Gene Conversion

Generally, crossing over is expected to be symmetrical and different alleles from two different parents will be inherited according to Mendel's laws (see Ch. 1). In other words, when two parents reproduce sexually, different alleles from each parent should appear with equal frequency in the offspring. Occasional exceptions to this occur by a mechanism known as gene conversion. The name refers to the fact that one allele is converted to the other. The mechanism involves the mismatch repair system operating upon the intermediate structures generated by recombination.

Under normal circumstances, the two strands of a DNA molecule are complementary in sequence and therefore represent the same genetic information. Consequently, any particular double helical DNA molecule carries a single allele of a gene.

gene conversion Recombination and repair of DNA during meiosis that leads to replacement of one allele by another. This may result in a non-

Mendelian ratio among the progeny of a genetic cross non-homologous end joining DNA repair system found in eukaryotes that mends double-stranded breaks

Eukaryotic cells can mend double-stranded breaks in the DNA.

Sometimes one allele of a gene is converted into another by mismatch repair.

FIGURE 14.26 Non-Homologous End Joining in Mammals

Double-stranded breaks are recognized by the Ku proteins, which bind one to each end. The two Ku proteins recruit DNA-PK to the complex. DNA-PK phosphorylates XRCC4 protein, which then recruits DNA ligase IV to join the two broken ends.

Double stranded break in DNA

Ku PROTEINS WITH DNA-DEPENDENT PROTEIN KINASE (DNA-PK) BIND TO BREAK

Ku PROTEINS WITH DNA-DEPENDENT PROTEIN KINASE (DNA-PK) BIND TO BREAK

Phosphate group

Protein kinase activates XRCC4 by phosphorylation

FIGURE 14.26 Non-Homologous End Joining in Mammals

Double-stranded breaks are recognized by the Ku proteins, which bind one to each end. The two Ku proteins recruit DNA-PK to the complex. DNA-PK phosphorylates XRCC4 protein, which then recruits DNA ligase IV to join the two broken ends.

Gene conversion may be widespread but is difficult to detect under normal conditions.

However, if the two strands of a DNA molecule do not base pair completely then, strictly speaking, each strand represents a different allele. Such heteroduplex DNA only exists transiently and will soon be corrected by the mismatch repair system; nonetheless, its existence provides the opportunity for gene conversion.

During recombination short heteroduplex regions are created in the DNA next to the crossover point, as discussed above. [This is true whether crossing over generates hybrid DNA molecules or whether the "original" DNA molecules are regenerated from the Holliday junction as shown in Fig. 14.04 above.] Consider a crossover between two DNA molecules carrying different alleles of the same gene. If the crossover occurs within the coding sequence of the gene of interest, then heteroduplexes will be formed in which the two strands represent the two alleles of the gene (Fig. 14.27). Two alternative possibilities now exist. Replication may occur immediately, in which case the four daughter molecules of DNA produced will show a normal Mendelian ratio (a 3 : 1 ratio in the example illustrated in Fig. 14.27). Alternatively, the mismatch repair system may correct the mismatched base pairs in the heteroduplex region before replication. In this case, one strand is altered to match the other which, in effect, converts one allele into the other allele (in the figure R is converted to r) and the ratio of progeny is changed (from 3:1 to 4:0 in the example in Fig. 14.27).

Such occasional deviations are difficult to detect since gene conversion is equally likely in either direction. Thus the deviations will cancel out and Mendelian ratios will

dsDNA

r dsDNA

Crossing over

HETERODUPLEX Repair by mismatch repair system

Cell division Cell division

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