Homologous chromosome pairing: The linchpin of accurate segregation in meiosis

Meiosis is a specialized cell division that occurs in sexually reproducing organisms, generating haploid gametes containing half the chromosome number through two rounds of cell division. Homologous chromosomes pair and prepare for their proper segregation in subsequent divisions. How homologous chromosomes recognize each other and achieve pairing is an important question. Early studies showed that in most organisms, homologous pairing relies on homologous recombination. However, pairing mechanisms differ across species. Evidence indicates that chromosomes are dynamic and move during early meiotic stages, facilitating pairing. Recent studies in various model organisms suggest conserved mechanisms and key regulators of homologous chromosome pairing. This review summarizes these findings and compare similarities and differences in homologous chromosome pairing mechanisms across species.     

Homologous pairing and chromosome dynamics in meiosis and mitosis

Pairing of homologous chromosomes is an essential feature of meiosis, acting to promote high levels of recombination and to ensure segregation of homologs. However, homologous pairing also occurs in somatic cells, most regularly in Dipterans such as Drosophila, but also to a lesser extent in other organisms, and it is not known how mitotic and meiotic pairing relate to each other. In this article, I summarize results of recent molecular studies of pairing in both mitosis and meiosis, focusing especially on studies using fluorescent in situ hybridization (FISH) and GFP-tagging of single loci, which have allowed investigators to assay the pairing status of chromosomes directly. These approaches have permitted the demonstration that pairing occurs throughout the cell cycle in mitotic cells in Drosophila, and that the transition from mitotic to meiotic pairing in spermatogenesis is accompanied by a dramatic increase in pairing frequency. Similar approaches in mammals, plants and fungi have established that with few exceptions, chromosomes enter meiosis unpaired and that chromosome movements involving the telomeric, and sometimes centromeric, regions often precede the onset of meiotic pairing. The possible roles of proteins involved in homologous recombination, synapsis and sister chromatid cohesion in homolog pairing are discussed with an emphasis on those for which mutant phenotypes have permitted an assessment of effects on homolog pairing. Finally, I consider the question of the distribution and identity of chromosomal pairing sites, using recent data to evaluate possible relationships between pairing sites and other chromosomal sites, such as centromeres, telomeres, promoters and heterochromatin. I cite evidence that may point to a relationship between matrix attachment sites and homologous pairing sites.     

Homologous recombination and transposition generate chromosome I neopolymorphism during meiosis in Saccharomyces cerevisiae

We have studied the meiotic segregation of a chromosome length polymorphism (CLP) in the yeast Saccharomyces cerevisiae. The neopolymorphism frequently observed within the smallest chromosomes (I, VI, III and IX) is not completely understood. We focused on the analysis of the structure of chromosome I in 88 segregants from a cross between YNN295 and FL100trp. Strain FL100trp is known to carry a reciprocal translocation between the left arm of chromosome III and the right arm of chromosome I. PCR and Southern hybridization analyses were performed and a method for the rapid detection of chromosome I rearrangements was developed. Seven chromosome I types were identified among the 88 segregants. We detected 22 recombination events between homologous chromosomes I and seven ectopic recombination events between FL100trp chromosome III and YNN295 chromosome I. These recombination events occurred in 20 of the 22 tetrads studied (91%). Nine tetrads (41%) showed two recombination events. This showed that homologous recombination involving polymorphic homologues or heterologous chromosomes is the main source of neopolymorphism. Only one of the seven chromosome I variants resulted from a transposition event rather than a recombination event. We demonstrated that a Ty1 element had transposed within the translocated region of chromosome I, generating mutations in the 3′ LTR, at the border between U5 and PBS. Received: 7 May 1999 / Accepted: 14 February 2000     

Homologous chromosome pairing remains an unsolved problem: a test of a popular hypothesis utilizing maize meiosis

A recently proposed and popular model for the mechanism of meiotic homologue pairing relies on prior association of nonhomologous chromosome arms of most similar length. According to this model, the diploid complement is organized into two genomic linear chains, each containing the various heterologues in the same sequence. At meiosis, then, appression of the two genomic chains could presumably readily accomplish homologue pairing. This model fails in its simplest form when observations of meiotic pairing of homologues in heterozygotes for arm length alterations are compared with computer-simulated predictions of the model. Contrary to predictions of the model, heterozygotes for arm length changes were found to exhibit only small frequencies of homologue-pairing failure, and this only for a single homologue pair in each case. It is difficult to conceive of a reasonable modification of this model that would be consistent with the observations.     

Homologous recombinational repair proteins in mouse meiosis

Eukaryotic meiotic recombination requires numerous biochemical processes, including break initiation, end resection, strand invasion and heteroduplex formation, and, finally, crossover resolution. In this review, we discuss primarily those proteins involved in the initial stages of homologous recombination, including SPO11, MRE11, RAD50, NBS1, DMC1, RAD51, RAD51 paralogs, RAD52, RPA, RAD54, and RAD54B. Focusing on the mouse as a model organism, we discuss what is known about the conserved roles of these proteins in vertebrate somatic cells and in mammalian meiosis. We consider such information as gene expression in gonadal tissue, protein localization patterns on chromosomal cores in meiocyte nuclei, and information gleaned from mouse models.     

Homologous chromosome pairing.

Commonly accepted precepts are challenged: (1) that homologous chromosome pairing is normally mediated by nuclear envelope attachment sites; (2) that crossover site establishment awaits synaptic completion; and (3) that it is the function of the synaptonemal complex to hold homologues in register so that equal crossing over can occur, and perhaps to provide machinery for the crossover process. Although these views may eventually be shown to be true, it is felt that currently available evidence does not warrant their full acceptance, and that alternatives should be considered. As examples of alternatives the following ideas, with some supporting evidence, are suggested: (1) homologous chromosome pairing (in non-haplont organisms) may be accomplished by chance meeting of homologue segments (followed by establishment of invisible, elastic connectors) at congression for a mitotic metaphase (in many cases perhaps the premeiotic mitosis); (2) crossover sites may be established before, during, or immediately following initiation of synapsis; and (3) the synaptonemal complex may somehow function in the crossover process at the inception of its formation, but its complete deployment throughout each normal bivalent may serve some other role, such as mediation of the binding of sister chromatids apparently required for chiasma maintenance until anaphase I.     

Peculiarities of chromosome organization in meiosis

Meiotic and mitotic chromosomes have a complex of differences. (1) At the early prophase I of meiosis, chromosomes acquire protein axial elements (AEs) that were absent in mitosis; in addition to somatic cohesins, AEs contain the meiosis-specific cohesins REC8, SMC1β, and STAG3. (2) At the middle prophase I, protein lateral elements (LEs) of synaptonemal complexes (SCs) are formed on the basis of AEs. The LE proteins are not conserved, but in Saccharomyces cerevisiae and Arabidopsis thaliana they contain functional domains with conserved secondary structures. Among the almost 679 thousand proteins of primitive eukaryotes that we studied by bioinformatics methods, in green and brown algae, some lower fungi, and Coelenterata, we revealed proteins or functional domains similar to SC proteins. (3) During the pachytene and diplotene stages of meiosis, chromosomes of spermatocytes and mother pollen cells acquire a general structure resembling the structure of amphibian and avian lampbrush chromosomes in miniature. Lateral chromatin loops with sizes of 90, 160, and even over 480 Kb were observed in human spermatocytes during the diplotene stage. In combination, all these observations confirm the considerable conservation of the scheme of molecular and ultrastructural organization of meiotic chromosomes in a large variety of eukaryotic organisms.     

Genetic control of chromosome synapsis in yeast meiosis

Both meiosis-specific and general recombination functions, recruited from the mitotic cell cycle, are required for elevated levels of recombination and for chromosome synapsis (assembly of the synaptonemal complex) during yeast meiosis. The meiosis-specific SPO11 gene (previously shown to be required for meiotic recombination) has been isolated and shown to be essential for synaptonemal complex formation but not for DNA metabolism during the vegetative cell cycle. In contrast, the RAD52 gene is required for mitotic and meiotic recombination but not for synaptonemal complex assembly. These data suggest that the synaptonemal complex may be necessary but is clearly not sufficient for meiotic recombination. Cytological analysis of spread meiotic nuclei demonstrates that chromosome behavior in yeast is comparable with that observed in larger eukaryotes. These spread preparations support the immunocytological localization of specific proteins in meiotic nuclei. This combination of genetic, molecular cloning, and cytological approaches in a single experimental system provides a means of addressing the role of specific gene products and nuclear structures in meiotic chromosome behavior.     

Sex chromosome pairing during male meiosis in marsupials

The pairing of the sex chromosomes at pachytene has been examined in twenty-two species of Australian marsupials, including four with complex sex chromosome systems. The axial elements of the sex chromosomes associate in all but one species. However, no synaptonemal complex has been observed between the axes of the X and Y chromosome in any of the examined species. Both the type of association between the sex chromosome axes, and the structural modifications of these axes are conserved within taxonomic groupings. In three species with complex sex chromosome systems, the t(XA), Y, A trivalents do not have a favoured relative orientation of the axes of the Y and A chromosomes, whereas in a fourth species with a t(XA₁), t(A₂YA₂), A₂ system the t(XA₁) and A₂ axes are in a cis arrangement with each other.     

Molecular perspectives of chromosome pairing at meiosis

Ideas about the mechanisms that regulate chromosome pairing, recombination, and segregation during meiosis have gained in molecular detail over the last few years. The purpose of this article is to survey briefly the shifts in paradigms and experiments that have generated new perspectives. It has never been very clear what it is that brings together the homologous chromosomes at meiotic prophase. For a while it appeared that the synaptonemal complex might be the nuclear organelle responsible for synapsis, but the supporting evidence has not been entirely convincing. Whatever the mechanism, it has always been assumed that homologous synapsis creates the opportunity for homologous DNA sequences to initiate recombination. At present, alternative ideas are developing. Attractive is the concept that double strand DNA repair mechanisms, that find and use the undamaged homologue for repair, have evolved into a meiotic mechanism for the recognition and pairing of homologous sequences. Subsequent intimate synapsis of homologous chromosomes in the context of the synaptonemal complex may serve later functions in the regulation of interference and segregation at first anaphase. A number of areas that are being tested at present and some that may be investigated in the future are discussed at the end of the review.     

Chemically induced abnormal chromosome behavior at meiosis in maize

Experimental induction of a variety of meiotic abnormalities in maize microsporocytes is described. One class of abnormal chromosome behavior observed is characterized by aberrant centromere-spindle interactions such that the first meiotic division may be equational, the second disjunctional. This abnormality was found following treatment with ethylene oxide-treated cornstarch extracts, ethylene glycol, polyethylene glycols and glyoxal, at synapsed chromosome stages. These is no evidence that crossover frequency was affected in abnormal cells although premature loss of chiasmata may follow such treatment. The results suggest novel approaches to studies of the mechanism of co- and auto-orientation, chiasma maintenence and chromosome functions during synapsis.     

Genetically controlled chromosome breakage and reunions in the meiosis

Three mutants of Pisum sativum showing anomalies in the conjugation phase of meiosis, were investigated cytogenetically. Inspite of apparent normal chromosome pairing there is a strong reduction of chiasma number resulting into univalent formation. Simultaneously, chromosome aberrations appear as consequence of breakage and reunions in the prophase stage. The combined occurrence of these anomalies and their respective quantitative relationships to each other have been explained in the light of breakage-reunion hypothesis through the action of following factors: pairing behaviour, breakage frequency, number of breakages at one locus in the chromatid tetrads, behaviour of breakage ends and effects of environment. Due to the interaction of these factors all the anomalies found in our mutants are explainable.This study was supported by the Euratom I.T.A.L. and the Ministry of Science and Education, BRD. The second author is presently on a post doctoral fellowship of the Humboldt-Foundation.     

Behavior of the chromosome core in mitosis and meiosis

A simple method has been described for the visualization of chromosome cores with light microscopy in conventional chromosome preparations. The technique is relatively simple, highly reproducible and can be used effectively on fresh and aged slides. The following observations have been made: (1) a core existed in mitotic chromosomes in all the materials employed, confirming the findings of Howell and Hsu (1979). (2) The microchromosomes of the chicken and double minutes of a human carcinoma cell line also exhibited the core structure. (3) The core structure of meiotic chromosomes appear weak, disorganized, and disintegrating.     

Emerging roles for centromeres in meiosis I chromosome segregation

Centromeres are an essential and conserved feature of eukaryotic chromosomes, yet recent research indicates that we are just beginning to understand the numerous roles that centromeres have in chromosome segregation. During meiosis I, in particular, centromeres seem to function in many processes in addition to their canonical role in assembling kinetochores, the sites of microtubule attachment. Here we summarize recent advances that place centromeres at the centre of meiosis I, and discuss how these studies affect a variety of basic research fields and thus hold promise for increasing our understanding of human reproductive defects and disease states.     

The cytogenetics of homologous chromosome pairing in meiosis in plants

Three activities hallmark meiotic cell division: homologous chromosome pairing, synapsis, and recombination. Recombination and synapsis are well-studied but homologous pairing still holds many black boxes. In the past several years, many studies in plants have yielded insights into the mechanisms of chromosome pairing interactions. Research in several plant species showed the importance of telomere clustering on the nuclear envelope (telomere bouquet formation) in facilitating alignment of homologous chromosomes. Homologous pairing was also shown to be tied to the early stages of recombination by mutant analyses in Arabidopsis and maize. In contrast, little is known about the mechanisms that guide homolog interaction after their rough alignment by the bouquet and before the close-range recombination-dependent homology search. The relatively large and complex genomes of plants may require additional mechanisms, not needed in small genome eukaryotes, to distinguish between local homology of duplicated genes or transposable elements and global chromosomal homology. Plants provide an excellent large genome model for the study of homologous pairing and dissection of this process.