Bayesian modeling of skewed X inactivation in genetically diverse mice identifies a novel Xce allele associated with copy number changes

Female mammals are functional mosaics of their parental X-linked gene expression due to X chromosome inactivation (XCI). This process inactivates one copy of the X chromosome in each cell during embryogenesis and that state is maintained clonally through mitosis. In mice, the choice of which parental X chromosome remains active is determined by the X chromosome controlling element (Xce), which has been mapped to a 176-kb candidate interval. A series of functional Xce alleles has been characterized or inferred for classical inbred strains based on biased, or skewed, inactivation of the parental X chromosomes in crosses between strains. To further explore the function structure basis and location of the Xce, we measured allele-specific expression of X-linked genes in a large population of F1 females generated from Collaborative Cross (CC) strains. Using published sequence data and applying a Bayesian “Pólya urn” model of XCI skew, we report two major findings. First, inter-individual variability in XCI suggests mouse epiblasts contain on average 20–30 cells contributing to brain. Second, CC founder strain NOD/ShiLtJ has a novel and unique functional allele, Xce^g, that is the weakest in the Xce allelic series. Despite phylogenetic analysis confirming that NOD/ShiLtJ carries a haplotype almost identical to the well-characterized C57BL/6J (Xce^b), we observed unexpected patterns of XCI skewing in females carrying the NOD/ShiLtJ haplotype within the Xce. Copy number variation is common at the Xce locus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weak Xce alleles.     

Ecological and geological processes impacting speciation modes drive the formation of wide-range disjunctions within tribe Putorieae (Rubiaceae)

Wide-range geographically discontinuous distributions have long intrigued scientists. We explore the role of ecology, geology, and dispersal in the formation of these large-scale disjunctions, using the angiosperm tribe Putorieae (Rubiaceae) as a case study. From DNA sequences of nuclear ITS and six plastid markers, we inferred a phylogeny with 65% of all known Putorieae species. Divergence times, ancestral ranges, and diversification rate shifts were then estimated using Bayesian inference. We further explored species climatic tolerances and performed ancestral niche reconstruction to discriminate among alternative speciation modes, including geographical and ecological vicariance, and ecogeographical, ecological, and dispersal-mediated speciation. As a result, we identified seven major clades in Putorieae, some of which exhibit striking geographical disjunctions, matching the Rand Flora pattern, with sister species in the Canary Islands andeastern and southern Africa. Initial diversification within the tribe occurred in the early Miocene, coincident with a period of climate warming; however, most clades diverged within the last 10 Myr. Aridification and high extinction rates, coupled with ecological vicariance, explain the oldest disjunctions. Adaptation to new environmental conditions, after allopatry, is observed in several clades. Dispersal, either long-distance or via corridors made available by mountain uplift, is behind the most recent disjunctions. Some of these events were followed by ecological speciation and rapid diversification, with species becoming adapted to xeric or increasingly colder continental climates. We show that an integrative approach may help discriminate among speciation modes invoked to explain disjunctions at macroevolutionary time scales, even when extinction has erased the signature of past events.     

Childhood rare diseases and the UN convention on the rights of the child

Purpose

The aim of this case control study was to evaluate the prognostic value of automatically quantified retinal vessel tortuosity from fundus images and vessel density from OCT-A in Fabry disease and to evaluate the correlation of these with systemic disease parameters.

Methods

Automatically quantified perimacular retinal vessel tortuosity (MONA REVA software), acquired by fundus imaging, and perifoveal retinal vessel density, acquired by optic coherence tomography angiography (OCT-A) were compared between 26 FD patients and 26 controls. Gender and FD phenotype were analyzed to the obtained retinovascular data and correlated to the Mainz severity score index (MSSI) and plasma lyso-Gb3.

Results

Automatically quantified retinal vessel tortuosity indices of FD patients were significantly lower, reflecting an increased vessel tortuosity, compared to controls (p = 0.008). Males with a classical phenotype showed significantly lower retinal vessel tortuosity indices compared to males with an oligosymptomatic phenotype and females with a classical or oligosymptomatic phenotype (p < 0.001). The retinal vessel tortuosity index correlated significantly with systemic disease severity parameters [global MSSI (r = − 0.5; p < 0.01), cardiovascular MSSI (r = − 0.5; p < 0.01), lyso-Gb3 (r = − 0.6; p < 0.01)].

Conclusion

We advocate fundus imaging based automatically quantified retinal vessel tortuosity index over OCT-A imaging as it is a quick, non-invasive, easily assessable, objective and reproducible marker.

     

Senescence‐associated β‐galactosidase reveals the abundance of senescent CD8+ T cells in aging humans

Aging leads to a progressive functional decline of the immune system, rendering the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this decline remains unclear, however, since markers that label immune cells with classical features of cellular senescence accurately and comprehensively have not been identified. Using a second‐generation fluorogenic substrate for β‐galactosidase and multi‐parameter flow cytometry, we demonstrate here that peripheral blood mononuclear cells (PBMCs) isolated from healthy humans increasingly display cells with high senescence‐associated β‐galactosidase (SA‐βGal) activity with advancing donor age. The greatest age‐associated increases were observed in CD8+ T‐cell populations, in which the fraction of cells with high SA‐βGal activity reached average levels of 64% in donors in their 60s. CD8+ T cells with high SA‐βGal activity, but not those with low SA‐βGal activity, were found to exhibit features of telomere dysfunction‐induced senescence and p16‐mediated senescence, were impaired in their ability to proliferate, developed in various T‐cell differentiation states, and had a gene expression signature consistent with the senescence state previously observed in human fibroblasts. Based on these results, we propose that senescent CD8+ T cells with classical features of cellular senescence accumulate to levels that are significantly higher than previously reported and additionally provide a simple yet robust method for the isolation and characterization of senescent CD8+ T cells with predictive potential for biological age.