Hartl, Jones - Genetics. Principlers and analysis - 1998 (522927), страница 84
Текст из файла (страница 84)
For unknown reasons, nondisjunction of chromosome 21 is more likely to happen in oogenesis thanin spermatogenesis, and so the abnormal gamete in Down syndrome is usually the egg.Chromosome 21 is a small chromosome and therefore is somewhat less likely to undergo meiotic crossing-overthan a longer one. Noncrossover bivalents sometimes have difficulty aligning at the metaphase plate because theylack a chiasma to hold them together, so there is an increased risk of nondisjunction. Among the events ofnondisjunction that result in Down syndrome, about 40 percent are derived from such nonexchange bivalents.(Students already familiar with trisomy 21 may know it as Down's syndrome, with an apostrophe s.
This textfollows current practice in human genetics in avoiding the possessive form of proper names used to designatesyndromes.)The risk of nondisjunction of chromosome 21 increases dramatically with the age of the mother, and the risk ofDown syndrome reaches 6 percent in mothers of age 45 and older (Figure 7.14). Thus many physicians recommendthat older women who are pregnant have cells from the fetus tested in order to detect Down syndrome prenatally.This can be done from 15 to 16 weeks after fertilization by amniocentesis, in which cells of a developing fetus areobtained by insertion of a fine needle through the wall of the uterus and into the sac of fluid (the amnion) thatcontains the fetus, or even earlier in pregnancy by sampling cells from another of the embryonic membranes (thechorion).
In about 3 percent of families with a Down syndrome child, the risk of another affected child is veryhigh—up to 20 percent of births. This high risk is caused by a chromosome abnormality called a translocation inone of the parents, which will be considered in Section 7.6.Dosage CompensationAbnormal numbers of sex chromosomes usually produce less severe phenotypic effects than do abnormal numbersof autosomes. For example, the effects of extra Y chromosomes are relatively mild. This is in part because the Ychromosome in mammals is largely heterochromatic. In human beings, there is a region at the tip of the short armof the Y that is homologous with a corresponding region at the tip of the short arm of the X chromosome.
It is inthis region of homology that the X and Y chromosomes synapse in spermatogenesis, and an obligatory crossover inthe region holds the chromosomes together and ensures proper separation during anaphase I. The crossover is saidto be obligatory because it takes place somewhere in this region in every meiotic division. The shared X–Yhomology defines the pseudoautosomal region. Genes within the pseudoautosomal region show a pattern ofinheritance very similar to ordinary autosomal inheritance, because they are not completely linked to either the Xchromosome or the Y chromosome but can exchange between the sex chromosomes by crossing-over. Near thepseudoautosomal region, but not within it, the Y chromosome contains the master sex-controller gene SRY atposition Yp11.3.
SRY codes for a protein transcription factor, the testis-determining factor (TDF), which triggersmale embryonic develop-Page 275ment by inducing the undifferentiated embryonic genital ridge, the precursor of the gonad, to develop as a testis. Atranscription factor, as the name implies, is a component that, together with other factors, stimulates transcriptionof its target genes. Apart from the pseudoautosomal pairing region and SRY, the Y chromosome contains very fewgenes, so extra Y chromosomes are milder in their effects on phenotype than are extra autosomes.Extra X chromosomes have milder effects than extra autosomes because, in mammals, all X chromosomes exceptone are genetically inactivated very early in embryonic development.
The inactivation tends to minimize thephenotypic effects of extra X chromosomes, but there are still some effects due to a block of genes near the tip ofthe short arm that are not inactivated.In female mammals, X-chromosome inactivation is a normal process in embryonic development.
In human beings,at an early stage of embryonic development, one of the two X chromosomes is inactivated in each somatic cell;different tissues undergo X inactivation at different times. The X chromosome that is inactivated in a particularsomatic cell is selected at random, but once the decision is made, the same X chromosome remains inactive in allof the descendants of the cell.X-chromosome inactivation has two consequences. First, it equalizes the number of active copies of X-linkedgenes in females and males. Although a female has two X chromosomes and a male has only one, because ofinactivation of one X chromosome in each of the somatic cells of the female, the number of active X chromosomesin both sexes is one. In effect, gene dosage is equalized except for the block of genes in the short arm of the X thatescapes inactivation.
This equalization in dosage of active genes is called dosage compensation. The mammalianmethod of dosage compensation by means of X inactivation was originally proposed by Mary Lyon and is calledthe single-active-X principle.Figure 7.14Frequency of Down syndrome number of cases per 100 live births) related toage of mother. The graph is based on 438 Down syndrome births (among 330,859total births) in Sweden in theperiod 1968 to 1970.[Data from E. B.
Hook and A. Lindsjö. 1978. Am. J. Human Genet. 30:19.]Page 276Connection Lyonization of an X ChromosomeMary F. Lyon 1961Medical Research Council,Harwell, EnglandGene Action in the X Chromosome of the Mouse (Mus musculus L.)How do organisms solve the problem that females have two X chromosomes whereas males have only one? Unlessthere were some type of correction (called dosage compensation), the unequal number would mean that for all thegenes in the X chromosome, cells in females would have twice as much gene product as cells in males.
It would bedifficult for the developing organism to cope with such a large difference in dosage for so many genes. Theproblem of dosage compensation has been solved by different organisms in different ways. The hypothesis putforward in this paper is that in the mouse (and, by inference, in other mammals), the mechanism is very simple:One of the X chromosomes, chosen at random in each cell lineage early in development, becomes inactivated andremains inactivated in all descendant cells in the lineage. In certain cells, the inactive X chromosome becomesvisible in interphase as a deeply staining "sex-chromatin body." We now know that there are a few genes in theshort arm of the X chromosome that are not inactivated.
There is also good evidence that the inactivation of therest of the X chromosome takes place sequentially from an "X-inactivation center." We also know that in marsupialmammals, such as the kangaroo, it is always the paternal X chromosome that is inactivated.It has been suggested that the so-called sex chromatin body is composed of one heteropyknotic [that is, deeplystaining during interphase] X chromosome . .
.. TheThe coat of the tortoiseshell cat, being a mosaic of the black and yellow colours of the twohomozygous genotypes, fulfills this expectation.present communication suggests that evidence of mouse genetics indicates: (1) that the heteropyknotic Xchromosome can be either paternal or maternal in origin, in different cells of the same animal; (2) that it isgenetically inactivated. The evidence has two main parts. First, the normal phenotype of XO females in the mouseshows that only one active X chromosome is necessary for normal development, including sexual development.The second piece of evidence concerns the mosaic phenotype of female mice heterozygous for some sex-linked [Xlinked] mutants. All sex-linked mutants so far known affecting coat colour cause a "mottled" or "dappled"phenotype, with patches of normal and mutant colour.
. . . It is here suggested that this mosaic phenotype is due tothe inactivation of one or other X chromosome early in embryonic development. If this is true, pigment cellsdescended from the cells in which the chromosome carrying the mutant gene was inactivated will give rise to anormal-coloured patch and those in which the chromosome carrying the normal gene was inactivated will give riseto a mutant-coloured patch. . . . Thus this hypothesis predicts that for all sex-linked genes of the mouse in whichthe phenotype is due to localized gene action the heterozygote will have a mosaic appearance . . .. The geneticevidence does not indicate at what early stage of embryonic development the inactivation of the one Xchromosome occurs.
. . . The sex-chromatin body is thought to be formed from one X chromosome in the rat andin the opossum. If this should prove to be the case in all mammals, then all female mammals heterozygous for sexlinked mutant genes would be expected to show the same phenomena as those in the mouse. The coat of thetortoiseshell cat, being a mosaic of the black and yellow colours of the two homozygous genotypes, fulfills thisexpectation.Source: Nature 190:372The second consequence of X-chromosome inactivation is that a normal female is a mosaic for X-linked genes(Figure 7.15A).
That is, each somatic cell expresses the genes in only one X chromosome, but the X chromosomethat is active genetically differs from one cell to the next. This mosaicism has been observed directly in females thatare heterozygous for X-linked alleles that determine different forms of an enzyme, A and B; when cells from theheterozygous female are individually cultured in the laboratory, half of the clones are found to produce only the Aform of the enzyme and the other half to produce only the B form.
Mosaicism can be observed directly in womenwho are heterozygous for an X-linked recessive mutation that results in the absence of sweat glands; these womenexhibit patches of skin in which sweat glands are present (these patches are derived from embryonic cells in whichthe normal X chromosome remained active and the mutant X was inactivated) and other patches of skin in whichsweat glands are absent (these patches are derived from embryonic cells in which the normal X chromosome wasinactivated and the mutant X remained active.)Page 277Figure 7.15(A) Schematic diagram of somatic cells of a normal female showing that the female is a mosaic forX-linked genes.
The two X chromosomes are shown in red and blue. An active X is depicted as a straightchromosome, an inactive X as a tangle. Each cell has just one active X, but the particular X that remainsactive is a matter of chance. In human beings, the inactivation includes all but a few genes in the tip ofthe short arm. (B) Fluorescence micrograph of a human cell showing a Barr body (bright spot at the upperleft; see arrow.) This cell is from a normal human female, and it has one Barr body.[Micrograph courtesy of A. J.
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
