Mouse X-linked microRNA cluster regulates meiotic checkpoint and Prdm9-driven hybrid sterility in a copy number-dependent manner

One of the reproductive barriers between diverging populations during formation of a new species is the sterility of their hybrids. The Prdm9-driven hybrid male sterility of Mus musculus musculus × Mus musculus domesticus hybrids depends on the interaction between PRDM9, a histone methyltransferase that determines the positions of meiotic recombination hotspots, and an as yet unknown X-linked genetic factor within the Hybrid sterility X2 (Hstx2) locus. Here, we report that the Mir465 microRNA (miRNA) gene cluster is the predicted Hstx2 hybrid sterility factor. We show that removal of the Mir465 genes restores the fertility of sterile hybrids and improves meiotic synapsis of homologous chromosomes. Mir465 knockout also restores spermatogenesis in sterile chromosomal translocation carriers, demonstrating that Mir465 acts as a meiotic checkpoint that can be activated independently of Prdm9 intersubspecific incompatibility. Furthermore, the Mir465 knockout increases the global recombination rate in hybrids and in parental Mus m. domesticus mice. This demonstrates that Mir465 is responsible for the phenotypes of the two overlapping genetic loci, the Hstx2 engaged in fertility of hybrids and the Meiotic recombination 1 (Meir1) controlling the recombination rate. The finding of enlarged Mir465 clusters in all European Mus m. musculus samples tested and the identification of differentially expressed targets suggest that the reproductive barrier between the two subspecies is sensitive to copy number variation of Mir465 genes. Together, the underdominant interaction between Prdm9 and Mir465 provides a rare example of Dobzhansky–Muller incompatibility in hybrids of closely related species, making it accessible for further analysis at the molecular level

The propeptide of yeast cathepsin D inhibits programmed necrosis

The lysosomal endoprotease cathepsin D (CatD) is an essential player in general protein turnover and specific peptide processing. CatD-deficiency is associated with neurodegenerative diseases, whereas elevated CatD levels correlate with tumor malignancy and cancer cell survival. Here, we show that the CatD ortholog of the budding yeast Saccharomyces cerevisiae (Pep4p) harbors a dual cytoprotective function, composed of an anti-apoptotic part, conferred by its proteolytic capacity, and an anti-necrotic part, which resides in the protein's proteolytically inactive propeptide. Thus, deletion of PEP4 resulted in both apoptotic and necrotic cell death during chronological aging. Conversely, prolonged overexpression of Pep4p extended chronological lifespan specifically through the protein's anti-necrotic function. This function, which triggered histone hypoacetylation, was dependent on polyamine biosynthesis and was exerted via enhanced intracellular levels of putrescine, spermidine and its precursor S-adenosyl-methionine. Altogether, these data discriminate two pro-survival functions of yeast CatD and provide first insight into the physiological regulation of programmed necrosis in yeast

Статистичне виведення для багаторазово цензурованої зліва вибірки типу i для розподілу Вейбулла

Left-censored data with one or more detection limits occur frequently in many application areas. In this paper, the computational procedure for calculation of maximum likelihood estimates of the parameters for type I multiply left-censored data from underlying Weibull distribution is suggested and used considering various numbers of detection limits. The expected Fisher information matrix is analytically determined and its performance is compared with sample (observed) Fisher information matrix using simulations. Simulations are focused primarily on the properties of estimators for small sample sizes. Real data illustration is included.Во многих областях науки часто встречаются задачи с цензурированными слева данными с одной или несколькими границами обнаружения. В данной работе предложена процедура для вычисления оценок максимальной правдоподобности параметров многократного цензурирования слева типа I для распределения Вейбулла с учетом разного числа границ обнаружения. Ожидаемая информационная матрица Фишера определена аналитически и ее вид сравнен с выборочной (наблюдаемой) информационной матрицей Фишера. Моделирование основано, главным образом, на свойствах оценок выборок малых размеров. Примеры проиллюстрированы на реальных данных.У багатьох галузях науки часто зустрічаються задачі з цензурованими зліва даними з однією або кількома межами виявлення. У цій роботі запропоновано процедуру для обчислення оцінок максимальної правдоподібності параметрів багаторазового цензурування зліва типу I з розподілу Вейбулла з урахуванням різної кількості меж виявлення. Очікувану інформаційну матрицю Фішера визначено аналітично та її вигляд порівняно з вибірковою (спостережуваною) інформаційною матрицею Фішера. Моделювання здебільшого ґрунтується на властивостях оцінок вибірок малих розмірів. Приклади проілюстровано на реальних даних