Volume 526 Number 7571

Editorials

Variety of life p.5

An effort to sequence thousands of people’s genomes reaches the end of the beginning.

doi: 10.1038/526005b

Testing times p.5

The unfolding Volkswagen saga highlights the need for better funding of regulatory science — and should prompt regulators to keep a closer eye on whether their rules are working.

doi: 10.1038/526005a

Goals galore p.6

The latest global targets from the United Nations must be translated into realistic policies.

doi: 10.1038/526006a

News

News Features

Bitcoin and beyond p.21

The digital currency has caused any number of headaches for law enforcement. Now entrepreneurs and academics are scrambling to build a better version.

doi: 10.1038/526021a

News & Views

Primordial stars brought to light p.46

The earliest stars are of huge importance to the chemical history of the cosmos, but have previously existed only in theory. There is now strong evidence that such population III stars exist in the brightest galaxy yet found in the early Universe.

doi: 10.1038/526046a

Platelet mimicry p.47

Cloaking drug-loaded nanoparticles with platelet membranes enhances the drugs' abilities to target desired cells and tissues. This technology might improve treatments for cardiovascular and infectious diseases. See Letter p.118

doi: 10.1038/nature15218

Spring greening in a warming world p.48

Warmer temperatures have been associated with an earlier emergence of spring leaves each year. New data, however, suggest that leaf emergence is becoming less sensitive to temperature as global temperatures rise. See Letter p.104

doi: 10.1038/nature15633

A molecular tightrope p.50

The identification of a regulatory site on the UBE3A protein that can be phosphorylated to alter its enzymatic activity provides insight into the aetiology of two human neurodevelopmental diseases, Angelman syndrome and autism.

doi: 10.1038/526050b

Flat transistor defies the limit p.51

A transistor has been demonstrated that operates at low supply voltages by exceeding a theoretical limit. The finding opens up avenues to the development of integrated circuits that have extremely low power consumption. See Letter p.91

doi: 10.1038/526051a

The end of the start for population sequencing p.52

In the final phase of a seven-year project, the genomes of 2,504 people across five continental regions have been sequenced. The result is a compendium of in-depth data on variation in human populations. See Articles p.68 & p.75

doi: 10.1038/526052a

Review

CRISPR-Cas immunity in prokaryotes p.55

The CRISPR-Cas systems of bacteria and archaea provide adaptive immunity against invading mobile genetic elements such as phages and plasmids; this Review describes the discovery of these systems and the mechanisms of immunity, including recent progress in establishing the molecular basis of host immunization.

doi: 10.1038/nature15386

Articles

The origins of high hardening and low ductility in magnesium p.62

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.

doi: 10.1038/nature15364

A global reference for human genetic variation OPEN p.68

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.

doi: 10.1038/nature15393

An integrated map of structural variation in 2,504 human genomes OPEN p.75

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.

doi: 10.1038/nature15394

The UK10K project identifies rare variants in health and disease OPEN p.82

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.

doi: 10.1038/nature14962

Letters

A subthermionic tunnel field-effect transistor with an atomically thin channel p.91

A new type of device, the band-to-band tunnel transistor, which has atomically thin molybdenum disulfide as the active channel, operates in a fundamentally different way from a conventional silicon (MOSFET) transistor; it has turn-on characteristics and low-power operation that are better than those of state-of-the-art MOSFETs or any tunnelling transistor reported so far.

doi: 10.1038/nature15387

Declining global warming effects on the phenology of spring leaf unfolding p.104

Spring leaf unfolding has been occurring earlier in the year because of rising temperatures; however, long-term evidence in the field from 7 European tree species studied in 1,245 sites shows that this early unfolding effect is being reduced in recent years, possibly because the reducing chilling and/or insolation render trees less responsive to warming.

doi: 10.1038/nature15402

New genomic and fossil data illuminate the origin of enamel p.108

Enamel is a tissue unique to vertebrates, and nowadays associated with teeth; here, histological material from a fossil bony fish and genomic data from an extant, armour-plated fish are analysed to show that enamel originated on the body surface and only later colonized the teeth.

doi: 10.1038/nature15259

Whole‐genome sequencing identifies EN1 as a determinant of bone density and fracture p.112

The extent to which low‐frequency (minor allele frequency (MAF) between 1–5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population‐specific, coding variants. Here we identify novel non‐coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole‐genome sequencing (n = 2,882 from UK10K (ref. 10); a population‐based genome sequencing consortium), whole‐exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low‐frequency non‐coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10−14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low‐frequency non‐coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non‐coding variants. These findings provide evidence that low‐frequency non‐coding variants have large effects on BMD and fracture, thereby providing rationale for whole‐genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

doi: 10.1038/nature14878

Nanoparticle biointerfacing by platelet membrane cloaking p.118

The authors report a new biomimetic nanodelivery platform in which polymeric nanoparticles enclosed in the plasma membrane of human platelets are used for disease-relevant targeting, and the therapeutic potential of the concept is demonstrated in animal models of coronary restenosis and systemic bacterial infection.

doi: 10.1038/nature15373

The soft palate is an important site of adaptation for transmissible influenza viruses p.122

Efficient airborne transmission of influenza viruses between humans is associated with use of α2,6-linked sialic acids, not α2,3-linked sialic acids; however, using a loss-of-function approach in which a 2009 pandemic H1N1 influenza virus was engineered to bind α2,3 sialic acids, this study shows in ferrets that the soft palate is an important site for the switch of receptor usage to take place, and reveals that this tissue rapidly selects for transmissible influenza virus with human receptor preference.

doi: 10.1038/nature15379