In between germline mutation and independent assortment of chromosomes during meiosis, genetic variation is given further complexity in sexually reproducing organisms via the process of homologous recombination: the exchange of genetic material between homologous chromosomes during gamete formation that passes new combinations of grandpaternal and grandmaternal DNA into the resulting haploid cells. During leptotene stage of prophase I, Double Strand Breaks (DSBs) are induced in excess across the genome by sporulation-specific 11 (Spo11), a topoisomerase-like enzyme (see Fig.1). These DSBs are subsequently repaired by homologous recombination leading to two distinct classes of recombinant molecules: Crossovers (COs) and non-reciprocal gene conversions without exchange of flanking regions or Noncrossovers (NCOs). COs involve a reciprocal exchange of flanking regions of DNA between homologous chromosomes whereas NCOs are non-exchange transfers of DNA segments from one chromosome to the other. The lasting impact of this shuffling of haplotypes between generations is the generation of genetic diversity.Fig. 1 Simplified diagram showing meiotic recombination between non-sister chromatids in mammalians (two non-sister chromatids are distinguished by red and blue colours and their sister chromatids are not shown). During leptotene stage of prophase I, Double Strand Breaks (DSBs) are induced in excess across the genome by Spo11. Spo11 is then endonucleotically removed followed by strand resection with Exo1 exonuclease activity leaving 3’ overhangs. One of the single strand ends invades a non-sister chromatid and uses it as a template to extend its own DNA and this results in a D-loop formation. From this point on, recombination can go down two different routes: 1. Double Strand Break Repair (DSBR) pathway or 2. Synthesis-Dependent Strand Annealing (SDSA) pathway. In the DSBR pathway, the second strand is captured by the D-loop followed by DNA synthesis and ligation. The resulting double Holliday junction (dHJ) can be resolved in two possible ways, one leading to a CO event, where flanking regions of DNA have been exchanged between non-sister chromatids, and the other leading to a NCO, with unequal segments of DNA being exchanged between chromatids. In the SDSA pathway, the invading strand is displaced from the D-loop and reanneals back to the sister chromatid following by DNA synthesis and ligation. This results in a non-reciprocal gene conversion without exchange of flanking regions or NCO, where a segment of DNA has been transferred back into the chromatid where the DSB originated. Note that the eventual products of recombination are determined by mismatch repair of the heteroduplex DNA shown here whereby either of the strands may be used as the template for mismatch repair.
Since recombination is crucial for successful meiosis, DSBs are induced in excess across chromosomes so that non-sister chromatids can search for homology and pair up. Most of these DSBs are thought to be repaired into NCOs but one or two COs per chromosome are required for correct chromosome disjunction. Non-disjunction can result in aneuploidy where gamete cells may form with an abnormal number of chromosomes. For example, a gamete containing three instead of the usual two copies of chromosome 21 can still be fertilised but lead to a child born with Down Syndrome.