Paternal microbiome perturbations impact offspring fitness.

The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks1-4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5-9. However, the systemic impact of the gut microbiome on the germline-and consequently on the F1 offspring it gives rise to-is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.

Large Drosophila germline piRNA clusters are evolutionarily labile and dispensable for transposon regulation.

PIWI proteins and their guiding Piwi-interacting small RNAs (piRNAs) are crucial for fertility and transposon defense in the animal germline. In most species, the majority of piRNAs are produced from distinct large genomic loci, called piRNA clusters. It is assumed that germline-expressed piRNA clusters, particularly in Drosophila, act as principal regulators to control transposons dispersed across the genome. Here, using synteny analysis, we show that large clusters are evolutionarily labile, arise at loci characterized by recurrent chromosomal rearrangements, and are mostly species-specific across the Drosophila genus. By engineering chromosomal deletions in D. melanogaster, we demonstrate that the three largest germline clusters, which account for the accumulation of >40% of all transposon-targeting piRNAs in ovaries, are neither required for fertility nor for transposon regulation in trans. We provide further evidence that dispersed elements, rather than the regulatory action of large Drosophila germline clusters in trans, may be central for transposon defense.

Genome Reduction Is Associated with Bacterial Pathogenicity across Different Scales of Temporal and Ecological Divergence.

Emerging bacterial pathogens threaten global health and food security, and so it is important to ask whether these transitions to pathogenicity have any common features. We present a systematic study of the claim that pathogenicity is associated with genome reduction and gene loss. We compare broad-scale patterns across all bacteria, with detailed analyses of Streptococcus suis, an emerging zoonotic pathogen of pigs, which has undergone multiple transitions between disease and carriage forms. We find that pathogenicity is consistently associated with reduced genome size across three scales of divergence (between species within genera, and between and within genetic clusters of S. suis). Although genome reduction is also found in mutualist and commensal bacterial endosymbionts, genome reduction in pathogens cannot be solely attributed to the features of their ecology that they share with these species, that is, host restriction or intracellularity. Moreover, other typical correlates of genome reduction in endosymbionts (reduced metabolic capacity, reduced GC content, and the transient expansion of nonfunctional elements) are not consistently observed in pathogens. Together, our results indicate that genome reduction is a consistent correlate of pathogenicity in bacteria.

The AIP (aryl hydrocarbon receptor-interacting protein) gene and its relation to the pathogenesis of pituitary adenomas.

Pituitary adenomas are monoclonal neoplasms that may secrete excessive quantities of their endogenous hormones, or may not be associated with any obvious syndrome, in which case they are known as non-functioning pituitary adenomas. Around 2 % have been said to occur in a familial setting, in the absence of any other tumor, now described as familial isolated pituitary adenomas (FIPA). Some 15-30 % of such families harbor inactivating germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene, along with 20 % of pediatric seemingly sporadic cases. AIP mutants are referred to as having pituitary adenoma predisposition, and present with early onset, aggressive macroadenomas, most of which secrete somatotropin. Evidence from transfection studies implies that AIP acts as a tumor suppressor; although whether this is mediated through an interaction with the aryl hydrocarbon receptor, phosphodiesterases, or with cell cycle regulators such as survivin or RET remains controversial. However, at present an interaction with the cyclic AMP pathway seems most plausible. Recently, evidence has shown that AIP may act at the cell surface, causing changes in integrin function. The presence of AIP mutations in a significant proportion of FIPA families as well as in apparently sporadic cases, particularly in young patients, suggests a need to screen such patients for AIP mutations to enable better clinical management. However, the absence of AIP mutations in over half of such cases highlights the need to search for further gene mutations.