# 4.1.1: Homologous recombination

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Learning Objectives

• Diagram the process of homologous recombination to explain how meiosis generates new combinations of alleles on chromosomes.
• Understand that recombination involves a physical breakage and ligation of the DNA backbones of sister chromatids and occurs during the pachytene of prophase of meiosis I.
• Recall that Holliday junctions are linked strands of DNA generated during recombination that must be resolved by additional DNA cuts and ligations and can lead to either recombinant or nonrecombinant chromosomes.

Because each chromosome undergoes at least one recombination event during meiosis, new combinations of alleles are generated. The arrangement of alleles inherited from each parent are not preserved, but rather the new germ cells carry chromosomes with new combinations of alleles of the genes. This remixing of combinations of alleles is a rich source of diversity in a population.

Over time, recombination will separate alleles at one locus from alleles at a linked locus. A chromosome is not fixed through generations, but rather it is "fluid," having many different combinations of alleles. This allows nonfunctional (less functional) alleles to be cleared from a population. If recombination did not occur, then one deleterious mutant allele would cause an entire chromosome to be eliminated from the population. However, with recombination, the mutant allele can be separated from the other genes on that chromosome. Then negative selection can remove defective alleles of a gene from a population while affecting the frequency of alleles only of genes in tight linkage to the mutant gene. Conversely, the rare beneficial alleles of genes can be tested in a population without being irreversibly linked to any potentially deleterious mutant alleles of nearby genes. This keeps the effective target size for mutation close to that of a gene, not the whole chromosome.

## Mechanisms of recombination

Recombination occurs when a piece of the paternal chromosome is swapped for the homologous piece of DNA on the matching maternal chromosome (or vice versa). Obviously, this kind of a DNA swap must be done carefully and with equivalence, so that the resultant DNA does not gain or lose information. To ensure this precision in recombination, the non-sister homologous chromatids are held together via proteins in a synaptonemal complex (SC) during prophase I. This ladder-like complex begins to form in the zygotene stage of prophase I and completes in pachytene. The complete SC consists of proteinaceous lateral elements (aka axial elements) that run along the length of the chromatids and a short central element composed of fibrous proteins forming the rungs of the ladder perpendicular to the two lateral elements.

Recombination may occur with or without the formation of double-strand breaks, and in fact, can occur without the formation of the synaptonemal complex, although the SC probably enhances the efficiency of recombination. In S. pombe, meiosis occurs without the formation of a synaptonemal complex, but there are small discontinuous structures somewhat similar to parts of the SC. In the fruit fly, Drosophila melanogaster, females undergo meiosis using a synaptonemal complex, but males do not undergo meiotic recombination, and their chromosomes do not form synaptonemal complexes. In most cases, recombination is preceded by the formation of recombination nodules, which are protein complexes that form at potential points for recombination.

The best studied mechanism for meiotic recombination involves a double-stranded break of one of the chromosomes initiated by the meiosis-specific endonuclease, Spo11. The 5’ ends (one in each direction) of this cut are degraded slightly to form 3’ single-stranded overhangs. These unpaired ends lead to the formation of Holliday junctions (named after Robin Holliday) with a strand from another chromatid acting as a template for synthesis of the missing portion of the chromatids, leading to two sister chromatids that are "entangled" by having one strand of DNA paired with a different chromatid. This entanglement may be resolved with or without a crossover. The recombination is initiated in pachytene and completes in diplotene, at which time the synaptonemal complex breaks down. As the chromatids begin to separate, chiasmata (sites where chromatids remain in contact) become apparent at some of the recombination sites. As prophase completes, the chiasmata resolve from the center of the chromosomes to the ends.

## Recombination can also be used as a repair mechanism!

Homologous recombination occurs in meiotic cells. In most species, every chromosome will undergo at least one recombination event. However, the ability to use one chromosome as a template for a broken one can also be used in instances of DNA damage, especially DNA backbone breaks. Remember that outside of meiosis I, homologous chromosomes are not "paired up" in cells, although recent studies suggest they would be in the same region of the nucleus during interphase. The ability of the cell to use homologous recombination to repair a broken chromosome depends on whether or not it can "find" a homologous sequence to use as a template to re-synthesize a damaged chromosome.