Project description:Chromosome errors, or aneuploidy, affect an exceptionally high number of human conceptions, causing pregnancy loss and congenital disorders. Here, we have followed chromosome segregation in human oocytes from females aged 9 to 43 years and report that aneuploidy follows a U-curve. Specific segregation error types show different age dependencies, providing a quantitative explanation for the U-curve. Whole-chromosome nondisjunction events are preferentially associated with increased aneuploidy in young girls, whereas centromeric and more extensive cohesion loss limit fertility as women age. Our findings suggest that chromosomal errors originating in oocytes determine the curve of natural fertility in humans.
Project description:An increase in the incidence of aneuploidy is well documented with increasing maternal age, in particular in human females. Remarkably, little is known regarding the underlying molecular basis for the age-associated increase in aneuploidy, which is a major source of decreased fertility in humans. Using mouse as a model system we find that eggs obtained from old mice (60-70 weeks of age) display a 6-fold increase in the incidence of hyperploidy as assessed by chromosome spreads. Expression profiling of transcripts in oocytes and eggs obtained from young and old mice reveals that approximately 5% of the transcripts are differentially expressed in oocytes obtained from old females when compared to oocytes obtained from young females (6-12 weeks of age) and that this fraction increases to approximately 33% in eggs. The latter finding indicates that the normal pattern of degradation of maternal mRNAs that occurs during oocyte maturation is dramatically altered in eggs obtained from old mice and could therefore be a contributing source to the decline in fertility. Analysis of the differentially expressed transcripts also indicated that the strength of the spindle assembly checkpoint is weakened and that higher errors of microtubule-kinetochore interactions constitute part of molecular basis for the age-associated increase in aneuploidy in females. Last, BRCA1 expression is reduced in oocytes obtained from old females and RNAi-mediated reduction of BRCA1 in oocytes obtained from young females results in perturbing spindle formation and chromosome congression following maturation
Project description:Four separate biological collections of unfertilized eggs laid by wildtype females mated with sterile males, eggs dechorionated and snap-forzen in liquid nitrogen 0-1 hour after egg lay. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
Project description:An increase in the incidence of aneuploidy is well documented with increasing maternal age, in particular in human females. Remarkably, little is known regarding the underlying molecular basis for the age-associated increase in aneuploidy, which is a major source of decreased fertility in humans. Using mouse as a model system we find that eggs obtained from old mice (60-70 weeks of age) display a 6-fold increase in the incidence of hyperploidy as assessed by chromosome spreads. Expression profiling of transcripts in oocytes and eggs obtained from young and old mice reveals that approximately 5% of the transcripts are differentially expressed in oocytes obtained from old females when compared to oocytes obtained from young females (6-12 weeks of age) and that this fraction increases to approximately 33% in eggs. The latter finding indicates that the normal pattern of degradation of maternal mRNAs that occurs during oocyte maturation is dramatically altered in eggs obtained from old mice and could therefore be a contributing source to the decline in fertility. Analysis of the differentially expressed transcripts also indicated that the strength of the spindle assembly checkpoint is weakened and that higher errors of microtubule-kinetochore interactions constitute part of molecular basis for the age-associated increase in aneuploidy in females. Last, BRCA1 expression is reduced in oocytes obtained from old females and RNAi-mediated reduction of BRCA1 in oocytes obtained from young females results in perturbing spindle formation and chromosome congression following maturation Experiment Overall Design: We profiled the global gene expression in GV & MII oocyte by maternal aging, and identified the genes differentially expressed.
Project description:Fertile pollen is critical for the survival, fitness and dispersal of flowering plants, and directly contributes to crop productivity. Extensive mutational screening studies have been carried out to dissect the genetic regulatory network determining pollen fertility, but we still lack fundamental knowledge about whether and how pollen fertility is controlled in natural populations. We used a genome-wide association study (GWAS) to show that ZmGEN1A and ZmMSH7, two DNA repair-related genes, confer natural variation in maize pollen fertility. Mutants defective in both genes exhibited abnormalities in meiotic or post-meiotic DNA repair, leading to reduced pollen fertility. More importantly, ZmMSH7 underwent selection during maize domestication, and its disruption resulted in a substantial increase in grain yield and protein content for both inbred and hybrid. Overall, our study describes the first systematic examination of natural genetic effects on pollen fertility in plants, providing valuable genetic resources for optimizing male fertility. Moreover, ZmMSH7 may be a potential candidate for simultaneous improvement of grain yield and quality.
Project description:Aneuploidy, an imbalance in chromosome copy numbers, causes genetic disorders, and drives cancer progression, drug tolerance, and antimicrobial resistance. While aneuploidy can confer stress resistance, it is not well understood how cells overcome the fitness burden caused by aberrant chromosomal copy numbers. Studies using both systematically generated and natural aneuploid yeasts triggered an intense debate about the role of dosage compensation, concluding that aneuploidy is transmitted to the transcriptome and proteome without significant buffering at the chromosome-wide level, and is, at least in lab strains, associated with significant fitness costs. Conversely, systematic sequencing and phenotyping of large collections of natural isolates revealed that aneuploidy is frequent and has few, if any, fitness costs in nature. To address these discrepant findings, we developed a platform that yields highly precise proteomic measurements across large numbers of genetically diverse samples and applied it to natural isolates collected as part of the 1011 genomes project (Peter, J. et al, 2018). For 613 of the isolates, we were able to match the proteomes to their corresponding transcriptomes and genomes, subsequently quantifying the effect of aneuploidy on gene expression by comparing 95 aneuploid with 518 euploid strains. We find, as in previous studies, that aneuploid gene dosage is not buffered chromosome-wide at the transcriptome level. Importantly, in the proteome, we detect an attenuation of aneuploidy by about 25% below the aneuploid gene dosage in natural yeast isolates. Furthermore, this chromosome-wide dosage compensation is associated with the ubiquitin-proteasome system (UPS), which is expressed at higher levels and has increased activity across natural aneuploid strains. Thus, through systematic exploration of the species-wide diversity of the yeast proteome, we shed light on a long-standing debate about the biology of aneuploids, revealing that aneuploidy tolerance is mediated through chromosome-wide dosage compensation at the proteome level.
Project description:Four separate biological collections of unfertilized eggs laid by wildtype females mated with sterile males, eggs dechorionated and snap-forzen in liquid nitrogen 0-1 hour after egg lay. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed