Human Molecular Genetics, 2000, Vol. 9, No. 16 2409-2419
© 2000 Oxford University Press
Counting cross-overs: characterizing meiotic recombination in mammals
Department of Genetics and the Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH, USA and 1Department of Genetics, Emory University School of Medicine, Atlanta, GA, USA
Received 7 July 2000; Revised and Accepted 13 July 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONWHERE AND HOW MANY:...WHEN AND WHO DOES...WHEN THINGS GO WRONG:...REFERENCES |
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Until recently, most of our understanding of meiotic recombination has come from studies of lower eukaryotes. However, over the past few years several components of the mammalian meiotic recombination pathway have been identified, and new molecular and cytological approaches to the analysis of mammalian meiosis have been developed. In this review, we discuss recent advances in three areas: the application of new techniques to study genome-wide levels of recombination in individual meioses; studies analyzing temporal aspects of the mammalian recombination pathway; and studies linking the genesis of human trisomies to alterations in meiotic exchange patterns.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONWHERE AND HOW MANY:...WHEN AND WHO DOES...WHEN THINGS GO WRONG:...REFERENCES |
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In their classic 1980 paper, Botstein et al. (1) proposed using DNA polymorphisms to construct a human linkage map and thereby uncover the location and, ultimately, the identity of human disease loci. In the two intervening decades, the wisdom of this suggestion has been amply justified, as linkage analysis has been the primary weapon in the disease gene hunter’s arsenal. Curiously, however, during this time human geneticists have devoted relatively little energy to studying the process that makes linkage analysis work, i.e. meiotic recombination. Instead, most of the advances in our understanding of meiosis and recombination have come from studies of lower eukaryotes, in particular Saccharomyces cerevisiae and Drosophila (2,3).
Fortunately, this situation is now changing. The identification of mammalian homologs of recombination proteins of lower organisms, the analysis of meiosis in appropriate knockout mice and the introduction of novel cytological and molecular technology to meiotic analysis have revitalized research into mammalian and human meiosis. In this review we summarize recent advances in three areas: the application of molecular and cytological techniques to study the number and location of meiotic exchanges in murine and human meioses; studies analyzing temporal aspects of the mammalian recombination pathway, making use of newly identified recombination proteins; and studies that have linked human non-disjunctional events with alterations in meiotic exchange patterns.
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WHERE AND HOW MANY: FREQUENCY AND DISTRIBUTION OF MEIOTIC EXCHANGES |
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TOPABSTRACTINTRODUCTIONWHERE AND HOW MANY:...WHEN AND WHO DOES...WHEN THINGS GO WRONG:...REFERENCES |
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The construction of different types of human genetic map has helped to reveal several important properties of mammalian meiotic recombination. For example, standard linkage analyses of whole chromosomes or chromosome regions have confirmed earlier cytogenetic reports of sex-specific differences, with females having higher recombination rates than males, and with males recombining preferentially in distal regions of the chromosome (4). These and other approaches, such as analysis of linkage disequilibrium or single sperm mapping, have been useful in defining recombination ‘hot spots’ (5,6) and in uncovering significant inter-individual variation in recombination over short intervals (7).
However, the majority of these analyses have been restricted to chromosome regions or single chromosomes, with no attempt being made to examine exchange patterns over all chromosomes. Recently, two different approaches—one cytogenetic and the other molecular—have been introduced that make it possible to analyze genome-wide exchange patterns in individual meioses.
Cytological approaches to crossing over
In a series of elegant studies conducted over two decades, Hulten and colleagues used conventional cytogenetics to analyze diakinesis preparations from human and murine meiocytes (8,9). This approach enabled them to examine chiasma patterns on individual chromosomes, as well as to estimate genome-wide chiasma frequencies. A number of general features of mammalian meiosis emerged from these studies, including evidence for positive interference and evidence for gender-specific differences in chiasma frequency and/or distribution, as well as the estimates of chiasma frequency. Whenever it has been possible to test these observations (e.g. by linkage analysis), they have proven accurate.
Conventional diakinesis analyses, however, are hindered by two obstacles. First, in the human, the cells of interest are relatively inaccessible: analysis of males requires a testicular biopsy and analysis of females is even more difficult, since recombination occurs in the fetal ovary. Thus, availability of material will always be limiting in cytological analyses of human recombination. Secondly, diakinesis preparations are difficult to analyze, even under ideal circumstances: chromosome morphology is suboptimal, interfering with banding and thus with chromosome identification, and the chromosomes are typically highly condensed, making localization of chiasmata to specific chromosome regions difficult. New multicolor approaches now make it possible to perform chromosome-specific analyses on diakinesis preparations (Fig. 1). Furthermore, and of greater importance, the introduction of new immunofluorescence techniques may make it possible to replace, or at least supplement diakinesis analysis with an alternative approach.
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In 1996, Baker et al. (10) reported an important meiotic role for the DNA mismatch repair protein, MLH1. In studies of male mice with a targeted disruption of the Mlh1 gene, meiotic crossing over was virtually eliminated. As a result, most chromosomes were present as univalents during meiosis I, causing the arrest of spermatocytes at this stage. Subsequently, Woods et al. (11) demonstrated that Mlh1-null females are similarly recombination-deficient. The basis for these recombination defects became clear when Baker et al. (10) immunostained surface-spread spermatocytes and oocytes from wild-type mice with an antibody to MLH1, and observed discrete foci on pachytene-stage synaptonemal complexes. The frequency and distribution of foci was remarkable: at mid-pachytene, the overall number and location of foci corresponded to previous cytogenetic analyses of chiasmata; in the male, a single MLH1 focus was observed at the distal end of the XY pairing region, consistent with previous genetic studies of the pseudoautosomal region; and in the female, some foci persisted into diplotene, and were observed at the sites of chiasmata. These results suggested that MLH1 contributed to the formation and/or processing of meiotic recombination events and that the meiotic abnormalities observed in null mice resulted from a breakdown in the recombination pathway. Importantly, the results implied that analysis of MLH1 foci in meiosis could be used as a surrogate for diakinesis studies in the analysis of meiotic exchange patterns.
More recent studies indicate that this is indeed the case. In 1999, Anderson et al. (12) conducted immunostaining studies of male mouse pachytene preparations using antibodies to MLH1 and SCP3, a component of the lateral element of the synaptonemal complex (Fig. 1 shows examples of this approach, as applied to human male and mouse female meiocytes). Their observations fulfilled several of the criteria predicted for a molecule that ‘marks’ the sites of exchanges: for example, the overall number of foci per genome was 
23, similar to previous estimates of chiasmata number in male mice; the number of foci varied depending on the length of the bivalent, with those joined by shorter synaptonemal complexes typically having only one focus and longer bivalents having one or two foci; there was a bias toward distally located foci, especially among bivalents with shorter synaptonemal complexes; and both chromosome-specific and genome-wide distributions of exchanges were non-random and consistent with positive interference.
Similar results have been presented for humans. Using comparable methodology, Barlow and Hulten (13) analyzed MLH1 foci in spermatocytes of a fertile male and in ooctyes of a female fetus. In the male, they observed 50 autosomal foci per nucleus, consistent with estimates of an overall genetic length of 2700 cM in the human male (14). Additionally, there was a bias toward distally placed foci, consistent with available data from linkage studies. Only a few analyzable cells were obtained from the female. Nevertheless, consistent with expectation the overall number of MLH1 foci was much higher (mean = 95) than that observed in the male, and distal foci were much less common than in the male, again as expected.
Thus, preliminary results from two mammalian species suggest that the frequency and distribution of MLH1 foci correspond to the number and location of meiotic cross-over events. If confirmed in further analyses, this will have major implications for future studies of mammalian recombination. For example, the ability to use immunostaining methodology will make it possible to examine temporal and spatial relationships between chiasma formation and recombination pathway proteins; indeed, several groups have already initiated these analyses (15). Additionally, the enhanced resolution afforded by the immunostaining approach will make it possible to localize cross-overs to specific chromosome regions. This will allow us to conduct experiments that are impossible or impractical using diakinesis preparations: for example, comparisons of chiasma distributions among individuals (or, in the mouse, between strains or in F1 hybrids); combined fluorescence in situ hybridization/immunostaining studies to determine whether MLH1 foci localize to specific chromosomal sites/DNA sequences (e.g. putative recombination hot spots defined by other approaches); and analyses of chiasmata in individuals with possible meiotic defects (e.g. infertile males). Cytological studies of crossing over, previously the provence of a small number of laboratories, may well become the method of choice in analyzing exchange patterns in mammalian meiosis.
Genome-wide recombination scans
In the late 1990s, genome scans became a staple of human gene mapping studies. More recently, Broman and colleagues have demonstrated the utility of this approach in characterizing basic properties of meiotic recombination. In an initial study, Broman et al. (14) used >8000 short tandem repeat polymorphisms (STRPs) to construct genetic maps for each of the 22 autosomes and the X chromosome, based on eight of the Centre d’Etude du Polymorphisme Humain (CEPH) reference families. Altogether, nearly 1 000 000 genotypes were scored, with the average distance between markers being 0.5 cM. As expected, each of the chromosomes displayed a female:male length ratio of >1. Genome-wide, the ratio was 1.6 (4435 cM in females and 2730 cM in males). Sex-specific differences in the location of recombinational events were also observed, with female:male ratios typically highest around centromeres and lowest in telomeric regions.
In addition to analyses of individual chromosomes, Broman et al. (14) also examined the overall number of detectable recombinational events per meiosis. In females, the average was 40 events and among males, 23. Interestingly, significant variation in the number of observable recombinants was evident among the eight mothers in the families, but not among fathers. No age effect on recombination was observed.
In other analyses, Broman and Weber (16) have used their mapping database to examine cross-over interference patterns in human meiosis. In both males and females, evidence for strong positive interference was observed, with no obvious variation between sexes or among chromosomes. Among chromosomes with at least one exchange per arm, a negative correlation was observed between the locations of the exchanges on the two arms. Thus, the centromere did not appear to be a barrier to interference.
Many of the general aims of these studies—construction of chromosome-specific maps, examination of sex-specific differences in exchange events and analysis of interference—can also be addressed using cytological methodology, as described above. However, Broman and colleagues have also asked questions that cannot be approached cytologically, due to the lack of suitable cytogenetic polymorphisms. For example, they recently used their genome scan data to search for segments of homozygosity among CEPH individuals (17). Surprisingly, relatively long (10–20 cM) homozygous stretches were identified in a number of the individuals. Indeed, in one of the families, all individuals showed at least one homozygous segment, with the results most likely attributable to inheritance of two copies of the same ancestral chromosome segment (autozygosity).
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WHEN AND WHO DOES IT: TEMPORAL ASPECTS OF MAMMALIAN RECOMBINATION |
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In 1989, Sun et al. (18) provided evidence that in the budding yeast S.cerevisiae, meiotic recombination was mediated through double-strand breaks (DSBs). In the intervening decade, there has been an explosion of information from lower eukaryotes, detailing the roles of specific proteins in the initiation of DSBs, the processing of recombination intermediates, and the association of recombination with the synaptonemal complex (19,20). Information on recombination in mammals has been slower in coming. However, over the past 2–3 years the pace has quickened, with many of the major players now being identified. In this section, we briefly review recent studies of the mammalian recombination pathway, focusing on immunolocalization studies and studies of knockout mice. Because a number of recent studies have detailed meiotic abnormalities in DNA mismatch repair-deficient mice, the role of mismatch repair proteins in mammalian meiosis is presented separately. The meiotic roles of other protein families, for example cohesins and condensins, have been reviewed elsewhere (e.g. ref. 21) and are not considered here.
Overview of the process
During prophase of the first meiotic division, homologous chromosomes condense, pair and synapse, and exchange genetic material in preparation for segregation at metaphase I. Stripped to its basics, this requires two processes that are common to almost all organisms, including mammals. First, the chromosomes are broken (by DSBs) and rejoined, with some of the breakage–reunion events that occur between homologs leading to recombinant products, visualized microscopically as chiasmata. Secondly, a meiosis-specific structure, the synaptonemal complex (SC), is formed that facilitates synapsis and recombination between the homologs.
Recent studies indicate that the temporal relationship between these two processes varies among different organisms. In S.cerevisiae, DSBs occur before synapsis; indeed, DSBs are thought to be essential for formation of a normal SC (3). However, in other organisms this appears not to be the case, for example in Drosophila (22) and Caenorhabditis elegans (23). SC formation is essentially normal in mutants that abolish recombination. Perhaps surprisingly, recent evidence suggests that mammals follow the yeast paradigm, with DSBs occurring before synapsis (S. Keeney, F. Baudat and M. Jasin, personal communication).
Initiation and processing of DSBs
In S.cerevisiae, an exhaustive search for the initiating event in double-strand breakage led to the identification of the responsible protein, Spo11 (24). Spo11 has sequence similarity to a family of type II topoisomerases originally identified in archebacteria (25), and presumably acts through a topoisomerase-like transesterification mechanism in which Spo11 is covalently bound to the target DNA. Homologs of yeast Spo11 have now been identified in several other organisms and appear to have a similar role in initiation of DSBs, suggesting that this component of the recombination pathway has been conserved throughout evolution. The recent identification of murine and human Spo11 homologs (26–28) was thus not unexpected. Relatively little is yet known about the meiotic activities of these mammalian SPO11 proteins. Nevertheless, initial expression studies indicate that they are present in gonadal tissue, and are expressed at time points consistent with a role in DSB formation. Therefore, it seems likely that in mammals, as well as other organisms, SPO11 is responsible for initiation of DSBs.
Relatively little is known about the recombinogenic proteins that act downstream of SPO11. However, recent studies by Heyting and co-workers (29,30) suggest that a complex containing RAD50 and MRE11 proteins functions early in the process. In S.cerevisiae, null mutants of Rad50 and Mre11 prevent formation of DSBs, whereas certain non-null mutants block the 5'
3' resection of DSB ends (31). Thus, Rad50 and Mre11 proteins appear to be important in both the formation and in the early processing of DSBs. This may well be the case in mammals as well. Immunostaining studies indicate that the two proteins co-localize within mouse spermatocyte nuclei, and that they are most abundant very early in meiosis I, before the appearance of components of the SC (29,30).
Further processing of DSBs requires the activity of strand invasion proteins. In mammals as in other organisms, this is accomplished by bacterial RecA-like proteins, at least two of which, RAD51 and DMC1, are known to function in mammalian meiosis (32). Recently, two-hybrid and co-immunoprecipitation studies have demonstrated that human DMC1 and RAD51 interact directly with one another (33).
Functional studies of the meiotic role of mammalian Rad51 have been limited, due to the fact that targeted mutations of the murine locus result in embryonic lethality. However, mice deficient for Dmc1 have been generated (34,35) and their meiotic phenotypes examined. As expected, meiosis is grossly abnormal: chromosomes are unable to synapse and, in the most mature spermatocytes, consist of 40 univalents rather than the normal 20 bivalents. Consequently, germ cells arrest early in prophase and both males and females are sterile.
The synaptonemal complex
In S.cerevisiae and possibly in mammals as well, the earliest events in recombination occur prior to synapsis of homologous chromosomes. However, the later stages, including the formation of functional chiasmata, require that the homologs be brought into intimate association with one another. This process is mediated by a meiosis-specific structure, the synaptonemal complex. The mature SC is a tripartite structure, consisting of two lateral elements (to which the sister chromatids of an individual chromosome are tethered) and a central element (linking the two lateral elements of a homologous pair). Formation of the SC begins with the assembly of small segments of the lateral elements, referred to at this stage as axial elements. As synapsis proceeds, axial elements of a homologous pair approach one another and eventually the central element forms between them.
Three major protein components of the mammalian SC have been identified: SCP1 (also called SYN1), SCP2 and SCP3 (also called COR1) (for a review see ref. 36). SCP1 localizes to the central region of the SC (37,38). It contains an extended coiled-coil region and is thought to be a major component of the transverse filament, which links the two lateral elements. SCP2 and SCP3 form components of the axial/lateral elements, and are first detected on forming axial elements in leptotene and persist through diplotene (39). SCP2 has weak sequence similarity to Red1, an S.cerevisiae protein associated with axial/lateral elements (3). SCP3 has no known yeast homolog. It can form thick, cross-striated fibers and is thought to be the core structure of the lateral element (40,41).
Our understanding of the function of mammalian SC proteins has come largely from in vitro analyses or analyses of testicular samples from wild-type animals. Recently however, Yuan et al. (41) provided the first mutational analysis of the mammalian SC, as they generated a null mutation for Scp3 and analyzed meiotic progression in Scp3-deficient male mice. The animals were developmentally normal, consistent with a meiosis-specific function for SPC3, but were sterile due to a breakdown of spermatogenesis early in prophase. In immunostaining studies, axial elements were absent and the chromosomes were represented by 40 univalents rather than 20 bivalents, indicating that the homologs were unable to synapse with one another. Additionally, abnormalities in the spatial distribution of other recombination-associated proteins (e.g. RAD51) were observed. Thus, the report of Yuan et al. (41) provides the first genetic evidence that SCP3 is required for normal meiotic progression in mammals. However, intriguingly, Scp3-deficient females are fertile, although they are less fecund than wild-type controls. It will be extremely important to determine the basis for this sex-specific difference.
In addition to the axial/lateral and central elements, studies of lower eukaryotes have identified other meiosis-specific structures that are associated with the SC. These are the recombination nodules, electron-dense spherical structures located at discrete intervals along the SC and long thought to be protein complexes acting at the sites of breakage/processing of recombinational events (e.g. ref. 42). Two types of nodule are thought to exist: ‘early’ nodules, which are numerous and present on unsynapsed axial elements and briefly on the newly formed SC, and ‘late’ nodules, which are fewer in number and distributed non-randomly on the fully synapsed SC, presumably representing the sites where chiasmata will form (15). Due to the difficulty in visualizing recombination nodules in mammals, relatively little effort has been made to characterize them. However, with the development of immunolocalization methodologies, efforts are now underway to determine whether the distribution of any of the recombinogenic proteins is consistent with that predicted for recombination nodules. In initial studies, Ashley and co-workers (15,43) and Moens and co-workers (36,44,45) have investigated several putative recombination nodule proteins, using antibodies to SCP3(COR1) to mark the axial/lateral elements of the SC, and analyzing the spatial and temporal distribution of the different proteins. RAD51 and DMC1 are likely components of early nodules. Electron-microscopic studies of mouse spermatocyte chromosomes indicate that they co-localize at the cores of spermatocyte chromosomes, suggesting that they complex with one another (44). On immunostaining, discrete RAD51 and/or DMC1 foci are observed in association with the axial elements; foci are abundant early in prophase, at leptotene/zygotene, but effectively disappear from the synapsed lateral elements by mid pachytene (15). The number of foci far exceeds that predicted for functional chiasmata in both mouse and humans, consistent with a role in the formation of early, but not late, recombination nodules (43,46).
Other proteins are also known to associate with RAD51/DMC1 or with the forming axial elements. For example, Plug et al. (43) have shown that the single-stranded DNA-binding protein RPA localizes to axial elements at or near RAD51 foci during zygotene. However, whereas RAD51 foci disappear relatively quickly from the fully synapsed SC, some RPA foci persist, and frequently co-localize with MLH1, thought to be a component of late nodules (see below). This and other evidence has led Plug et al. (43) to suggest that a subset of early nodules are converted into late nodules, with RPA contributing to both structures.
Other proteins that have been shown to interact with DMC1/RAD51 or with RPA include the Bloom syndrome helicase BLM and the ataxia telangiectia-related DNA damage checkpoint control protein ATR (43,45,47,48). However, information on the spatial and/or temporal distribution of these proteins is equivocal and thus their positions in the recombination pathway are still uncertain.
One likely protein component of late nodules now has been identified, namely MLH1. As discussed in a previous section, the frequency and distribution of MLH1 foci on the fully synapsed SC closely parallels the number and placement of chiasmata. Thus, it seems likely that MLH1 foci mark the sites of the late recombination nodules.
Mismatch repair proteins and mammalian recombination
The mismatch repair (MMR) system was first characterized in Escherichia coli, where three proteins, MutS, MutL and MutH, mediate the repair of DNA mismatches (reviewed in ref. 49). The MMR system is highly conserved, but in higher eukaryotes the simple three-protein bacterial system has been replaced by multiple MutS and MutL proteins, and a number of additional proteins have been implicated (50).
In addition to their role in DNA repair, MMR proteins are also required for meiotic recombination. The meiotic roles of individual members of the MMR system have been best defined in S.cerevisiae. Six MutS homologs (Msh1–6) and four MutL homologs (Mlh1–3 and Pms1) have been identified and, based on mutant analysis, nine of these genes are thought to be involved in meiotic recombination (Table 1) (reviewed in ref. 51). Two of the MutS homologs, Msh4 and Msh5, have a meiosis-specific function and mutations in these genes result in decreased levels of recombination and increases in post-meiotic segregation (indicative of a failure to correct mismatches in heteroduplex DNA) (52–54). Recombination levels are not decreased in mutants for the MutS homologs Msh2 and Msh3, or for the MutL homolog Pms1; however, an increase in post-meiotic segregation is a feature of all three (55–57). In addition, these proteins are thought to play a role in preventing recombination between homologous sequences and, consistent with this, a slight increase in recombination is observed when these mutations are present on a non-isogenic genetic background (58–60). The MutL homolog, MLH1, is thought to physically interact with the other three MutL homologs, and mutations in this gene, as in the meiosis-specific genes, result in a decrease in recombination and an increase in post-meiotic segregation (51).
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In mammals, interest in MMR proteins was sparked by the publication, in 1993, of two papers demonstrating an association between mutations in MMR genes and some forms of hereditary cancer (61,62). Studies conducted over the intervening 7 years have considerably advanced our understanding of the role that loss of mismatch repair plays in the genesis of human cancers (reviewed in ref. 63). As one part of these efforts, targeted disruptions of seven of the mouse MMR genes have now been generated (53,64–73), making it possible to examine the meiotic roles of the gene products. For several of these, the meiotic phenotypes of the null animals suggest a high degree of functional conservation between the mouse and yeast homologs, for example (i) both male and female mice homozygous for targeted disruptions of either Msh4 or Msh5 are sterile, with disruption early in meiotic prophase, consistent with recombination failure (53,70,71); (ii) in the Mlh1-null mouse, synapsis of homologous chromosomes occurs normally, but recombination is virtually abolished, the result is sterility of both male and female null mice, with arrest during the meiotic divisions, presumably due to the presence of multiple univalent chromosomes (67,68,74); and (iii) the Pms2 (the mouse homolog of yeast Pms1) mutant mouse has an abnormal but poorly understood meiotic phenotyp; although the null female is fertile, the Pms2 null male is sterile; analysis of pachytene spermatocytes revealed evidence of synaptic disturbances (64); however, the level of meiotic disturbance is insufficient to explain the infertility, and a significant number of cells complete meiosis, as evidenced by the production of sperm.
Meiotic abnormalities have not yet been identified in the other null mutants, including those deficient for Msh2 or Msh3 (65,66,73). However, it is important to note that none of the studies were designed to address less obvious abnormalities, for example subtle alterations in chiasma frequency or distribution, or effects on the possible role of these proteins in preventing recombination between evolutionarily diverged sequences. Thus, more detailed meiotic analyses of these mutants may reveal subtle meiotic defects. In addition, one potentially interesting player, Mlh3, has yet to be analyzed. Recent studies in yeast have demonstrated a significant reduction in recombination in Mlh3 mutants (51), hence there is reason to suspect that, like the Mlh1 knockout mouse, targeted disruption of the Mlh3 gene will result in both male and female sterility.
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WHEN THINGS GO WRONG: RECOMBINATION AND HUMAN NON-DISJUNCTION |
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TOPABSTRACTINTRODUCTIONWHERE AND HOW MANY:...WHEN AND WHO DOES...WHEN THINGS GO WRONG:...REFERENCES |
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In 1968, Henderson and Edwards (75) proposed a link between recombination and human non-disjunction, suggesting that declining levels of recombination were the cause of the maternal age effect on trisomy. Specifically, they hypothesized that meiotic chromosomes of older women were held together by fewer chiasmata, and that consequently the chromosomes were more likely to non-disjoin at meiosis I. Their model, the so-called ‘production line’ hypothesis of maternal age-dependent non-disjunction, sparked a series of cytogenetic investigations into the relationship of chiasmate ‘disturbances’ and meiotic non-disjunction. However, because of the inherent difficulties in obtaining material from human gametes, most such studies involved analysis of mouse oocytes. Indeed, it was not until the advent of DNA polymorphism analysis in the mid 1980s that it became possible to test the production line model directly, and more generally the association of aberrant recombination and non-disjunction, in humans. The results of these analyses are incompatible with predictions of the production line hypothesis and it is now clear that this model cannot explain the maternal age effect on human trisomy. Nevertheless, the results provide ample evidence that Henderson and Edwards’ (75) major premise was correct, i.e. that alterations in recombination are an important determinant of human trisomy.
Alterations in the level and/or location of exchanges are a feature of most, if not all, human trisomies
In an analysis of 34 Down syndrome families, Warren et al. (76) provided the first direct evidence of an association between reduced recombination and human trisomy. Subsequently, their interpretations have been confirmed by Lamb et al. (77) who used centromere mapping techniques or analyses of meiotic exchange configurations to examine meiotic recombination in normal meioses and in meioses leading to trisomy 21. Results of studies of 200 maternal meiosis I-derived trisomies indicated two different recombination-associated avenues to chromosome 21 non-disjunction (Table 2). First, an estimated 35% of cases involved meioses in which the chromosomes 21 failed to pair and/or recombine, i.e. the chromosome 21 bivalent was achiasmate. This was not surprising since, from studies of other organisms, it is clear that mutants abolishing recombination invariably increase non-disjunction. However, the second avenue was unexpected, since it involved chromosome 21 bivalents in which at least one exchange had occurred (i.e. ‘chiasmate’ bivalents). Specifically, in the majority of chiasmate maternal meiosis I non-disjunctional events, a single exchange was observed in distal 21q. This exchange configuration was also observed in normal female meioses, but it was significantly enriched in the non-disjunctional events. Thus, it seems that, at least for chromosome 21, ‘distal-only’ exchanges are less efficient at segregating chromosomes than are medially placed exchanges. Similar observations have been made for spontaneous X chromosome non-disjunction in Drosophila (78), suggesting that this is a feature of meiosis in other organisms as well.
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Not surprisingly, much less is known about other human trisomies. Nevertheless, initial studies of maternal meiosis I-derived trisomies 15 (and UPD 15), 16 and 18 and sex chromosome trisomies, paternal meiosis I trisomies 21 and sex chromosome trisomies indicate that each is associated with a reduction in recombination (Table 2). Thus, it appears that alterations in recombination are a feature of all human trisomic conditions. However, there is also mounting evidence that this effect varies considerably among individual chromosomes. For example, achiasmate bivalents are responsible for the majority of cases of paternally derived cases of 47,XXY (79), and for an estimated 20–40% of maternal meiosis I trisomies 15, 18 and 21, and sex chromosome trisomy (77,80–82); however, achiasmate events appear to be unimportant in the genesis of trisomy 16 (T. Hassold, unpublished data). Furthermore, distally placed exchanges appear to be an important contributor to trisomies 16 and 21, but have not been identified in any of the other trisomies (83). Thus, it seems unlikely that any one trisomy can be used as a model for all human non-disjunctional events. Instead it appears that the effects of altered recombination on non-disjunction are mediated by chromosome-specific properties.
Since meiotic recombination occurs at meiosis I, there was no reason to believe that exchange patterns would be altered in trisomies of meiosis II origin. Thus, it was somewhat surprising when Lamb et al. (84) reported a significant increase in recombination, especially in the proximal region of 21q, in trisomy 21 of maternal meiosis II origin. Lamb et al. (84) offered two possible explanations for this unusual observation. First, the presence of proximal chiasmata could lead to ‘chromosome entanglement’ at meiosis I, with the two homologous chromosomes 21 travelling together to the same pole. If at meiosis II the bivalent divided reductionally, the result would be two disomic gametes, each with identical centromeres, thus leading to the case being scored as a meiosis II error. Alternatively, the presence of proximal chiasmata might interfere with centromeric sister chromatid cohesion, resulting in premature separation of sister chromatids at meiosis I. If the sisters travelled to the same pole at meiosis I, they would have a 50% chance of migrating together again at meiosis II, leading to an apparent meiosis II error. Regardless of the correctness of these or other models, the implication of the observations was clear: virtually all cases of maternal trisomy 21, even those scored as arising at meiosis II, have their genesis at meiosis I, so that efforts to identify determinants of human non-disjunction might well be restricted to an examination of events occurring during meiosis I.
However, subsequent studies of trisomy 18 indicate that other chromosomes may behave differently. In studies of 88 maternal meiosis II-derived cases, Bugge et al. (81) were unable to identify any significant effect of recombination, suggesting that non-disjunction did indeed occur at meiosis II. Therefore, similar to the situation for meiosis I trisomies, it appears that observations for one trisomy may not apply to other chromosomes.
Maternal age, recombination and non-disjunction
The association between increasing maternal age and trisomy is arguably the most important etiological factor in human genetic disease. The risk of trisomy is at least 15 times greater for women in their forties than for women in their twenties, and appears to be exerted on all women, regardless of reproductive history, race, geography or socioeconomic status.
Despite the clinical importance of the maternal age effect, we know virtually nothing about its origin. Thus, the demonstration of an association between recombination and human trisomy led to an obvious question: are abnormal levels or locations of meiotic exchanges linked to maternal age? Initial studies of trisomies 21 and 16 indicated that the answer was yes. In both conditions, genetic maps based on maternal meiosis I errors were similarly reduced in younger and older women and, in trisomy 21, maps associated with meiosis II errors were similarly increased in younger and older women. From this it was suggested that there might be two ‘hits’ to maternal age-related non-disjunction (84). The first hit would involve the establishment of a suboptimal chiasmate configuration (e.g. a bivalent with a single, distally placed exchange) in the fetal oocyte; this event would be age independent. The second hit would involve abnormal processing of the susceptible bivalent at metaphase I, and would be the age-dependent component of the process. If this model is correct, it implies that the non-disjunctional process is similar in women of different ages. The increase in trisomy with age simply derives from the fact that the older ovary is less efficient than the younger ovary in processing certain types of exchange configuration.
More recently, several groups have extended these initial studies, asking whether the observations on trisomies 16 and 21 could be confirmed, and whether they extended to other chromosomes as well. Results of these analyses for three conditions, trisomies 15, 16 and 21 of maternal meiosis I origin, are provided in Figure 2. The results for both trisomies 16 and 21 are consistent with the earlier observations, i.e. the exchange distributions appear to be unaffected by maternal age. However, the results clearly are different for trisomy 15, as the proportion of events scored as achiasmate decreases with age and the proportion of three to four chiasmate events increases with age (80).
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How can we account for these different results? One possibility is that there are at least two types of susceptible meiotic configuration—one type involving an achiasmate bivalent and the other a bivalent with a chiasma at an ‘unfortunate’ location (i.e. either too distal or too proximal)—with the two categories having different relationships with maternal age and varying in their importance in different trisomies. For example, an achiasmate bivalent may impart an age-independent risk; after all, failure to recombine should increase the risk of mal-segregation regardless of the age of the woman, and appears to be relatively more important in the genesis of trisomies 15 and 21 than that of trisomy 16 (Fig. 2). The apparent discrepancy between trisomies 15 and 21 might be a technical artifact, reflecting differences in the ability to detect real achiasmate events. That is, in female meiosis the chromosome 21 bivalent is typically held together by one to two chiasmata, whereas chromosome 15 is joined by two to three chiasmata; consequently, situations in which crossing over occurs but both recombinant or both non-recombinant chromatids are recovered, leading to scoring of the case as achiasmate, are more likely to involve trisomy 21. Thus, there may be an age-related reduction in the proportion of achiasmate cases in both trisomies 15 and 21, with the power to detect the effect reduced for trisomy 21.
The second category, involving a bivalent with an aberrantly located exchange, appears to be the most important risk factor for trisomy 16. Indeed, the majority of cases of trisomy 16 appear to involve meioses with distally located exchanges (T. Hassold, unpublished data). As there is no obvious age-related difference in the number of exchanges in trisomy 16 (Fig. 2), the originally stated features of the two-hit model may still apply to this condition.
The relationship between maternal age, recombination and non-disjunction for other human chromosomes is not yet clear. Analysis of these conditions, as well as analysis of additional cases of trisomies 15, 16 and 21, will be important determining whether the two-hit model of the maternal age effect applies to any, several or all human trisomies.
Genome-wide effects on recombination in nondisjunctional meioses
One of the most intriguing questions regarding the association of altered recombination and non-disjunction involves the extent of the effect: are the alterations in exchange patterns limited to the non-disjoining bivalent, or are there are genome-wide ‘disturbances’ in recombination in non-disjunctional meioses? Preliminary evidence for trisomy 21 suggests that, at least in some trisomy-generating meioses, the latter is the case (85). Utilizing DNA samples from the trisomic individual and his/her parents and grandparents, Savage Brown et al. (85) conducted genome-wide recombination screens in 15 maternal meiosis I-derived cases in which recombination between the non-disjoining bivalents had not been detected. They found evidence of a cell-wide reduction in recombination in the trisomy-generating meiosis, as the mean number of detectable exchanges was 35.5, significantly reduced from the value of 39.9 in CEPH controls. Centromeric and telomeric regions were similarly affected, and there was no evidence that specific chromosomes were driving the effect; thus, the reduction appeared to be global in nature. Savage Brown et al. (85) concluded that the effect was consistent with normal variation in recombination rates among oocytes and suggested that when the number of genome-wide recombination events falls below a threshold, specific chromosomes become more likely to non-disjoin.
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ACKNOWLEDGEMENTS |
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Research conducted in our laboratories and discussed in this report was supported by NIH grants HD21341 (to T.H.), HD32111 (to S.S.) and HD31866 (to P.H.). We gratefully acknowledge Dr Terry Ashley for providing comments on the manuscript.
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FOOTNOTES |
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+ To whom correspondence should be addressed at: Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA. Tel: +1 216 368 3433; Fax: +1 216 368 0491; Email: tjh6@po.cwru.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONWHERE AND HOW MANY:...WHEN AND WHO DOES...WHEN THINGS GO WRONG:...REFERENCES |
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D. Dumas and J. Britton-Davidian Chromosomal Rearrangements and Evolution of Recombination: Comparison of Chiasma Distribution Patterns in Standard and Robertsonian Populations of the House Mouse Genetics, November 1, 2002; 162(3): 1355 - 1366. [Abstract] [Full Text] [PDF]
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Y. Shinkai, H. Satoh, N. Takeda, M. Fukuda, E. Chiba, T. Kato, T. Kuramochi, and Y. Araki A Testicular Germ Cell-Associated Serine-Threonine Kinase, MAK, Is Dispensable for Sperm Formation Mol. Cell. Biol., May 15, 2002; 22(10): 3276 - 3280. [Abstract] [Full Text] [PDF]
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 C. A. Hodges, R. LeMaire-Adkins, and P. A. Hunt Coordinating the segregation of sister chromatids during the first meiotic division: evidence for sexual dimorphism J. Cell Sci., January 7, 2001; 114(13): 2417 - 2426. [Abstract] [Full Text] [PDF]
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