Hartl, Jones - Genetics. Principlers and analysis - 1998 (522927), страница 83
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Blood cells arrested in metaphase were stained with Giemsa and photographedwith a microscope. (A) The chromosomes as seen in the cell by microscopy. (B) Thechromosomes have been cut out of the photograph and paired with their homologs.[Courtesy of Patricia Jacobs.]within each region, the second number indicates the next-smaller division, again numbered outward from thecentromere. For example, the designation 1p34 indicates chromosome 1, short arm, division 34.
Some divisionscan be subdivided still further by the bands and interbands within them, which are numbered consecutively andindicated by a digit placed after a decimal point following the main division; for example, 1p36.2 means the secondband in 1p36. Some familiar genetic landmarks in the human genome are the Rh (Rhesus) blood group locus,which is somewhere in the region between 1p34 and 1p36.2; the ABO blood group locus at 9q34; the red-greencolor-blindness genes at Xq28, and the male-determining gene on the Y chromosome, called SRY (sex-determiningregion, Y), at Yp11.3.
At the base of each chromosome in Figure 7.12, the red number indicates the number ofgenes presently assigned a position on the chromosome. These numbers do not include the approximately 5000DNA markers used in developing the human genetic map. Many of the genes enumerated in Figure 7.12 areassociated with inherited diseases. There are a total of 3399 genes assigned a position on one of the autosomes, 251assigned a position on the X chromosome, and 19 assigned a position on the Y chromosome.The technique of chromosome painting seen earlier in Figure 7.6 has been applied to human chromosomes toachieve spectacular effects.
An example is shown in the metaphase spread and karyotype in Figure 7.13. Toproduce this effect, chromosomes were hybridized simultaneously with 27 different fluorescent DNA probes, eachspecific for hybridization with a single chromosome or chromosome arm. The probes were obtained bymicrodissection of metaphase nuclei to isolate each individual chromosome or chromosome arm, and theminuscule amount of DNA so obtained was amplified by the polymerase chain reaction (Section 5.8).
Afterhybridization, each chromosome was scanned along its length, and at each point, the fluorescent signalPage 271Connection The First Human Chromosomal DisorderJerome Lejeune,Marthe Gautier,and Raymond Turpin 1959National Center for Scientific Research, Paris, FranceStudy of the Somatic Chromosomes of Nine Down Syndrome Children (original in French)Down syndrome had been one of the greatest mysteries in human genetics. One of the mostcommon forms of mental retardation, the syndrome did not follow any pattern of Mendelianinheritance.
Yet some families had two or more children with Down syndrome. (Many of thesecases are now known to be due to a translocation involving chromosome 21.) This papermarked a turning point in human genetics by demonstrating that Down syndrome actuallyresults from the presence of an extra chromosome. It was the first identified chromosomaldisorder. The excerpt uses the term telocentric, which means a chromosome that has itscentromere very near one end. In the human genome, the smallest chromosomes are threevery small telocentric chromosomes. These are chromosomes 21, 22, and the Y.
A normalmale has five small telocentrics (21, 21, 22, 22, and Y); a normal female has four (21, 21, 22,and 22). (The X is a medium-sized chromosome with its centromere somewhat off center.) Inthe table that follows, note the variation in chromosome counts in the "doubtful" cells. Themethods for counting chromosomes were then very difficult, and many errors were madeeither by counting two nearby chromosomes as one or by including in the count of onenucleus a chromosome that actually belonged to a nearby nucleus.
Lejeune and collaboratorswisely chose to ignore these doubtful counts and based their conclusion only on the "perfect"cells. Sometimes good science is a matter of knowing which data to ignore.The culture of fibroblast cells from nine Down syndrome children reveals the presence of 47chromosomes, the supernumerary chromosome being a small telocentric one. The hypothesisof the chromosomal determination of Down syndrome is considered . . .. The observationsmade in these nine cases (five boys and four girls) are recorded in the table to the right.The number of cells counted in each case may seem relatively small. This is due to the factthat only the pictures [of the spread chromosomes] that claim a minimum of interpretationhave been retained in this table.
The apparent variation in the chromosome number in the"doubtful" cells, that is to say, cells inAnalysis of the chromosome set of the "perfect" cells reveals thepresence in Down syndrome boys of 6 small telocentric chromosomes(instead of 5 in the normal man) and 5 small telocentric ones in Downsyndrome girls (instead of 4 in the normal woman).which each chromosome cannot be noted individually with certainty, has been pointed out byseveral authors.
It does not seem to us that this phenomenon represents a cytological reality,but merely reflects the difficulties of a delicate technique. It therefore seems logical to prefera small number of absolutely certain counts ("perfect" cells in the table) to a mass of doubtfulobservations, the statistical variance of which rests solely on the lack of precision of theobservations. Analysis of the chromosome set of the "perfect" cells reveals the presence inDown syndrome boys of 6 small telocentric chromosomes (instead of 5 in the normal man)and 5 small telocentric ones in Down syndrome girls (instead of 4 in the normal woman) .
. ..It therefore seems legitimate to conclude that there exists in Down syndrome children a smallsuper-numerary telocentric chromosome,Number of chromosomes"Doubtful" cellsBoysGirls"Perfect"cell46474846474816102–11–2–21–9–3–11–7–4–3––1–5––––8–1161–5–212––8–3121–4–4112–4–accounting for the abnormal figure of 47.
To explain these observations, the hypothesis ofnondisjunction of a pair of small telocentric chromosomes at the time of meiosis can beconsidered . . .. It is, however, not possible to say that the supernumerary small telocentricchromosome is indeed a normal chromosome and at the present time the possibility cannot bediscarded that a fragment resulting from another type of aberration is involved.Source: Comptes rendus des séances de I'Académie des Sciences 248: 1721–1722 Translationin S.
H. Boyer. 1963. (Papers on Human Genetics). Englewood Cliffs, NJ: Prentice HallPage 272Figure 7.12Designations of the bands and interbands in the human karyotype. Below each chromosome is the number of genespresently assigned a location on the chromosome.[Data from V. A. McKusick. 1988. Mendelian Inheritance in Man, 8th ed. Baltimore: Johns Hopkins University Press.]was converted to a specific color in the visible spectrum. The chromosomes in Figure 7.13 are therefore "painted"in 27 different colors. This technique is of considerable utility in human cytogenetics because even complexchromosome rearrangements can be detected rapidly and easily.
The painting technique makes it possible todecipher some chromosome rearrangements, particularly those involving small pieces of chromosome, that are notamenable to analysis by conventional banding procedures.Page 273Figure 7.13(A) Metaphase spread and (B) karyotype in which human chromosomes have been "paintedin 27 different colors according to their hybridization with fluorescent probes specific to individualchromosomes or chromosome arms.[Courtesy of M. R.
Speicher and D. C. Ward. See M. R. Speicher, S. G.Ballard, and D. C. Ward. 1996. Nature Genetics 12: 368.]Page 274Trisomy in Human BeingsMonosomy or trisomy of most human autosomes is usually incompatible with life. Most zygotes with missingchromosomes or extra chromosomes either fail to begin embryonic development or undergo spontaneous abortionat an early stage. There are a few exceptions.
One exception is Down syndrome, which is caused by trisomy ofchromosome 21. Down syndrome affects about 1 in 750 live-born children. Its major symptom is mentalretardation, but there can be multiple physical abnormalities as well, such as major heart defects.Most cases of Down syndrome are caused by nondisjunction, which means the failure of homologouschromosomes to separate in meiosis, as explained in Chapter 3. The result of chromosome-21 nondisjunction is onegamete that contains two copies of chromosome 21 and one that contains none. If the gamete with two copiesparticipates in fertilization, then a zygote with trisomy 21 is produced. The gamete with one copy may alsoparticipate in fertilization, but zygotes with monosomy 21 do not survive even through the first few days or weeksof pregnancy.
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