Human nutrition, the gut microbiome and the immune system

Marked changes in socio-economic status, cultural traditions, population growth and agriculture are affecting diets worldwide. Understanding how our diet and nutritional status influence the composition and dynamic operations of our gut microbial communities, and the innate and adaptive arms of our immune system, represents an area of scientific need, opportunity and challenge. The insights gleaned should help to address several pressing global health problems.     

WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature

Macrophages have a critical role in inflammatory and immune responses through their ability to recognize and engulf apoptotic cells. Here we show that macrophages initiate a cell-death programme in target cells by activating the canonical WNT pathway. We show in mice that macrophage WNT7b is a short-range paracrine signal required for WNT-pathway responses and programmed cell death in the vascular endothelial cells of the temporary hyaloid vessels of the developing eye. These findings indicate that macrophages can use WNT ligands to influence cell-fate decisions--including cell death--in adjacent cells, and raise the possibility that they do so in many different cellular contexts.     

A phosphatase complex that dephosphorylates gammaH2AX regulates DNA damage checkpoint recovery

One of the earliest marks of a double-strand break (DSB) in eukaryotes is serine phosphorylation of the histone variant H2AX at the carboxy-terminal SQE motif to create gammaH2AX-containing nucleosomes. Budding-yeast histone H2A is phosphorylated in a similar manner by the checkpoint kinases Tel1 and Mec1 (ref. 2; orthologous to mammalian ATM and ATR, respectively) over a 50-kilobase region surrounding the DSB. This modification is important for recruiting numerous DSB-recognition and repair factors to the break site, including DNA damage checkpoint proteins, chromatin remodellers and cohesins. Multiple mechanisms for eliminating gammaH2AX as DNA repair completes are possible, including removal by histone exchange followed potentially by degradation, or, alternatively, dephosphorylation. Here we describe a three-protein complex (HTP-C, for histone H2A phosphatase complex) containing the phosphatase Pph3 that regulates the phosphorylation status of gammaH2AX in vivo and efficiently dephosphorylates gammaH2AX in vitro. gammaH2AX is lost from chromatin surrounding a DSB independently of the HTP-C, indicating that the phosphatase targets gammaH2AX after its displacement from DNA. The dephosphorylation of gammaH2AX by the HTP-C is necessary for efficient recovery from the DNA damage checkpoint.     

Genome-wide detection and characterization of positive selection in human populations

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.     

Melt-induced speed-up of Greenland ice sheet offset by efficient subglacial drainage

Fluctuations in surface melting are known to affect the speed of glaciers and ice sheets, but their impact on the Greenland ice sheet in a warming climate remains uncertain. Although some studies suggest that greater melting produces greater ice-sheet acceleration, others have identified a long-term decrease in Greenland's flow despite increased melting. Here we use satellite observations of ice motion recorded in a land-terminating sector of southwest Greenland to investigate the manner in which ice flow develops during years of markedly different melting. Although peak rates of ice speed-up are positively correlated with the degree of melting, mean summer flow rates are not, because glacier slowdown occurs, on average, when a critical run-off threshold of about 1.4?centimetres a day is exceeded. In contrast to the first half of summer, when flow is similar in all years, speed-up during the latter half is 62?±?16 per cent less in warmer years. Consequently, in warmer years, the period of fast ice flow is three times shorter and, overall, summer ice flow is slower. This behaviour is at odds with that expected from basal lubrication alone. Instead, it mirrors that of mountain glaciers, where melt-induced acceleration of flow ceases during years of high melting once subglacial drainage becomes efficient. A model of ice-sheet flow that captures switching between cavity and channel drainage modes is consistent with the run-off threshold, fast-flow periods, and later-summer speeds we have observed. Simulations of the Greenland ice-sheet flow under climate warming scenarios should account for the dynamic evolution of subglacial drainage; a simple model of basal lubrication alone misses key aspects of the ice sheet's response to climate warming.