Nutrient stores predict task behaviors in diverse ant species

In eusocial species, including ants and honeybees, sterile or non-reproductive workers can specialize in task-specific behaviors, such as brood care and foraging for food. The mechanisms underlying task-specific behaviors include genetic, physiological and environmental factors. Here we compare corporeal nutrient storage in nine species that differ in primary food preferences (carbohydrate-, protein- or lipid-based diet) to test whether foraging behavior is associated with lower individual nutrient stores. We also investigate whether low nutrient stores are limited to foragers or occur in other external, morphologically distinct, worker sub-castes. In six out of eight species where both brood care workers and foragers were sampled, foragers had significantly lower nutrient stores relative to brood care workers; the exceptions were two Solenopsis species. Foragers from five of these six species had lower lipid levels, supporting the link between lipid content and foraging behaviors reported in previous studies. Interestingly, three species had lower levels of both lipid and carbohydrate stores in foragers relative to brood care workers, and foragers of one species, Formica fusca, had lower carbohydrate levels but not lipid levels, suggesting that the association between nutrient stores and foraging behavior is not universal across ant species or across all seasons. In all three species with morphologically distinct sub-castes, lipid levels were lowest in non-foraging, external workers, i.e., majors or soldiers, indicating an additional link between nutrient depletion and the allocation of external tasks other than foraging

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

Aneuploidy, an imbalanced karyotype, is a widely observed feature of cancer cells that has long been hypothesized to promote tumorigenesis. Here we evaluate the fitness of cells with constitutional trisomy or chromosomal instability (CIN) in vivo using hematopoietic reconstitution experiments. We did not observe cancer but instead found that aneuploid hematopoietic stem cells (HSCs) exhibit decreased fitness. This reduced fitness is due at least in part to the decreased proliferative potential of aneuploid hematopoietic cells. Analyses of mice with CIN caused by a hypomorphic mutation in the gene Bub1b further support the finding that aneuploidy impairs cell proliferation in vivo. Whereas nonregenerating adult tissues are highly aneuploid in these mice, HSCs and other regenerative adult tissues are largely euploid. These findings indicate that, in vivo, mechanisms exist to select against aneuploid cells.National Institutes of Health (U.S.) (CA206157)Kathy and Curt Marble Cancer Research FundDavid H. Koch Institute for Integrative Cancer Research at MIT (Support Grant P30-CA14051)National Institute of General Medical Sciences (U.S.) (Training Grant T32GM007753

Defining the role of aneuploidy throughout tumorigenesis

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February, 2021Cataloged from the official PDF of thesis.Includes bibliographical references.Aneuploidy is a state of genome imbalance which alters the copy number of whole chromosomes. While aneuploidy is rare in healthy tissues, it is one of the most common features of cancerous tumors. Studies of aneuploid yeast and aneuploid mammalian cells growing in culture revealed that aneuploidy induces cellular stress and slows proliferation. So it is surprising that aneuploidy is a hallmark of cancer, a disease of cellular over-proliferation and inappropriate cell survival. We sought to elucidate aneuploidy's role in tumorigenesis by defining the factors that affect the prevalence of aneuploid cells in normal, pre-cancerous, and cancerous tissues. First, we investigated whether aneuploid mammalian cells experience fitness defects in vivo. We found that aneuploidy decreases hematopoietic stem cells' fitness and that aneuploid cells are selected against in normal, regenerating tissues in vivo.However, we also found that aneuploid cells can accumulate in the hematopoietic system when purifying selection is relaxed following bone marrow reconstitution. We then sought to extend our observations to the context of pre-cancerous tissues. We analyzed the prevalence of aneuploidy in the highly tumorigenic, but histologically normal tissues of women harboring heterozygous germline BRCA2 mutations. Using single-cell sequencing, we revealed that breast cells from BRCA2 mutation carriers lack aneuploidy but feature a distinct form of genome imbalance called sub-chromosomal copy number variants (CNVs), even before the initiation of tumorigenesis. We then analyzed the timing with which these two forms of genome imbalance--whole-chromosomal aneuploidy and sub-chromosomal CNVs--arise during tumorigenesis. We found that CNVs are present in the cells of early precursors of multiple cancers, but that whole-chromosomal aneuploidy arises late in tumorigenesis.Our findings propose that whole-chromosomal aneuploidy reduces cells' fitness in both normal and pre-cancerous tissues, and that aneuploidy is selected against throughout tumorigenesis. This has implications for the role of aneuploidy in cancer, suggesting that aneuploidy does not contribute to early tumorigenesis.by Rebecca Estelle Silberman.Ph. D.Ph.D. Massachusetts Institute of Technology, Department of Biolog

Mechanisms for curing yeast prions

Prions are infectious proteins that self-propagate by changing from their normal folded conformation to a misfolded conformation. The misfolded conformation, which is typically rich in β-sheet, serves as a template to convert the prion protein into its misfolded conformation. In yeast, the misfolded prion proteins are assembled into amyloid fibers or seeds, which are constantly severed and transmitted to daughter cells. To cure prions in yeast, it is necessary to eliminate all the prion seeds. Multiple mechanisms of curing have been found including inhibiting severing of the prion seeds, gradual dissolution of the prion seeds, asymmetric segregation of the prion seeds between mother and daughter cells during cell division, and degradation of the prion seeds. These mechanisms, achieved by using different protein quality control machinery, are not mutually exclusive; depending on conditions, multiple mechanisms may work simultaneously to achieve curing. This review discusses the various methods that have been used to differentiate between these mechanisms of curing.Intramural Program of the National Heart Lung Blood Institute of the National Institutes of Health (1ZIAHL000516

Aneuploidy Causes Non-genetic Individuality

Phenotypic variability is a hallmark of diseases involving chromosome gains and losses, such as Down syndrome and cancer. Allelic variances have been thought to be the sole cause of this heterogeneity. Here, we systematically examine the consequences of gaining and losing single or multiple chromosomes to show that the aneuploid state causes non-genetic phenotypic variability. Yeast cell populations harboring the same defined aneuploidy exhibit heterogeneity in cell-cycle progression and response to environmental perturbations. Variability increases with degree of aneuploidy and is partly due to gene copy number imbalances, suggesting that subtle changes in gene expression impact the robustness of biological networks and cause alternate behaviors when they occur across many genes. As inbred trisomic mice also exhibit variable phenotypes, we further propose that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuploidy. Keywords: aneuploidy; non-genetic heterogeneity; cell-to-cell variability; gene dosage effects; biological noise; Down syndrome; cancerNational Institutes of Health (U.S.) (Grant CA206157)National Institutes of Health (U.S.) (Grant GM118066)National Science Foundation (U.S.) (Grant DGE1122374