Genetic sex determination,sex chromosome size and sex-specific lifespans across tetrapods

Sex differences in lifespan are ubiquitous across the tree of life and exhibit broad taxonomic patterns that remain a puzzle, such as males living longer than females in birds and vice versa in mammals. The prevailing unguarded X hypothesis explains sex differences in lifespan by differential expression of recessive mutations on the X or Z chromosome of the heterogametic sex, but has only received indirect support to date. An alternative hypothesis is that the accumulation of deleterious mutations and repetitive elements on the Y or W chromosome might lower the survival of the heterogametic sex (‘toxic Y’ hypothesis). Here, we use a new database to report lower survival of the heterogametic relative to the homogametic sex across 136 species of birds, mammals, reptiles and amphibians, as expected if sex chromosomes shape sex-specific lifespans, and consistent with previous findings. We also found that the relative sizes of both the X and the Y chromosomes in mammals (but not the Z or the W chromosomes in birds) are associated with sex differences in lifespan, as predicted by the unguarded X and the ‘toxic Y’. Furthermore, we report that the relative size of the Y is negatively associated with male lifespan in mammals, so that small Y size correlates with increased male lifespan. In theory, toxic Y effects are expected to be particularly strong in mammals, and we did not find similar effects in birds. Our results confirm the role of sex chromosomes in explaining sex differences in lifespan across tetrapods and further suggest that, at least in mammals, ‘toxic Y’ effects may play an important part in this role.     

Exome Sequencing Identifies Rare Deleterious Mutations in DNA Repair Genes FANCC and BLM as Potential Breast Cancer Susceptibility Alleles

Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.     

(4-Piperidinylphenyl)aminoethyl amides as a novel class of non-covalent cathepsin K inhibitors

A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays.     

Variations in the behaviors to novel objects among five inbred strains of mice

Novelty stimuli cause various behavioral responses, such as exploration and avoidance, and contextual variables may contribute to the behavioral outputs. Here, we tried to compare the behavioral responses to novel objects of five inbred strains of mice (C57BL/6J, 129/svJae, C3H/HeJ, BALB/cJ and DBA/2J) by using a modified novel object test where a small light-weight cube wrapped with paper was presented to mice in a home cage without beddings. In response to these objects, the C57BL/6J, 129/svJae and C3H/HeJ mice showed mild exploratory behaviors, such as approaching, sniffing or brief contact. In striking contrast, the BALB/cJ and DBA/2J mice, which have been known to show high avoidance/low exploration in other behavioral paradigms, exhibited play-like secondary reactions toward the objects after initial primary exploratory behaviors. Specifically, DBA/2J mice would move the object around in the cage, holding it with their mouths, and BALB/cJ mice would gnaw the object, eventually stripping off the wrapping paper. Such behaviors decreased when similar objects were presented repeatedly. The present results suggest that active manipulations of novel objects may be a relevant parameter for measuring novelty-induced behaviors in mice and appear to be strongly influenced by genetic factors.     

Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1

Mutations in Cu/Zn superoxide dismutase (SOD1) are linked to motor neuron death in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism, although misfolded SOD1 aggregates are commonly associated with disease. Proteomic analysis of the transgenic SOD1(G93A) ALS rat model revealed significant up-regulation of endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI) family members in lumbar spinal cords. Expression of SOD1 mutants (mSOD1) led to an up-regulation of PDI in motor neuron-like NSC-34 cells but not other cell lines. Inhibition of PDI using bacitracin increased aggregate production, even in wild type SOD1 transfectants that do not readily form inclusions, suggesting PDI may protect SOD1 from aggregation. Moreover, PDI co-localized with intracellular aggregates of mSOD1 and bound to both wild type and mSOD1. SOD1 was also found in the microsomal fraction of cells despite being a predominantly cytosolic enzyme, confirming ER-Golgi-dependent secretion. In SOD1(G93A) mice, a significant up-regulation of unfolded protein response entities was also observed during disease, including caspase-12, -9, and -3 cleavage. Our findings therefore implicate unfolded protein response and ER stress-induced apoptosis in the patho-physiology of familial ALS. The possibility that PDI may be a therapeutic target to prevent SOD1 aggregation is also raised by this study.     

High-resolution habitat and bathymetry maps for 65,000 sq. km of Earth’s remotest coral reefs

Coral Reefs - With compelling evidence that half the world’s coral reefs have been lost over the last four decades, there is urgent motivation to understand where reefs are located and their...