome analysis. The cells are removed from the patient and stimulated by chemicals and nutrients to divide rapidly in a test tube. The cells are fixed, then dropped onto glass slides in such a way as to spread the chromosomes of any cell that was in mitotic metaphase at the time of fixation. The slides are stained and the chromosomes are photographed for later analysis. In the original technique, the primary analytical tool was scissors! The pattern of chromosome movements in meiosis was discussed in the previous lab session. Recall that homologous chromosomes align side-by-side along the equator in metaphase I and segregate during anaphase I (see below). In meiosis II, the sister chromatids separate to yield four gametes, each containing one representative of each of the chromosomes typical of the species. 83 MI M II Meiosis sometimes fails to segregate the chromosomes correctly, and these failures almost always lead to the death of the fetus formed by the defective gamete. There are a few exceptions, as you will see below. Consider non-disjunction, the failure of homologous chromosomes to segregate in meiosis I . In our hypothetical species, some of the gametes resulting from the non-disjunction will have too many chromosomes, and some will have too few (see below). MI M II The defective gametes may be fertilized by normal gametes; the expected outcomes are: Monosomic Trisomic Those cells (embryos) that have only one representative of a chromosome type are said to be monosomic for that chromosome. 84 Those cells that have three representatives of a chromosome type are said to be trisomic. (The normal condition is disomic.) In humans, the autosomes are numbered from 1-22 in order of decreasing size. (Your instructor will show an overhead depicting a typical male chromosome spread and the resulting ordered karyotype. Notice that in addition to the 22 pairs of autosomes, the male possesses a large X and a small Y.) If an individual were to have three chromosomes 13, then the resulting condition or genetic defect would be termed trisomy-13. An individual with a single chromosome 20 would have monosomy-20, and so forth. Most human monosomics and trisomics spontaneously abort or are stillborn. The most notable exceptions are those having Down's syndrome or Trisomy-21. These individuals suffer from numerous physical and mental defects and tend to experience premature aging (if surgery corrects their internal physical defects to allow their survival at all). How would Down's syndrome arise, i.e., how does a person become trisomic for chromosome 21? An interesting correlation exists between the age of the mother and the likelihood of bearing a child with Down'syndrome. Women under 35 almost never have children with Down's syndrome, while a few percent of children born by mothers over 40 have Down's syndrome (regardless of the age of the father). What conclusion(s) can you draw from this information? Sex chromosomes can also undergo non-disjunction. In a female, this can sometimes lead to the production of eggs containing either 0 or 2 X-chromosomes. In males, the X and Y chromosomes behave as if 85 they were homologous, segregating at meiosis I. In some cases, however, they fail to segregate, leading to gametes containing no sex chromosomes or both an X and a Y. Fill in the table below to see what kinds of sex chromosome abnormalities might result from fertilization involving gametes containing normal and abnormal numbers of sex chromosomes. Can you think of any other, rarer abnormalities which might arise? Recall that the presence of a Y chromosome is sufficient, in the presence of one or more X chromosomes, to confer maleness. (But because the X chromosome carries information of vital importance, a Y alone is fatal.) Based on this, what are the sexes of the individuals in the table above? 86 A single X, sometimes referred to as XO, is Turner's syndrome. XXX, or Triplo-X, occurs at about the same frequency as Turner's syndrome, about 1 in 1000 females. Finally, XXY, or Klinefelter's syndrome, occurs in about 1 in 1000 males. These conditions, which usually result in sterility, are described in your text. Analysis of chromosome spreads At the supply table you will find xerox copies of banded chromosome spreads (stained to reveal a bar-code pattern unique to each chromosome). Your task is to cut out the chromosomes and arrange them in the usual manner, from autosome pair 1 to autosome pair 22 in descending order, keeping the sex chromosomes separate. Then, having arranged the chromosomes, decide what genetic defect, if any, is demonstrated. Report your result to your instructor, who might provide a suitable reward for the correct diagnosis – but be prepared to explain how the defect arose. Obviously, karyotyping unbanded chromosomes would be difficult. To make things easier, scientists devised ways to stain the chromosomes so that they have characteristic stripes or bands; all chromosomes #1 have the same banding pattern, so the two copies can be identified easily. The same applies to chromosomes 2-22 and the X and Y chromosomes. Today, human geneticists can stain chromosomes specific colors using a technique known as FISH (fluorescent in situ hybridization) or chromosome painting to further reduce the likelihood of error in the diagnosis of chromosome disorders. Internet Resources To see examples of FISH, go to http://www.health.auckland.ac.nz/webpath/genhtml/genetidx.htm. For more information about Down's syndrome and other genetic disorders, see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM. 87