Hartl, Jones - Genetics. Principlers and analysis - 1998 (522927), страница 89
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The double recombinants are present inthe rarest classes of progeny and differ from the parental genotypes in exchanging the gene that is in the middle ofthe three. The double recombinants are Zn1 Tp2 + and zn1 tp2 TB-10L1, which means that the translocationbreakpoint lies between zn1 and tp2. Hence, the map distance between zn1 and the breakpoint isand that between the translocation breakpoint and tp2 isThe genetic map of the region containing the TB-10L1 translocation breakpoint isRobertsonian TranslocationsA special type of nonreciprocal translocation is a Robertsonian translocation, in which the centromeric regions oftwoPage 294Figure 7.32Formation of a Robertsonian translocationby fusion of two acrocentric chromosomesin thecentromeric region.Figure 7.33A karyotype of a child with Down syndrome, carrying a Robertsoniantranslocation of chromosomes 14 and 21 (arrow).
Chromosomes 19and 22 are faint in this photo; this has no significance.[Courtesy of Irene Uchida.]nonhomologous acrocentric chromosomes become fused to form a single centromere (Figure 7.32). Robertsoniantranslocations are important in human genetics, especially as a risk factor to be considered in Down syndrome.When chromosome 21 is one of the acrocentrics in a Robertsonian translocation, the rearrangement leads to afamilial type of Down syndrome in which the risk of recurrence is very high.
Approximately 3 percent of childrenwith Down syndrome are found to have one parent with such a translocation.A Robertsonian translocation that joins chromosome 21 with chromosome 14 is shown in Figure 7.33 (arrow). Theheterozygous carrier is phenotypically normal, but a high risk of Down syndrome results from aberrant segregationin meiosis. The possible modes of segregation are shown in Figure 7.34. The symbol rob refers to the translocation,and the +, or -, preceding a chromosome number designates an extra copy, or a missing copy, of the entirechromosome. Among the several possible types of gametes that can arise, one contains a normal chromosome 21along with the 14/21 Robertsonian translocation (Figure 7.34A).
If this aberrant gamete is used in fertilization, thenthe fetus will contain two copies of the normal chromosome 21 plus the 14/21 translocation. In effect, the fetuscontains three copies of chromosome 21 and hence has Down syndrome. The other abnormal gametes that resultfrom adjacent-1 or adjacent-2 segregation either are missing chromosome 21 or chromosome 14 or containeffectively two copies of chromosome 14 (Figure 7.34A and B). If these gametes participate in ertilization, theresult is monosomy 21, monosomy 14, or trisomy 14, respectively. The monosomic embryos undergo very earlyspontaneous abortion; the trisomy 14-fetus undergoes spontaneous abortion later in pregnancy.
Hence families witha high risk of translocation Down syndrome also have a high risk of spontaneous abortion due to otherchromosome abnormalities. Alternate segregation of a Robertsonian translocation yields gametes carrying eitherthe translocation or both normal chromosomes (Figure 7.34C). Because thesePage 295Figure 7.34Segregation of Robertsonian translocation between chromosomes 14 and 21. (A) Adjacent-1 segregation, in which thegametes formed from the pole at the top have, effectively, an extra copy of chromosome 21.
(B) Adjacent-2 segregation.The gametes are either duplicated or deficient for chromosome 14. (C) Alternate segregation. Half of the gametes give riseto phenotypically normal children who are carriers of the Robertsonian translocation.Page 296gametes derive from reciprocal products of meiosis, the nonaffected children have a risk of 1 2 of carrying thetranslocation.7.7—Position Effects on Gene ExpressionGenes near the breakpoints of chromosomal rearrangement become repositioned in the genome and flanked by newneighboring genes.
In many cases, the repositioning of a gene affects its level of expression or, in some cases, itsability to function; this is called position effect. These effects have been studied extensively in Drosophila andalso in yeast. In Drosophila, the most common type of position effect results in a mottled (mosaic) phenotype thatis observed as interspersed patches of wildtype cells, in which the wildtype gene is expressed, and mutant cells, inwhich the wildtype gene is inactivated. The phenotype is said to show variegation, and the phenomenon is calledposition-effect variegation (PEV). In the older literature, PEV is often referred to as variegated or V-type positioneffect.Figure 7.35Position-effect variegation (PEV) is often observed when an inversion orother chromosome rearrangement repositions a gene normally ineuchromatin to a new location in or near heterochromatin.
In this example,an inversion in the X chromosome of Drosophila melanogaster repositionsthe wildtype allele of the white gene near heterochromatin. PEV of the w+allele is observed as mottled red and white eyes.PEV usually results from a chromosome aberration that moves a wildtype gene from a position in euchromatin to anew position in or near heterochromatin (Figure 7.35). (Euchromatin and heterochromatin are discussed in Chapter6.) Figure 7.36 illustrates some of the patterns of wildtype (red) and mutant (white) facets that are observed in maleflies that carry a rearranged X chromosome in which an inversion repositions the wildtype w+ allele intoheterochromatin.
The same types of patterns are found in females heterozygous for the rearranged X chromosomeand an X chromosome carrying the w allele. The patterns of w+ expression coincide with the clonal lineages in theeye; that is, all of the red cells in a particular patch derive from a single ancestral cell in the embryo in which the w+allele was activated. In contrast with the pattern shown in Figure 7.36, other chromosome rearrangements withPEV yield a salt-and-pepper pattern of mosaicism, which consists of numerous very small patches of wildtypetissue, and still others yield a combination of many small and a few large patches. These patterns imply that geneactivation can be very late in development as well as very early.Although the mechanism of PEV is not understood in detail, it is thought to result from the unusual chromatinstructure of heterochromatin interfering with gene activation.
The determination of gene expression ornonexpression is thought to take place when the boundary between condensed heterochromatin and euchromatin isestablished. Where heterochromatin is juxtaposed with euchromatin, the chromatin condensation characteristic ofheterochromatin may spread into the adjacent euchromatin, inactivating euchromatic genes in the cell and all of itsdescendants.
A similar inactivation phenomenon takes place in cells of female mammals when euchromatic genestranslocated to the X chromosome become heterochromatic and inactive. The length of the euchromatic region thatis inactivated ranges from 1 to 50 bands in the Drosophila polytene chromosomes, depending on the particularchromosome abnormality. At the molecular level, this range is approximately 20 to 1000 kb. The term spreading,with its implication of smoothPage 297Figure 7.36Patterns of red and white sectors in the eye of Drosophila melanogaster resulting from position-effect variegation.
Eachgroup of contiguous facets of the same color derives from a single cell in development. Such large patches of red are atypical.More often, one observes numerous very small patches of red or a mixture of many small and a few large patches.continuity, should not be taken literally, however, because in both Drosophila and mammals, chromosomal regionsaffected by PEV are known to contain active genes interspersed with inactive ones. It is likely that heterochromaticregions associate to form a relatively compact ''compartment" in the nucleus, and the presence of heterochromatinnear a euchromatic gene may silence the gene simply by attracting it into the heterochromatic compartment.The heterochromatin of different chromosomes differs in its ability to induce variegation of specific genes and inits response to environmental or genetic modifiers.
Environmental modifiers include temperature; genetic modifiersinclude the presence of extra blocks of heterochromatin (such as a Y chromosome). Some mutations that affectchromatin structure also suppress PEV, and certain euchromatic DNA sequences, when repositioned intoheterochromatin, act as "insulators" protecting nearby genes by binding with chromatin-associated proteins thatprevent inactivation.
Other than position-effect variegation, genes are rarely shut down completely because of theirposition in the genome. Most genes can be expressed irrespective of neighboring genes, but the level of expressionmay vary substantially according to position.7.8—Chromosome Abnormalities and CancerCancer is an unrestrained proliferation and migration of cells. In all known cases, cancer cells derive from therepeated division of a single mutant cell whose growth has become unregulated, and so cancer cells initiallyconstitute a clone.
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