Meiotic Recombination Pathways

Abstract

During meiosis, one round of DNA replication is followed by two rounds of division to create the gametes that are obligatory for biparental reproduction. To achieve the reductional segregation that is required during the first meiotic division, most eukaryotes utilise a program that involves the deliberate formation of DNA double‐stranded breaks in their genomes, followed by regulated homologous recombination and reciprocal exchange of genetic material between homologous chromosomes. This reciprocal exchange of genetic information physically links the homologous chromosomes to one another and provides the tension that is necessary for their segregation. Meiotic recombination is highly regulated to ensure that at least one reciprocal crossover event occurs between each pair of homologous chromosomes.

Key Concepts

  • Meiotic recombination physically links the homologous chromosomes to one another, creating the tension that is required for their segregation.
  • Meiosis I is a reductional segregation that halves the ploidy of the cell. This process requires bi‐orientation of the homologous chromosomes but mono‐orientation of the sister chromatids, a feat that is achieved through structural modification of the sister chromatid centromeres by monopolin.
  • Directed homologous recombination physically links the homologous chromosomes to one another, through preferential use of the homologous chromosome as the repair template, rather than the sister chromatid, followed by resolution of the recombination intermediate into a crossover.
  • DNA double‐stranded break fate is decided early in the meiotic recombination pathway, with crossovers exclusively arising through a double‐Holliday junction intermediate and non‐crossovers primarily being formed through the synthesis‐dependent strand annealing pathway.
  • Formation of the synaptonemal complex, a proteinaceous structure that assembles between homologous chromosomes during meiosis, is interdependent with meiotic recombination.

Keywords: recombination; meiosis; synaptonemal complex; crossover; interhomolog bias

Figure 1. Mitotic and meiotic chromosome segregation. (a) Mitotic chromosome segregation. (1a) The chromosome has achieved stable bipolar attachment; sister chromatids are attached to opposite poles at their centromeres. While forces from the poles pull on the centromeres, separation of chromatids is prevented by cohesin that glues the sisters together. (2a) Cohesin is degraded at the metaphase to anaphase transition. (3a) The chromosomes to segregate from one another. (b) A meiotic chromosome is shown at meiotic MI. (1b) The chromosome has achieved stable bipolar attachment; sister centromeres are attached to the same pole, homologous centromeres to opposite poles. Pulling forced from the poles are resisted by chiasmata which are, in turn, prevented from falling apart by the meiotic cohesin located distal to the chiasma with respect to the centromere. (2b) Cohesin is degraded at the MI metaphase/anaphase transition (except in the region proximal to the centromere). (3b) Homologous centromeres disjoin. MII then occurs by a mechanism, similar to that in mitosis. (4b) Centromere proximal cohesin is degraded after bipolar attachment of sister centromeres to the MII spindle and (5b) sisters disjoin.
Figure 2. Structural changes in meiotic chromosomes during recombination. Chromosome structure at different substages of meiotic prophase. Axial elements (red) and recombination nodules (yellow) are first seen in leptotene. Chromatin is relatively uncondensed at this stage. Assembly of transverse filaments (pink) to form the central region of the SC occurs during zygotene as chromatin is condensing. SC assembly is complete in pachytene and chromatin is condensed. Many recombination nodules disappear during late zygotene/early pachytene with remaining nodules marking the sites that will become chiasmata, that is the sites of CO events. SCs disappear during diplotene. In addition, chromatin decondenses and then recondenses during this stage. Chiasmata become visible when chromatin recondenses. Inset: Organisation of the SC chromatin loops are attached at their base to the lateral elements. Each lateral element organises a pair of sister chromatids into a ‘parallel’ set of loops. Transverse filaments connect the lateral elements. A recombination nodule sits immediately above the central region of the SC.
Figure 3. Meiotic homologous recombination pathways. Each line represents a DNA strand. Dotted lines indicate newly synthesised DNA. Only the two interacting chromatids are shown (meiotic cells contain two additional chromatids that are not engaged in a given event). The names of S. cerevisiae proteins implicated to function at specific stages of recombination are given. More information about the characteristics of these proteins may be found at http://www.yeastgenome.org/ During DSB formation, a Spo11 dimer, with the aid of its accessory factors, forms DSBs via a topoisomerase‐like nucleophilic attack remaining covalently attached to 5′ ends. Next, in the end resection phase, Spo11 is removed and 5′ ends are degraded to yield 3′ overhanging ssDNA tails. Following end resection, Dmc1 and its accessory factors, namely Mei5‐Sae3 and Rad51, form a filament on the ssDNA tail. The Dmc1 filament then carries out homology search, in which it searches the genome for an identical intact duplex DNA that it can use as a donor to template the recombination event. Upon identifying a suitable donor, the Dmc1 filament promotes strand invasion to form a nascent D‐loop. D‐loop reversal by a helicase or helicase‐topoisomerase complex allows homology search to begin anew and select a different donor, or the D‐loop can be irreversibly extended by a DNA polymerase. Resolution of the recombination intermediate into a CO or NCO product can follow one of two major pathways (bold) or a minor pathway. (Left) The class I CO pathway gives rise to the majority of the interhomolog COs in the cell. CO formation is designated early in the pathway, at or prior to single‐end invasion (SEI) formation. SEIs formation is promoted by the ZMM proteins (see ‘SC Initiation at CO Sites’). Second end capture mediated by Rad52 forms a double‐Holliday junction (dHJ), which will be resolved into a CO by the concerted activities of Exo1 and Mlh1‐Mlh3. (Middle) In the NCO pathway, disruption of the extended D‐loop allows the newly extended end of the break to pair with the opposite end, in a process known as synthesis‐dependent strand annealing (SDSA). NCO formation is then completed by fill‐in DNA synthesis and ligation. (Right) A minor pathway forms both COs and NCOs through unbiased resolution of dHJs. The COs formed by this pathway are not subject to CO interference, in contrast to the class I COs, which constitute the majority of the COs in the cell. Resolution is thought to be carried out by the Mus81‐Mms4 heterodimer. Box I, Recombination partner choice. The Dmc1 filament can invade either the intact sister chromatid or one of the two chromatids of the homologous chromosome. Meiotic recombination is biased toward interhomolog recombination. Box II, COs link homologs. Interhomolog COs physically link the homologous chromosomes, which together with sister chromatid cohesin, provide the tension that is required for biorientation of the homologous chromosomes and reductional segregation.
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Further Reading

Berchowitz LE and Copenhaver GP (2010) Genetic interference: don't stand so close to me. Current Genomics 11: 91–102.

Brown MS and Bishop DK (2015) DNA strand exchange and RecA homologs in meiosis. Cold Spring Harbor Perspectives in Biology 7: a016659.

Hunter N (2015) Meiotic recombination: the essence of heredity. Cold Spring Harbor Perspectives in Biology 7: a016618.

Lam I and Keeney S (2015) Mechanism and regulation of meiotic recombination initiation. Cold Spring Harbor Perspectives in Biology 7: a016634.

Pyatnitskaya A, Borde V and De Muyt A (2019) Crossing and zipping: molecular duties of the ZMM proteins in meiosis. Chromosoma 128: 181–198.

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Reitz, Diedre(Dec 2020) Meiotic Recombination Pathways. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029228]