You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Transmission Distortion Affecting Human Noncrossover but Not Crossover Recombination: A Hidden Source of Meiotic Drive}
Article:
Abstract:
Meiotic recombination ensures the correct segregation of homologous chromosomes during gamete formation and contributes to DNA diversity through both large-scale reciprocal crossovers and very localised gene conversion events, also known as noncrossovers. Considerable progress has been made in understanding factors such as PRDM9 and SNP variants that influence the initiation of recombination at human hotspots but very little is known about factors acting downstream. To address this, we simultaneously analysed both types of recombinant molecule in sperm DNA at six highly active hotspots, and looked for disparity in the transmission of allelic variants indicative of any cis-acting influences. At two of the hotspots we identified a novel form of biased transmission that was exclusive to the noncrossover class of recombinant, and which presumably arises through differences between crossovers and noncrossovers in heteroduplex formation and biased mismatch repair. This form of biased gene conversion is not predicted to influence hotspot activity as previously noted for SNPs that affect recombination initiation, but does constitute a powerful and previously undetected source of recombination-driven meiotic drive that by extrapolation may affect thousands of recombination hotspots throughout the human genome. Intriguingly, at both of the hotspots described here, this drive favours strong( G/C) over weak( A/T) base pairs as might be predicted from the well-established correlations between high GC content and recombination activity in mammalian genomes.
Introduction:
During meiosis, homologous chromosomes have to find each other and engage in recombination to segregate accurately. To provoke stable pairing, DNA double-stranded breaks( DSBs) are introduced by SPO11, and subsequently repaired using the homologue instead of the identical sister-chromatid as a template( reviewed in[1]). This tethering of homologous chromosomes provides the necessary connection for accurate reductional segregation. Failure to place at least one crossover( CO) event per chromosome pair can result in non-disjunction and therefore gamete aneuploidy, a major cause of developmental abnormality and spontaneous miscarriage in humans[2]. Recombination events are not randomly distributed in the human genome, but instead cluster into “hotspots” 1–2 kb wide in which crossover resolution points define a normal distribution around a central point, presumably reflecting a diffuse zone of DSB formation plus the outward migration of Holliday junction intermediates from a DSB site[3],[4]. Hotspot activity is regulated in trans by the protein “PR-domain containing 9”( PRDM9)[5]–[9], whose DNA binding domain consists of tandem-repeat zinc-fingers( ZnFs) encoded by a minisatellite. Small variations in this tandem array can alter the DNA binding specificity of PRDM9 as shown by significant differences in hotspot usage between individuals with differing alleles[5],[6],[9]–[11]. PRDM9 might function by triggering chromatin remodelling via histone 3 lysine 4 trimethylation, allowing SPO11 to introduce DSBs and thus initiate recombination[12],[13]. Additional insights into factors influencing human hotspot activity have come through observations of biased gene conversion accompanying CO. Extensive studies in yeast have indicated that DSB formation is followed by 5′ resection, invasion of the resulting 3′-overhang into a non-sister chromatid, D-loop formation and DNA synthesis, with the repair of heteroduplex DNA leading to gene conversion[14],[15]. Ordinarily, there is no net bias in this process as CO resolution points from reciprocal orientations map to the same intervals in humans[16],[17]. However, biased conversions accompanying CO have been directly observed in some sperm assays as deviations from the expected 1∶1 ratio of allele frequencies amongst recombinant progeny[9],[18]–[20]. This can arise if initiation occurs more frequently on one chromosome than the other and the broken strand is corrected with information from the uncut homologue. Heterozygosity at a single SNP can lead to such differences in initiation between interacting haplotypes and can directly influence hotspot activity in cis[18],[19]. Indeed the over-transmission of alleles from a DSB-suppressed haplotype to recombinant progeny results in meiotic drive in favour of hotspot-suppressing variants and therefore hotspot extinction over time; the stronger the meiotic drive, the faster the hotspot will attenuate[18],[19],[21],[22]. This form of cis-regulation has so far been described at four human recombination hotspots, the autosomal hotspots DNA2, NID1[18],[19] and 5A[9] as well as hotspot SPRY3 located in the minor pseudoautosomal region( PAR2)[20]. In several cases suppressing SNP variants have been noted to occur within degenerate GC-rich sequences proposed as binding sites for different classes of PRDM9 variants[5],[8],[9],[11],[20],[23],[24]. However hotspots with and without these sequence motifs can be equally regulated by PRDM9 and motif-disrupting SNPs have also been associated with active haplotypes[9]. Indeed, recent in vitro studies have highlighted the complexity with which the long ZnF array of the mouse Prdm9 protein binds to DNA[25] and this is likely true of human PRDM9 too. Recombination hotspot analysis in humans has to date largely focused on the description of COs as these can be readily detected in pools of sperm DNA even in the presence of a large excess of non-recombined molecules[26]. However in the mouse, cytological evidence has shown that only ∼10% of DSBs go on to form COs while the remainder are repaired without exchange of flanking markers[27],[28]. These localised gene conversion-only events are also known as noncrossovers( NCOs) and are only detectable if heteroduplex DNA intermediates encompass informative markers. NCOs do not appear to be sufficient for correct chromosome segregation but are thought to aid homologue pairing and/or the regulated placement of COs[29]. SNP enrichment techniques have allowed the identification of NCO events at human recombination hotspots[30] and have shown that these gene conversions co-localise with the centre of the CO distribution and involve short tracts[31]. Given that the same SNP heterozygosities that lead to transmission distortion( TD) amongst COs similarly affect NCOs[19], and that NCO frequency as well as CO frequency is regulated by PRDM9[9],[20], it is clear that these two classes of recombinants arise from the same initiating DSBs. Indeed, yeast models postulate distinct pathways that diverge shortly after DSB initiation, with the canonical DSB repair( DSBR) pathway[32] mainly producing COs and the synthesis-dependent strand annealing( SDSA) pathway[33],[34] mainly NCOs[35]. We have little information on the factors influencing human recombination events downstream of DSB induction. However, it is clear from sperm analysis that the balance between NCO and CO can be very variable between hotspots( <1∶12 to ∼3∶1 NCO∶CO)[36], and at least at SPRY3 between men too( ∼35-fold range)[20]. At the SPRY3 hotspot some men also show more extreme TD amongst NCOs than COs at a hotspot-attenuating SNP, suggesting that cis-effects are mediated not only through recombination initiation frequencies but also through downstream processing. Given that this hotspot is located in the pseudoautosomal region PAR2, it is unclear whether this finding is more generally applicable to hotspots elsewhere in the genome. To gain further insight into differential processing, we have therefore analysed six highly active and marker-rich autosomal hotspots for both COs and NCOs. At two of these hotspots, we identified a novel type of biased gene conversion acting solely upon the NCO class of recombinant. This bias is not predicted to lead to hotspot attenuation but represents a previously unappreciated yet significant source of meiotic drive operating in the human genome.
Discussion:
We describe for the first time direct evidence of TD arising solely from the NCO class of recombinant at two human hotspots. In each case, a single SNP heterozygosity close to the centre of the hotspot appears to be triggering this biased gene conversion but without effect on de novo CO events. Thus, hotspots that appear to be generating balanced recombinant progeny when analysed just for COs may in fact harbour biased gene conversion generated through the production of NCOs. Until now, biased gene conversion at human hotspots has predominantly been observed amongst COs, the more widely studied class of recombinant[18],[19],[21]. Where NCOs have also been studied at these hotspots, a comparable bias has been noted amongst this class of event too[9],[19],[20]. At such hotspots, haplotypes can be designated as being either active or relatively suppressed, since men homozygous for the opposing alleles at the key SNPs display substantially different recombination frequencies. This is consistent with differential initiation between haplotypes causing biased transmission of SNP alleles. The ensuing TD leads to so-called hotspot drive in favour of hotspot-suppressing variants[38], which along with the rapid evolution of PRDM9[39]–[41] is likely responsible for the fast turnover in hotspot locations[8],[21],[42]–[45]. In contrast, the biased conversion noted at hotspots F and K in the present study was restricted to NCOs, and a model of preferential initiation cannot easily explain this. Indeed, men homozygous for different alleles at the key SNP( K7. 4) at hotspot K display very similar CO frequencies, indicating that DSBs are induced with comparable frequencies on both chromosomes. These data therefore suggest that the biases in NCO at hotspots F and K arise at a later stage and that the intermediates destined for the two fates must be recognised or processed differently during mismatch repair( MMR). Under a classical model of MMR, wherein mismatches are deeply embedded in a patch of heteroduplex, a bias could occur if there is a strand preference for introducing a nick since this determines which of the two DNA strands is degraded and thus ultimately establishes the direction of repair[46]. In this case, the nicking preference would be directly dictated by the two bases involved in the mismatch. Alternatively, if the mismatch occurs during strand invasion, then a bias might arise if the efficiency of mismatch recognition depends on the orientation of the mismatched bases with respect to the invading and recipient strands. Removal of mismatches at this stage is achieved through chew-back of the invading strand followed by repair synthesis using the recipient strand as a template[15]. There are a number of possibilities as to why such biased MMR should preferentially affect NCOs and not COs. For example, it could be that the chromatin configurations for the two types of intermediate differ, with those destined to be NCOs being more open and thus allowing better access for the MMR machinery. Another explanation might be that NCO invasions persist for a longer time, allowing biased MMR to occur, while CO invasions are processed more rapidly, healing the DNA ends and thus preventing biased free-end-mediated MMR from acting. Alternatively, it could also be that very short invasions lead to NCOs and that any mismatches within these heteroduplex tracts are easily recognised by the inherently biased MMR system. In contrast, COs might involve longer invasions that might more successfully hide such mismatches from this process. Our data from these two hotspots represent the largest autosomal surveys of inter-individual variation in NCO∶CO ratio to date. The only comparable dataset is that from the PAR2 hotspot SPRY3, for which 35-fold variation between men was noted[20]. This is not dissimilar to the difference previously observed between hotspots as estimated from just one or two men at each. However, at each of hotspots F and K the observed differences in this ratio are much more modest and not significantly different between men, supporting the possibility that variability of the NCO∶CO ratio at SPRY3 may reflect aspects of chromosome pairing and exchange that are unique to the sex chromosomes in male meiosis, rather than being a more general feature of hotspots[20]. We have observed this biased NCO conversion at two recombination hotspots from a total of six examined. This relatively high proportion suggests that NCO-specific bias is likely to be a general phenomenon, potentially affecting thousands of the 33, 000 human recombination hotspots identified from LD patterns in the human genome[47]. In contrast to the previously described instances of hotspot drive, this form of biased gene conversion will not lead to the demise of recombination hotspots, though it may nonetheless have a significant impact on the base composition of the genome. Interestingly, at both F and K, the affected SNPs in NCOs display preferential repair of weak( A/T) to strong( G/C) base pairs. Genomes are known to have evolved towards greater GC richness[48], with the enrichment of GC alleles corresponding to sites of recombination[49],[50], yet our empirical studies of TD that affects both CO and NCO in humans have thus far failed to show any overriding base composition bias[9],[18]–[21]. Of course it remains to be seen whether the GC bias seen at F and K also occurs at other hotspots that might exhibit NCO-specific biased gene conversion. We have shown that this form of meiotic drive is sufficiently strong to promote allele fixation, and it is tempting to speculate that our findings might represent a form of biased gene conversion acting on the human genome that contributes to the correlation between GC content and recombination and thus evolution of genomic base composition.
Meiosis is an essential feature of sexual reproduction that maintains chromosome number over generations . This specialised form of cell division creates gametes containing a single copy of each chromosome so that each parent contributes half their genetic information to an offspring . Accurate partitioning first requires intimate association of the two parental copies of each chromosome and concomitant exchange between them . These exchanges consist of both large-scale reciprocal crossovers , essential for correct chromosome segregation , and very localised gene conversion events , or noncrossovers , thought to be involved in correct chromosome pairing . Ordinarily , the reshuffling of genetic variants between generations by recombination will not alter their population frequency only their haplotypic context , with a parent passing on a given variant to 50% of its gametes according to Mendel's law of inheritance . However , by screening for both types of recombinant amongst the sperm DNA of healthy men , we have identified a novel form of biased transmission that is restricted to noncrossovers and favours eventual fixation of one variant over another in the population . This previously undetected source of meiotic drive will not alter recombination propensity but is likely to be a common and potent force acting on the human genome .