Hartl, Jones - Genetics. Principlers and analysis - 1998 (522927), страница 85
Текст из файла (страница 85)
R. de Jonge.]In certain cell types, the inactive X chromosome in females can be observed microscopically as a densely stainingbody in the nucleus of interphase cells. This is called a Barr body (upper left in Figure 7.15B). Although cells ofnormal females have one Barr body, cells of normal males have none. Persons with two or more X chromosomeshave all but one X chromosome per cell inactivated, and the number of Barr bodies equals the number ofinactivated X chromosomes.Although all mammals use X chromosomal inactivation for dosage compensation in females, the choice of whichchromosome to inactivate is not always random. In marsupial mammals, which include the kangaroo, the koala,and the wombat, the X chromosome that is inactivated is always the one contributed by the father. The result is thatfemale marsupials are not genetic mosaics of paternal and maternal X-linked genes.
A female marsupial expressesthe X-linked genes that she inherited from her mother.The Calico Cat As Evidence for X-Chromosome InactivationIn nonmarsupial mammals, the result of random X inactivation in females can sometimes be observed in theexternal phenotype. One example is the "calico" pattern of coat coloration in female cats. Two alleles affecting coatcolor are present in the X chromosome in cats. One allele results in an orange coat color (sometimes referred to as"yellow"), the other in a black coat color. Because he has only one X chromosome, a normal male has either theorange or the black allele. A female can be heterozygous for orange and black, and in this case the coat color is''calico"—a mosaic of orange and black patches mixed with patches of white.
Figure 7.16 is a photograph of afemale cat with the classic calico pattern.Page 278Figure 7.16A female cat that is heterozygous for the orange and black coat-coloralleles and shows the classic "calico" pattern of patches of orange, black,and white fur.The orange and black patches result from X chromosome inactivation. In cell lineages in which the X chromosomebearing the orange allele is inactivated, the X chromosome with the black allele is active and so the fur is black.
Incell lineages in which the X chromosome with the black allele is inactivated, the orange allele in the active Xchromosome results in orange fur.The white patches have a completely different explanation. The white patches are due to an autosomal gene S forwhite spotting, which prevents pigment formation in the cell lineages in which it is expressed. Why the S gene isexpressed in some cell lineages and not others is not known. Homozygous SS cats have more white thanheterozygous Ss cats.
The female in the photograph is homozygous.Sex-Chromosome AbnormalitiesMany types of sex-chromosome abnormalities have been observed. As noted, they are usually less severe in theirphenotypic effects than are abnormal numbers of autosomes. The four most-common types are• 47,XXX This condition is often called the trisomy-X syndrome.
The number 47 in the chromosome designationrefers to the total number of chromosomes, and XXX indicates that the person has three X chromosomes. Peoplewith the karyotype 47,XXX are female. Many are phenotypically normal or nearly normal, though the frequency ofmild mental retardation is somewhat greater than among 46,XX females.• 47,XYY This condition is often called the double-Y syndrome. These people are male and tend to be tall, but theyare otherwise phenotypically normal. At one time it was thought that 47,XYY males developed severe personalitydisorders and were at a high risk of committing crimes of violence, a belief based on an elevated incidence of47,XYY among violent criminals.
Further study indicated that most 47,XYY males have slightly impaired mentalfunction and that, although their rate of criminality is higher than that of normal males, the crimes are mainlynonviolent petty crimes such as theft. The majority of 47,XYY males are phenotypically and psychologicallynormal, have mental capabilities in the normal range, and have no criminal convictions.Page 279• XXY This condition is called Klinefelter syndrome. Affected persons are male. They tend to be tall, do notundergo normal sexual maturation, are sterile, and in some cases have enlargement of the breasts.
Mild mentalimpairment is common.• 45,X Monosomy of the X chromosome in females is called Turner syndrome. Affected persons arephenotypically female but short in stature and without sexual maturation. Mental abilities are typically within thenormal range.The Fragile-X SyndromeAn important form of inherited mental retardation is associated with a class of X chromosomes containing a site atXq27–Xq28 (toward the end of the long arm) that tends to break in cultured cells that are starved for DNAprecursors, such as the nucleotides. The X chromosomes containing this site are called fragile-X chromosomes,and the associated form of mental retardation is the fragile-X syndrome. The fragile-X syndrome affects about 1in 2500 children.
It accounts for about half of all cases of X-linked mental retardation and is second only to Downsyndrome as a cause of inherited mental impairment. The fragile-X syndrome has an unusual pattern of inheritancein which approximately 1 in 5 males with the fragile-X chromosome are phenotypically normal and also havephenotypically normal children. However, the heterozygous daughters of such a "transmitting male" often haveaffected sons, and about one-third of their heterozygous daughters are also affected.
This pattern is illustrated inFigure 7.17. The transmitting male denoted I-2 is not affected, but the X chromosome that he transmits to hisdaughters (II-2 and II-5) somehow becomes altered in the female germ line in such a way that sons and daughtersin the next generation (III) are affected. Affected and normal grand-daughters of the transmitting male sometimeshave affected progeny (generation IV). Males who are affected are severely retarded and do not reproduce. Amongfemales, there is substantial variation in severity of expression (variable expressivity). In general, females are lessseverely affected than males, and, as noted, some heterozygous females are not affected at all (incompletepenetrance).The molecular basis of the fragile-X chromosome has been traced to a trinucleotide repeat of the form (CCG)npresent in the DNA at the site where the breakage takes place.
Normal X chromosomes have from 6 to 54 tandemcopies of the repeating unit (the average is average is about 30), and affected persons have more than 230 copies ofthe repeat. Transmitting males have an intermediate number, between 52 and 230 copies, which is called thefragile-X "premutation." The unprecedented feature of the premutation is that, in females, it invariably increases incopy number to reach a level of 230 copies or greater, at which stage the chromosome causes mental retardation.The amplification in the number of copies present in the germ line of daughters of transmitting males is relatedFigure 7.17Pedigree showing transmission of the fragile-X syndrome.
Male I-2 is notaffected, but his daughters (II-2 and II-5) have affected children andgrand-children.[After C. D. Laird. 1987. Genetics, 117: 587.]Page 280to the cycle of X-chromosome inactivation and reactivation. Chromosomes with the premutation that go throughthe X-inactivation cycle become permanently altered.
In these chromosomes, the inactivation of a gene designatedFMR1 (fragile-site mental retardation-l) is irreversible, and the gene is unable to be reactivated in oogenesis. The Xchromosome is said to have undergone a process of imprinting. Current evidence suggests that imprinting isassociated with the addition of methyl groups (—CH3) to certain cytosine bases in the DNA. Failure to remove themethyl groups irreversibly inactivates FMR1 and also triggers amplification of the CCG repeats. The variableexpressivity of the fragile-X syndrome in affected females also is related to X-chromosome inactivation: Moreseverely affected females have a higher proportion of cells in which the normal X chromosome is inactivated.Chromosome Abnormalities in Spontaneous AbortionApproximately 15 percent of all recognized pregnancies in human beings terminate in spontaneous abortion, and inabout half ofTable 7.1 Chromosome abnormalities per 100,000 recognized human pregnancies15,000 abort spontaneously7500 chromosomally abnormal85,000 live births550 chromosomally abnormal015953000950005610128275318170012291022300135203504241130XYY446XXY444TrisomyC: 6–12F: 19–20Sex chromosomes1350821441416422552Triploid12750Tetraploid450XOXXXTranslocationsBalancedUnbalancedPolyploidOther (mosaics.
etc.)28049Total7500550Page 281them, the fetus has a major chromosome abnormality. Table 7.1 summarizes the average rates of chromosomeabnormality found per 100,000 recognized pregnancies in several studies. Many of the spontaneously abortedfetuses have trisomy of one of the autosomes. Triploids and tetraploids also are common in spontaneous abortions.Note that the majority of trisomy-21 fetuses are spontaneously aborted, as are the vast majority of 45,X fetuses. Ifall trisomy-21 fetuses survived to birth, the incidence of Down syndrome would rise to 1 in 250, approximately athreefold increase from the incidence observed.Although many autosomal trisomies are found in spontaneous abortions, autosomal monosomies are not found.Monosomic embryos do exist.
They are probably created in greater numbers than the trisomic fetuses becausechromosome loss, leading to monosomy, is usually much more frequent than chromosome gain, leading to trisomy.The absence of autosomal monosomies in spontaneously aborted fetuses is undoubtedly due to these embryosbeing aborted so early in development that the pregnancy goes unrecognized. The spontaneous abortionssummarized in Table 7.1, although they represent a huge fetal wastage, serve the important biological function ofeliminating many fetuses that are grossly abnormal in their development because of major chromosomeabnormalities.7.6—Abnormalities in Chromosome StructureThus far, abnormalities in chromosome number have been described.
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
