According to the Dobzhansky-Muller model, hybrid sterility is a consequence of the independent evolution of related taxa resulting in incompatible genomic interactions of their hybrids. The model implies that the incompatibilities evolve randomly, unless a particular gene or nongenic sequence diverges much faster than the rest of the genome. Here we propose that asynapsis of heterospecific chromosomes in meiotic prophase provides a recurrently evolving trigger for the meiotic arrest of interspecific F1 hybrids. We observed extensive asynapsis of chromosomes and disturbance of the sex body in >95% of pachynemas of Mus m. musculus × Mus m. domesticus sterile F1 males. Asynapsis was not preceded by a failure of double-strand break induction, and the rate of meiotic crossing over was not affected in synapsed chromosomes. DNA double-strand break repair was delayed or failed in unsynapsed autosomes, and misexpression of chromosome X and chromosome Y genes was detected in single pachynemas and by genome-wide expression profiling. Oocytes of F1 hybrid females showed the same kind of synaptic problems but with the incidence reduced to half. Most of the oocytes with pachytene asynapsis were eliminated before birth. We propose the heterospecific pairing of homologous chromosomes as a preexisting condition of asynapsis in interspecific hybrids. The asynapsis may represent a universal mechanistic basis of F1 hybrid sterility manifested by pachytene arrest. It is tempting to speculate that a fast-evolving subset of the noncoding genomic sequence important for chromosome pairing and synapsis may be the culprit. meiosis | meiotic sex chromosome inactivation | Prdm9 | chromosome substitution strains | Haldane's rule H ybrid sterility (HS) is a postzygotic reproductive isolation mechanism contributing to the genesis of new species. It occurs when two parental forms, each which is fertile, produce a sterile hybrid. The widespread occurrence of HS in animal and plant species puzzled evolutionary biologists until Theodosius Dobzhansky and later Herman Muller devised a two-gene model now termed "Dobzhansky-Muller (D-M) incompatibility" (1, 2). The model postulates functional incompatibility of a minimum of two interacting genes that, after independent evolution in two related taxa, lose their ability to cooperate when combined in a hybrid (3, 4). HS almost invariably obeys the Haldane's rule of preferential impairment of the heterogametic (XY or ZW) sex (5); hence male sterility occurs predominantly in mammalian or Drosophila hybrids, whereas in birds and Lepidoptera female hybrids are most often affected (5, 6). HS is under the control of multiple genes, a disproportionally large number of which are located on the X chromosome (7,8). The development of methods of molecular genetics renewed interest in HS (4), and, as a result, OdsH, Ovd, and JYalpha HS genes defined by their DNA sequence were identified in Drosophila (9-11). We identified Prdm9 as a vertebrate HS gene in mouse intersubspecific hybrids (12, 13). Although generalizati...

Chromosome segregation errors are highly frequent in mammalian female meiosis, and their incidence gradually increases with maternal age. The fate of aneuploid eggs is obviously dependent on the stringency of mechanisms for detecting unattached or repairing incorrectly attached kinetochores. In case of their failure, the newly formed embryo will inherit the impaired set of chromosomes, which will have severe consequences for its further development. Whether spindle assembly checkpoint (SAC) in oocytes is capable of arresting cell cycle progression in response to unaligned kinetochores was discussed for a long time. It is known that abolishing SAC increases frequency of chromosome segregation errors and causes precocious entry into anaphase; SAC, therefore, seems to be essential for normal chromosome segregation in meiosis I. However, it was also reported that for anaphase-promoting complex (APC) activation, which is a prerequisite for entering anaphase; alignment of only a critical mass of kinetochores on equatorial plane is sufficient. This indicates that the function of SAC and of cooperating chromosome attachment correction mechanisms in oocytes is different from somatic cells. To analyze this phenomenon, we used live cell confocal microscopy to monitor chromosome movements, spindle formation, APC activation and polar body extrusion (PBE) simultaneously in individual oocytes at various time points during first meiotic division. Our results, using oocytes from aged animals and interspecific crosses, demonstrate that multiple unaligned kinetochores and severe congression defects are tolerated at the metaphase to anaphase transition, although such cells retain sensitivity to nocodazole. This indicates that checkpoint mechanisms, operating in oocytes at this point, are essential for accurate timing of APC activation in meiosis I, but they are insufficient in detection or correction of unaligned chromosomes, preparing thus conditions for propagation of the aneuploidy to the embryo.

Although a positive correlation between aneuploidy and maternal age was first reported almost a century ago, the underlying mechanisms remain mostly unknown. Different hypotheses regarding age-related aneuploidy rise have been presented, but so far none of them can explain its full mechanism. Age-related aneuploidy is more likely to result from complex events taking place during the entire period of germ cell development, than from the failure of one particular mechanism. Recent findings confirm that the spindle assembly checkpoint (SAC) does not control and correct kinetochore-microtubule attachments in oocytes, enabling further propagation of aneuploidy, which has occurred in the earlier phases of oogenesis. In this review we will discuss the following hypotheses: the "limited oocyte pool" hypothesis, the "two hits" hypothesis, weakened centromeric cohesion and cohesin loss, different functions of the spindle assembly checkpoint and finally, changes in global gene expression.