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Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000.

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An Introduction to Genetic Analysis. 7th edition.

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Inversions

If two breaks occur in one chromosome, sometimes the region between the breaks rotates 180 degrees before rejoining with the two end fragments. Such an event creates a chromosomal mutation called an inversion. Unlike deletions and duplications, inversions do not change the overall amount of the genetic material, so inversions are generally viable and show no particular abnormalities at the phenotypic level. In some cases, one of the chromosome breaks is within a gene of essential function, and then that breakpoint acts as a lethal gene mutation linked to the inversion. In such a case, the inversion could not be bred to homozygosity. However, many inversions can be made homozygous; furthermore, inversions can be detected in haploid organisms. In these cases, the breakpoint is clearly not in an essential region. Some of the possible outcomes of inversion at the DNA level are shown in Figure 17-14.

Figure 17-14. Effects of inversions at the DNA level.

Figure 17-14

Effects of inversions at the DNA level. Genes are represented by A, B, C, and D. Template strand is dark green; nontemplate strand is light green; jagged lines indicate break in DNA. The letter P stands for promoter; thick arrow indicates the position (more...)

Most analyses of inversions use heterozygous inversions—diploids in which one chromosome has the standard sequence and one carries the inversion. Microscopic observation of meioses in inversion heterozygotes reveals the location of the inverted segment because one chromosome twists once at the ends of the inversion to pair with the other, untwisted chromosome; in this way the paired homologs form an inversion loop (Figure 17-15).

Figure 17-15. The chromosomes of inversion heterozygotes pair in a loop at meiosis.

Figure 17-15

The chromosomes of inversion heterozygotes pair in a loop at meiosis. (a) Diagrammatic representation; each chromosome is actually a pair of sister chromatids. (b) Electron micrographs of synaptonemal complexes at prophase I of meiosis in a mouse heterozygous (more...)

The location of the centromere relative to the inverted segment determines the genetic behavior of the chromosome. If the centromere is outside the inversion, then the inversion is said to be paracentric, whereas inversions spanning the centromere are pericentric:

Image ch17fu9.jpg

How do inversions behave genetically? Crossing-over within the inversion loop of a paracentric inversion connects homologous centromeres in a dicentric bridge while also producing an acentric fragment—a fragment without a centromere. Then, as the chromosomes separate in anaphase I, the centromeres remain linked by the bridge, which orients the centromeres so that the noncrossover chromatids lie farthest apart. The acentric fragment cannot align itself or move and is, consequently, lost. Tension eventually breaks the bridge, forming two chromosomes with terminal deletions (Figure 17-16). The gametes containing such deleted chromosomes may be inviable but, even if viable, the zygotes that they eventually form are inviable. Hence, a crossover event, which normally generates the recombinant class of meiotic products, instead produces lethal products. The overall result is a lower recombinant frequency. In fact, for genes within the inversion, the RF is zero. For genes flanking the inversion, the RF is reduced in proportion to the relative size of the inversion.

Figure 17-16. Meiotic products resulting from a single crossover within a paracentric inversion loop.

Figure 17-16

Meiotic products resulting from a single crossover within a paracentric inversion loop. Two nonsister chromatids cross over within the loop.

Inversions affect recombination in another way too. Inversion heterozygotes often have mechanical pairing problems in the region of the inversion; these pairing problems reduce the frequency of crossing-over and hence the recombinant frequency in the region.

The net genetic effect of a pericentric inversion is the same as that of a paracentric one—crossover products are not recovered—but for different reasons. In a pericentric inversion, because the centromeres are contained within the inverted region, the chromosomes that have crossed over disjoin in the normal fashion, without the creation of a bridge. However, the crossover produces chromatids that contain a duplication and a deficiency for different parts of the chromosome (Figure 17-17). In this case, if a nucleus carrying a crossover chromosome is fertilized, the zygote dies because of its genetic imbalance. Again, the result is the selective recovery of noncrossover chromosomes in viable progeny.

Figure 17-17. Meiotic products resulting from a meiosis with a single crossover within a pericentric inversion loop.

Figure 17-17

Meiotic products resulting from a meiosis with a single crossover within a pericentric inversion loop.

MESSAGE

Two mechanisms reduce the number of recombinant products among the progeny of inversion heterozygotes: elimination of the products of crossovers in the inversion loop and inhibition of pairing in the region of the inversion.

It is worth adding a note about homozygous inversions. In such cases the homologous inverted chromosomes pair and cross over normally, there are no bridges, and the meiotic products are viable. However, an interesting effect is that the linkage map will show the inverted gene order.

Geneticists use inversions to create duplications of specific chromosome regions for various experimental purposes. For example, consider a heterozygous pericentric inversion with one breakpoint at the tip (T) of the chromosome, as shown in Figure 17-18. A crossover in the loop produces a chromatid type in which the entire left arm is duplicated; if the tip is nonessential, a duplication stock is generated for investigation. Another way to make a duplication (and a deficiency) is to use two paracentric inversions with overlapping breakpoints (Figure 17-19). A complex loop is formed, and a crossover within the inversion produces the duplication and the deletion. These manipulations are possible only in organisms with thoroughly mapped chromosomes for which large sets of standard rearrangements are available.

Figure 17-18. Generation of a viable nontandem duplication from a pericentric inversion close to a dispensable chromosome tip.

Figure 17-18

Generation of a viable nontandem duplication from a pericentric inversion close to a dispensable chromosome tip.

Figure 17-19. Generation of a nontandem duplication by crossing-over between two overlapping inversions.

Figure 17-19

Generation of a nontandem duplication by crossing-over between two overlapping inversions.

We have seen that genetic analysis and meiotic chromosome cytology are both good ways of detecting inversions. As with most rearrangements, there is also the possibility of detection through mitotic chromosome analysis. A key operational feature is to look for new arm ratios. Consider a chromosome that has mutated as follows:

Image ch17fu10.jpg

Note that the ratio of the long to the short arm has been changed from about 4 to about 1 by the pericentric inversion. Paracentric inversions do not alter the arm ratio, but they may be detected microscopically if banding or other chromosome landmarks are available.

MESSAGE

The main diagnostic features of inversions are inversion loops, reduction of recombinant frequency, and reduced fertility from unbalanced or deleted meiotic products, all observed in individuals heterozygous for inversions. Some inversions may be directly observed as an inverted arrangement of chromosomal landmarks.

Inversions are found in about 2 percent of humans. The heterozygous inversion carriers generally show no adverse phenotype but produce the expected array of abnormal meiotic products from crossing-over in the inversion loop. Let us consider pericentric inversions as an example. Persons heterozygous for pericentric inversions produce offspring with the duplicationdeletion chromosomes predicted; these offspring show varying degrees of abnormalities depending on the lengths of the chromosome regions affected. Some phenotypes caused by duplication–deletion chromosomes are so abnormal as to be incapable of survival to birth and are lost as spontaneous abortions. However, there is a way to study the abnormal meiotic products that does not depend on survival to term. Human sperm placed in contact with unfertilized eggs of the golden hamster penetrate the eggs but fail to fertilize them. The sperm nucleus does not fuse with the egg nucleus, and, if the cell is prepared for cytogenetic examination, the human chromosomes are easily visible as a distinct group (Figure 17-20). This technique makes it possible to study the chromosomal products of a male meiosis directly and is particularly useful in the study of meiotic products of men who have chromosome mutations.

Figure 17-20. Human sperm and hamster oocytes are fused to permit study of the chromosomes in the meiotic products of human males.

Figure 17-20

Human sperm and hamster oocytes are fused to permit study of the chromosomes in the meiotic products of human males. (After original art by Renée Martin.)

In one case, a man heterozygous for an inversion of chromosome 3 underwent sperm analysis. The inversion was a large one with a high potential for crossing-over in the loop. Four chromosome 3 types were found in the man’s sperm—normal, inversion, and two recombinant types (Figure 17-21). The sperm contained the four types in the following frequencies:

Image ch17e2.jpg

Figure 17-21. (a) Four different chromosomes 3 found in sperm of a man heterozygous for a large pericentric inversion.

Figure 17-21

(a) Four different chromosomes 3 found in sperm of a man heterozygous for a large pericentric inversion. The duplication-deletion types result from a crossover in the inversion loop. (b) Two complete sperm chromosome sets containing the two duplication–deletion (more...)

The duplication-q–deletion-p recombinant chromosome had been observed previously in several abnormal children, but the duplication-p–deletion-q type had never been seen, and probably zygotes receiving it are too abnormal to survive to term. Presumably, deletion of the larger q fragment has more severe consequences than deletion of the smaller p fragment.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2000, W. H. Freeman and Company.
Bookshelf ID: NBK22042

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