Pseudogenes populate the mammalian genome as remnants of artefactual incorporation of coding messenger RNAs into transposon pathways 1 . Here we show that a subset of pseudogenes generates endogenous small interfering RNAs (endo-siRNAs) in mouse oocytes. These endo-siRNAs are often processed from double-stranded RNAs formed by hybridization of spliced transcripts from proteincoding genes to antisense transcripts from homologous pseudogenes. An inverted repeat pseudogene can also generate abundant small RNAs directly. A second class of endo-siRNAs may enforce repression of mobile genetic elements, acting together with Piwi-interacting RNAs. Loss of Dicer, a protein integral to small RNA production, increases expression of endo-siRNA targets, demonstrating their regulatory activity. Our findings indicate a function for pseudogenes in regulating gene expression by means of the RNA interference pathway and may, in part, explain the evolutionary pressure to conserve argonaute-mediated catalysis in mammals.Small-RNA-directed gene silencing pathways have been adapted to accept numerous inputs and to act on many types of downstream targets. In few places is this more apparent than in animal germ lines where two classes of small RNAs-microRNAs (miRNAs) and Piwiinteracting RNAs (piRNAs)-with distinct biogenesis mechanisms and biological functions have been reported. Although miRNAs, as a group, are ubiquitously expressed, piRNAs have thus far been found only in germ cells and in a few gonadal somatic cells types 2 . piRNAs repress the activity of mobile genetic elements, forming a small RNA-based, innate immune system with both genetically encoded and adaptive components2 -9.In mice, a homozygous mutation in any single Piwi family member causes male sterility accompanied by gonadal hypotrophy 5 , 10 , 11. In Mili and Miwi2 mutants, meiosis is not completed and germ cells are progressively lost5. This correlates with an activation of transposons, particularly the non-long terminal repeat (LTR) retrotransposon, L1 (refs 5 , 12).
SUMMARY Accurate chromosome segregation during mitosis and meiosis depends on shugoshin proteins that prevent precocious dissociation of cohesin from centromeres. Shugoshins associate with PP2A, which is thought to de-phosphorylate cohesin and thereby prevent cleavage by separase during meiosis I. A crystal structure of a complex between a fragment of human Sgo1 and an AB’C PP2A holoenzyme reveals that Sgo1 forms a homodimeric parallel coiled-coil that docks simultaneously onto PP2A’s C and B’ subunits. Sgo1 homo-dimerization is a pre-requisite for PP2A binding. While hSgo1 interacts only with the AB’C holoenzymes, its relative Sgo2 interacts with all PP2A forms and may thus lead to dephosphorylation of distinct substrates. Mutant shugoshin proteins defective in the binding of PP2A cannot protect centromeric cohesin from separase during meiosis I or support the spindle assembly checkpoint in yeast. Finally, we provide evidence that PP2A’s recruitment to chromosomes may be sufficient to protect cohesin from separase in mammalian oocytes.
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...
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