Publications search

It is extremely expensive to conduct large sample size array- or sequencing based genome scale association studies. For a quantitative trait, an extreme case-control study design may improve the power and reduce the cost of variant calling. We investigated the performance of extreme study design when various proportions of samples are selected from the tails of phenotype distribution. Using simulations, we show that when risk genotypes become rare in the population and effect size is relatively small, it is beneficial to carry out an extreme sampling study. In particular, the number of selected cases and controls can even be unbalanced such that power is further increased, compared with a balanced selection. Our application to two data sets: methadone dose data and yearling weight data, demonstrated that similar results for full data analysis can be obtained using extreme sampling with only a fraction of the data. Using power analysis with simulated data and an experimental data application, we conclude that when full data is unavailable due to restricted budget, it is rewarding to employ an extreme sampling design in the sense that there can be immense cost reductions and qualitatively similar power as in the full data analysis.

Introduction Mass spectrometric data analysis of complex biological

A lysine-to-methionine mutation at lysine 27 of histone 3 (H3K27M) has been shown to promote oncogenesis in a subset of pediatric gliomas. While there is evidence that this "oncohistone" mutation acts by inhibiting the histone methyltransferase PRC2, the details of this proposed mechanism nevertheless continue to be debated. Recent evidence suggests that PRC2 must simultaneously bind both H3K27M and H3K27me3 to experience competitive inhibition of its methyltransferase activity. In this work, we used PRC2 inhibitor treatments in a transgenic H3K27M cell line to validate this dependence in a cellular context. We further used designer chromatin inhibitors to probe the geometric constraints of PRC2 engagement of H3K27M and H3K27me3 in a biochemical setting. We found that PRC2 binds to a bivalent inhibitor unit consisting of an H3K27M and an H3K27me3 nucleosome and exhibits a distance dependence in its affinity for such an inhibitor, which favors closer proximity of the 2 nucleosomes within a chromatin array. Together, our data precisely delineate fundamental aspects of the H3K27M inhibitor and support a model wherein PRC2 becomes trapped at H3K27M-H3K27me3 boundaries.

Glutamate amidation, a secondary modification of the peptidoglycan, was

Human anti-HIV-1 broadly neutralizing antibodies (bNAbs) protect against

As the capacity to isolate distinct neuronal cell types has advanced over the past several decades, new two- and three-dimensional in vitro models of the interactions between different brain regions have expanded our understanding of human neurobiology and the origins of disease. These cultures develop distinctive patterns of activity, but the extent that these patterns are determined by the molecular identity of individual cell types versus the specific pattern of network connectivity is unclear. To address the question of how individual cell types interact in vitro, we developed a simplified culture using two excitatory neuronal subtypes known to participate in the in vivo reticulospinal circuit: HB9(+) spinal motor neurons and Chx10(+) hindbrain V2a neurons. Here, we report the emergence of cell type-specific patterns of activity in culture; on their own, Chx10(+) neurons developed regular, synchronized bursts of activity that recruited neurons across the entire culture, whereas HB9(+) neuron activity consisted of an irregular pattern. When these two subtypes were cocultured, HB9(+) neurons developed synchronized network bursts that were precisely correlated with Chx10(+) neuron activity, thereby recreating an aspect of Chx10(+) neurons' role in driving motor activity. These bursts were dependent on AMPA receptors. Our results demonstrate that the molecular classification of the neurons comprising in vitro networks is a crucial determinant of their activity. It is therefore possible to improve both the reproducibility and the applicability of in vitro neurobiological and disease models by carefully controlling the constituent mixtures of neuronal subtypes.

Pumas are the most widely distributed felid in the Western Hemisphere. Increasingly, however, human persecution and habitat loss are isolating puma populations. To explore the genomic consequences of this isolation, we assemble a draft puma genome and a geographically broad panel of resequenced individuals. We estimate that the lineage leading to present-day North American pumas diverged from South American lineages 300-100 thousand years ago. We find signatures of close inbreeding in geographically isolated North American populations, but also that tracts of homozygosity are rarely shared among these populations, suggesting that assisted gene flow would restore local genetic diversity. The genome of a Florida panther descended from translocated Central American individuals has long tracts of homozygosity despite recent outbreeding. This suggests that while translocations may introduce diversity, sustaining diversity in small and isolated populations will require either repeated translocations or restoration of landscape connectivity. Our approach provides a framework for genome-wide analyses that can be applied to the management of similarly small and isolated populations.

Allostatic load reflects the cumulative effects of stressful experiences

Zika virus (ZIKV) infection during pregnancy causes congenital