Articles in 2015

The Structural Variation Analysis Group of The 1000 Genomes Project reports an integrated structural variation map based on discovery and genotyping of eight major structural variation classes in 2,504 unrelated individuals from across 26 populations; structural variation is compared within and between populations and its functional impact is quantified.

A novel drug, ribocil, is shown to mimic the binding of a natural ligand to a bacterial riboflavin riboswitch (a non-coding stretch of messenger RNA whose structure is affected by a ligand—usually one related to the function of the protein encoded by the messenger RNA) to cause inhibition of bacterial growth; the ability to target an RNA structural element with a synthetic small molecule may expand our view of the target space susceptible to therapeutic intervention.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

This study has determined the X-ray crystal structures of GLUT5 from Rattus norvegicus in an open, outward-facing conformation and GLUT5 from Bos taurus in an open, inward-facing conformation; comparison of these structures with previously published structures of the related Escherichia coli d-xylose:H⁺ symporter XylE suggests that transport in GLUT5 is controlled by both a global ‘rocker-switch’-type motion and a local ‘gated-pore’-type transport mechanism.

The transmembrane proteins SERINC3 and SERINC5 are identified as new restriction factors for HIV-1 replication; this restriction is counteracted by Nef and glycoGag, which prevent SERINC3 and SERINC5 from becoming incorporated into HIV-1 virions and from profoundly blocking HIV-1 infectivity, suggesting a potential new therapeutic strategy for immunodeficiency viruses.

The transmembrane protein SERINC5 is identified as a potent inhibitor of HIV-1 particle infectivity that is counteracted by Nef; Nef redirects SERINC5 from the plasma membrane to a Rab7-positive endosomal compartment, thus excluding it from HIV-1 particles, emphasizing the potential of SERINC5 as a potent anti-retroviral factor.

Crystal structures are presented of Thermus thermophilus CarH, a photoreceptor that uses a vitamin B₁₂ derivative, in all three relevant states: in the dark, both free and bound to operator DNA, and after light exposure.

Piezo1, a mechanosensitive cation channel, senses shear stress of blood flow for proper blood vessel development, regulates red blood cell function and controls cell migration and differentiation; here a trimeric architecture of this novel class of ion channel is reported, suggesting that Piezo1 may use its peripheral propeller-like ‘blades’ as force sensors to gate the central ion-conducting pore.

Practical applications of magnesium as a lightweight structural metal are limited by its high work hardening, low ductility and fracture at very low strains; now molecular dynamics simulations reveal the origins of these problems and offer a route to design magnesium alloys with improved mechanical properties.

In this study, the authors present an analysis of the malaria burden in sub-Saharan Africa between 2000 and 2015, and quantify the effects of the interventions that have been implemented to combat the disease; they find that the prevalence of Plasmodium falciparum infection has been reduced by 50% since 2000 and the incidence of clinical disease by 40%, and that interventions have averted approximately 663 million clinical cases since 2000, with insecticide-treated bed nets being the largest contributor.

A CRISPR-Cas9 approach is used to perform saturating mutagenesis of the human and mouse BCL11A enhancers, producing a map that reveals critical regions and specific vulnerabilities; BCL11A enhancer disruption is validated by CRISPR-Cas9 as a therapeutic strategy for inducing fetal haemoglobin by applying it in both mice and primary human erythroblast cells.

Gasdermin D is identified as the required substrate for pyroptosis, mediating caspase-11 function in the non-canonical inflammasome pathway; the cleaved N-terminal domain is shown to trigger pyroptosis.

The anaerobic oxidation of methane in marine sediments is performed by consortia of methane-oxidizing archaea and sulfate-reducing bacteria; an examination of the role of interspecies spatial positioning on single cell activity reveals that interspecies electron transfer may overcome the requirement for close spatial proximity, a proposition supported by large multi-haem cytochromes in ANME-2 genomes as well as redox-active electron microscopy staining.

The secreted factor follistatin-like 1 (FSTL1) becomes undetectable in the epicardium of infarcted hearts; when reconstituted using a collagen patch sutured onto an infarcted heart, FSTL1 can induce cell cycle entry and division of pre-existing cardiomyocytes, thus boosting heart function and survival in mouse and pig models of myocardial infarction.

CRISPR-Cas9 genome-editing screens identify gasdermin D as a substrate for inflammatory caspases, and its N-terminal cleavage fragment, as well as the equivalent regions in other gasdermins, is shown to be capable of inducing pyroptosis.

Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies.

A new light-activated probe that targets recently active neuronal spines for manipulation induces shrinkage of recently potentiated spines following a motor learning task; spine shrinkage disrupted learning, suggesting a causal relationship between the specific subset of targeted spines and the learned behaviour.

A short segment of α-synuclein called NACore (residues 68–78) is responsible for the formation of amyloid aggregates responsible for cytotoxicity in Parkinson disease; here the nanocrystal structure of this invisible-to-optical-microscopy segment is determined using micro-electron diffraction, offering insight into its function and simultaneously demonstrating the first use of micro-electron diffraction to solve a previously unknown protein structure.

A high-resolution electron cryo-microscopy structure of the zebrafish α1 glycine receptor bound to agonists or antagonists reveals the conformational changes that take place when the channel transitions from closed to open state.

Using biochemical fractionation and mass spectrometry, animal protein complexes are identified from nine species in parallel, and, along with genome sequence information, complex conservation is investigated and over one million protein–protein interactions are predicted in 122 eukaryotes.