Biological sciences

  • Letter |

    Evidence for hominin activity on Flores, Indonesia, has been thought to go back at least 800,000 years, as shown by fission-track dating at Mata Menge in the Soa Basin. However, new research at another locality in the Soa Basin uses the more accurate technique of 40Ar/39Ar dating to show that hominins were living on Flores at least a million years ago.

    • Adam Brumm
    • , Gitte M. Jensen
    •  & Michael Storey
  • Letter |

    An extensive genome-wide survey of over 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf, was conducted to shed light on the process of dog diversification. The results reveal that much of genome diversity came from Middle Eastern progenitors, combined with interbreeding with local wolf populations, and that recent evolution involved limited genetic variation to create the phenotypic diversity of modern dogs.

    • Bridgett M. vonHoldt
    • , John P. Pollinger
    •  & Robert K. Wayne
  • Letter |

    Reactive electrophiles are noxious chemicals, such as acrolein in cigarette smoke, and are detected by the ion channel TRPA1 in humans. Here it is shown that TRPA1 channels sense these chemicals in the gustatory chemosensory neurons of fruitflies and mosquitoes, too. Further findings show that, unlike with other chemical senses such as smell or taste, the detection of reactive electrophiles relies on an ancient sensor that has been conserved in molecular detail through some 500 million years of evolution.

    • Kyeongjin Kang
    • , Stefan R. Pulver
    •  & Paul A. Garrity
  • Letter |

    Variation in the regulation of gene transcription between individuals is thought to be a major cause of phenotypic diversity. Here, individual differences in the binding of transcription-factor proteins are studied. A well-known transcription factor in the yeast pheromone pathway is used as an example, and the underlying genetic loci responsible for variation in its binding are mapped. The study reveals new insights into the mechanisms of gene regulation, and new regulators of the yeast pheromone pathway.

    • Wei Zheng
    • , Hongyu Zhao
    •  & Michael Snyder
  • Letter |

    The amino-terminal tails of histone proteins are subject to a variety of post-translational modifications; addition or removal of these 'marks' facilitates gene activation or silencing. Here, a mechanism is defined that modulates the activity of the dual-specificity histone demethylase LSD1 during androgen-dependent transcription. Androgen-dependent signalling through protein kinase C beta I leads to phosphorylation of a histone amino acid, which prevents demethylation of an adjacent amino acid by LSD1.

    • Eric Metzger
    • , Axel Imhof
    •  & Roland Schüle
  • Article |

    Snakes are notoriously apt at generating 'thermal images' of predators or prey. The underlying physiology has been unclear, although in snakes such as pythons, vipers and boas, infrared signals are initially received by the pit organ. Here it is shown that pit-bearing snakes rely on heat detection by the ion channel TRPA1. This extends the sensory repertoire of the TRPA1 family of proteins, which detect chemical irritants in mammals and thermal variations in insects.

    • Elena O. Gracheva
    • , Nicholas T. Ingolia
    •  & David Julius
  • Letter |

    VEGF–B is shown to have an unexpected role in targeting lipids to peripheral tissues. VEGF–B controls endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. Bioinformatic analyses suggest that the uptake of these lipids is tightly coupled with lipid use by mitochondria. Mice that do not have VEGF–B accumulate less lipids in muscle, heart and brown adipose tissue, and instead shunt them to white adipose tissue.

    • Carolina E. Hagberg
    • , Annelie Falkevall
    •  & Ulf Eriksson
  • Letter
    | Open Access

    The freshwater cnidarian Hydra is a significant model for studies of axial patterning, stem cell biology and regeneration. Its (A+T)-rich genome has now been sequenced. Comparison of this genome with those of other animals provides insights into the evolution of epithelia, contractile tissues, developmentally regulated transcription factors, pluripotency genes and more.

    • Jarrod A. Chapman
    • , Ewen F. Kirkness
    •  & Robert E. Steele
  • Letter |

    A genome-wide RNA interference screen to systematically test the genetic basis for formation and function of the Drosophila muscle is described. A role in muscle for 2,785 genes is identified; many of these genes are phylogenetically conserved.

    • Frank Schnorrer
    • , Cornelia Schönbauer
    •  & Barry J. Dickson
  • Letter |

    In a mouse model of prostate cancer it is shown that infiltrating B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin accelerates the emergence of castration-resistant prostate tumours in this model. Interfering with this pathway may offer therapeutic strategies for androgen-independent prostate cancer.

    • Massimo Ammirante
    • , Jun-Li Luo
    •  & Michael Karin
  • Article |

    In mammals, embryos are considered to be sexually indifferent until the action of a sex-determining gene initiates gonadal differentiation. Here it is demonstrated that this situation is different for birds. Using rare, naturally occurring chimaeric chickens where one side of the animal appears male and the other female, it is shown that avian somatic cells possess an inherent sex identity and that, in birds, sexual differentiation is cell autonomous.

    • D. Zhao
    • , D. McBride
    •  & M. Clinton
  • Letter |

    There is much interest in understanding the genetic mechanisms that underlie individual variations in gene expression. Here, RNA sequencing has been used to study gene expression in lymphoblastoid cell lines derived from Nigerian individuals for whom extensive genotype information is known. Numerous genetic determinants of variation in gene expression were identified, including variation in transcription, splicing and allele-specific expression.

    • Joseph K. Pickrell
    • , John C. Marioni
    •  & Jonathan K. Pritchard
  • Letter |

    Here, sequencing has been used to characterize the mRNA fraction of the transcriptome in Caucasian individuals, to provide a fine-scale view of transcriptomes and to identify genetic variants that affect alternative splicing. Measuring allele-specific expression identified rare expression quantitative trait loci (eQTLs) and allelic differences in transcript structure, revealing new properties of genetic effects on the transcriptome.

    • Stephen B. Montgomery
    • , Micha Sammeth
    •  & Emmanouil T. Dermitzakis
  • Letter |

    Genotype and phenotype cannot be connected simply by one-to-one mapping; instead they are linked by the nonlinear process of development. Here, a computational model is described — based on real data about the development of seal teeth — that attempts to combine the three. The results show that a few genetic parameters regulating signalling during cusp development may explain variation among individuals. But a cellular parameter regulating epithelial growth may explain tooth-to-tooth variation along the jaw.

    • Isaac Salazar-Ciudad
    •  & Jukka Jernvall
  • Letter
    | Open Access

    Here, the genomes of birds representing eight populations of domestic chickens are compared with the genome of their wild ancestor, the red jungle fowl. The results reveal selective sweeps of favourable alleles and mutations that may have contributed to domestication. One selective sweep, for instance, occurred at the locus encoding the thyroid stimulating hormone receptor, which is important in metabolism and in the timing of vertebrate reproduction.

    • Carl-Johan Rubin
    • , Michael C. Zody
    •  & Leif Andersson
  • Letter |

    During Arabidopsis embryogenesis, a single cell is specified to become the founder cell of the root meristem — the hypophysis — in response to signals from adjacent cells. Hypophysis specification requires an auxin-responsive transcription factor, MONOPTEROS (MP), which promotes transport of auxin from the embryo to the hypophysis precursor. Here, MP target genes are identified and the means by which they mediate root formation is shown.

    • Alexandra Schlereth
    • , Barbara Möller
    •  & Dolf Weijers
  • Letter |

    Female gametes in flowering plants develop from a meiotic division of a precursor cell followed by mitotic divisions of one of the resulting haploid cells to yield the gametophyte. Here, ARGONAUTE 9 (AGO9) — a protein involved in RNA interference — is identified as a factor required for specification of the gametophyte. AGO9 is found not in the cell destined to be the gametophyte, but in the neighbouring companion cells, suggesting that it functions in a non-cell-autonomous manner.

    • Vianey Olmedo-Monfil
    • , Noé Durán-Figueroa
    •  & Jean-Philippe Vielle-Calzada
  • Letter |

    Signalling through the epidermal growth factor receptor (EGFR) is preceded by its dimerization, which has typically been thought to occur through a ligand-induced conformational change. Here, the dimerization dynamics of individual EGFR molecules have been determined in living cells in real time, using a quantum-dot-based approach. Unliganded EGFR molecules undergo spontaneous and reversible dimerization; these pre-formed dimers are primed for ligand binding and signalling and are enriched at the cell periphery.

    • Inhee Chung
    • , Robert Akita
    •  & Ira Mellman
  • Letter |

    In response to oncogenic stress, the tumour suppressor ARF activates the p53 protein. ARF protein is highly stable in most human cell lines, so it has been thought that ARF activation occurs mainly at the level of transcription. Here, however, ARF is shown to be unstable in normal human cells but stable in cancer cells, through a transcription-independent mechanism. A ubiquitin ligase for ARF is identified and shown to promote ARF degradation in normal cells. This activity is prevented in cancer cells, stabilizing ARF.

    • Delin Chen
    • , Jing Shan
    •  & Wei Gu
  • Letter |

    The organization of Hox clusters in several different reptiles is investigated, showing that the Hox clusters in squamates — lizards and snakes — have unexpectedly accumulated transposable elements, reflecting extensive genomic rearrangements of coding and non coding regulatory regions. Comparative expression analyses between two species showing different axial skeletons, the corn snake and the whiptail lizard, revealed major alterations in Hox13 and Hox10 expression features during snake somitogenesis, in line with the expansion of both caudal and thoracic regions.

    • Nicolas Di-Poï
    • , Juan I. Montoya-Burgos
    •  & Denis Duboule
  • Letter |

    During fasting SIRT3 is induced in liver and brown adipose tissue. One of SIRT3's substrates is shown to be long–chain acyl co-enzyme A dehydrogenase (LCAD). Without SIRT3 LCAD becomes hyperacetylated, which diminishes its activity, and reduces fatty acid oxidation. Mice without SIRT3 have all the hallmarks of fatty acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold. Thus, acetylation is a novel regulatory mechanism for fatty acid oxidation.

    • Matthew D. Hirschey
    • , Tadahiro Shimazu
    •  & Eric Verdin
  • Article
    | Open Access

    Deep metagenomic sequencing and characterization of the human gut microbiome from healthy and obese individuals, as well as those suffering from inflammatory bowel disease, provide the first insights into this gene set and how much of it is shared among individuals. The minimal gut metagenome as well as the minimal gut bacterial genome is also described.

    • Junjie Qin
    • , Ruiqiang Li
    •  & Jun Wang
  • Letter |

    Severe trauma can lead to death and sepsis in the absence of apparent infection. Here evidence shows that mitochondrial debris, released from damaged cells, is present in the circulation of seriously injured trauma patients. Such debris is shown to activate neutrophils via specific formyl peptide receptors, triggering systemic inflammation and end organ injury.

    • Qin Zhang
    • , Mustafa Raoof
    •  & Carl J. Hauser
  • Letter |

    A new genus and species is described from fragmentary remains of a reptile from the mid–Triassic of Tanzania. The finding clarifies the relationships among the silesaurs. It is among the earliest known ornithodirans (dinosaurs plus pterosaurs), and demonstrates that silesaurs were not two-legged carnivores, as expected, but larger and more herbivorous. Furthermore, the find shows that we still know very little about the earliest stages of dinosaur and pterosaur evolution.

    • Sterling J. Nesbitt
    • , Christian A. Sidor
    •  & Linda A. Tsuji
  • Letter |

    Each human cell contains hundreds of copies of mitochondrial DNA (mtDNA), making it difficult to characterize mtDNA completely. Here, massively parallel sequencing-by-synthesis of mtDNA reveals widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells, and homoplasmic and heteroplasmic mutations in cancer cells. The findings provide new insight into the nature and variability of mtDNA sequences, with implications for forensic analysis and the development of biomarkers for cancer.

    • Yiping He
    • , Jian Wu
    •  & Nickolas Papadopoulos
  • Letter |

    An understanding of how fat cells (adipocytes) develop will contribute to our understanding of obesity. The differentiation of committed preadipocytes into adipocytes is known to be controlled by PPARγ and several other transcription factors. But what turns a cell into a preadipocyte? Here, the zinc-finger protein Zfp423 is identified as a transcriptional regulator of preadipocyte determination.

    • Rana K. Gupta
    • , Zoltan Arany
    •  & Bruce M. Spiegelman
  • Letter |

    During development in Arabidopsis plants, populations of shoot stem cells and root stem cells are established at the embryo's apical and basal poles, respectively. PLETHORA genes are master regulators of root fate, but the regulators of shoot fate were unknown. Here, CLASS III HOMEODOMAIN-LEUCINE ZIPPER genes are identified as master regulators of apical/shoot fate, and are shown to be sufficient to convert the embryonic root pole into a second shoot pole.

    • Zachery R. Smith
    •  & Jeff A. Long
  • Article |

    A new strategy is presented to accurately profile the activity of human genes in endocytosis by combining genome-wide RNAi, automated high-resolution confocal microscopy and quantitative multi-parametric image analysis. Several novel components of endocytosis and endosome trafficking were uncovered; a systems analysis further revealed that the cell regulates the number, size and concentration of cargo within endosomes.

    • Claudio Collinet
    • , Martin Stöter
    •  & Marino Zerial
  • Letter |

    The unfolded protein response, known to contribute to the defence against infectious agents and toxins, is shown here to protect Caenorhabditis elegans larvae against detrimental effects of the innate immune response to infection with Pseudomonas aeruginosa. The findings establish innate immunity as a physiologically relevant inducer of ER stress during C. elegans development.

    • Claire E. Richardson
    • , Tristan Kooistra
    •  & Dennis H. Kim
  • Brief Communications Arising |

    • François Majo
    • , Ariane Rochat
    •  & Yann Barrandon
  • Article |

    Mutations near the ORMDL3 gene have been associated with childhood asthma. Here, in yeast, Orm proteins are shown to function in sphingolipid homeostasis; alterations in this control result in misregulation of sphingolipid production and accumulation of toxic metabolites. This raises the testable hypothesis that misregulation of sphingolipids may directly contribute to the development of asthma.

    • David K. Breslow
    • , Sean R. Collins
    •  & Jonathan S. Weissman
  • Letter |

    The Red Queen hypothesis predicts that coevolution should increase the rate of evolution at the molecular level. Here, genome sequencing in an experimental phage–bacteria system is used to show that this is true, but the effect is concentrated on specific loci, and also that coevolution drives greater diversification of phage populations.

    • Steve Paterson
    • , Tom Vogwill
    •  & Michael A. Brockhurst
  • Letter |

    Evolution from one fitness peak to another must involve either transitions through intermediates of low fitness or skirting round the fitness valley through compensatory mutations elsewhere. Here, the base pairs in mitochondrial tRNA stems is used as a model to show that deep fitness valleys can be traversed. Transitions between AU and GC pairs have occurred during mammalian evolution without help from genetic drift or mutations elsewhere.

    • Margarita V. Meer
    • , Alexey S. Kondrashov
    •  & Fyodor A. Kondrashov
  • Letter |

    Peptide hormones such as oxytocin and vasopressin influence social behaviour in several mammalian species. Here it is shown that a population of interneurons in the rat olfactory bulb releases vasopressin, and that vasopressin signalling is required in the olfactory system for proper social recognition in rats. Although vasopressin may not work in exactly the same way in humans, social recognition mediated by experience-dependent vasopressin release may be common.

    • Vicky A. Tobin
    • , Hirofumi Hashimoto
    •  & Mike Ludwig
  • Letter |

    The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.

    • Poulikos I. Poulikakos
    • , Chao Zhang
    •  & Neal Rosen
  • Letter |

    The existence of all-female species of whiptail lizard, formed as a hybrid between sexual species, has been known since 1962; however, how the meiotic program is altered to produce diploid eggs while maintaining heterozygosity has remained unclear. Here it is shown in parthenogenetic species that meiosis initiates with twice the number of chromosomes compared to sexual species, and that pairing and recombination takes place between genetically identical sister chromosomes instead of between homologues.

    • Aracely A. Lutes
    • , William B. Neaves
    •  & Peter Baumann
  • Letter |

    UCYN–A is a recently discovered nitrogen-fixing cyanobacterium with unusual metabolic features. The complete genome of this uncultivated organism is now presented, revealing a photofermentative metabolism and dependency on other organisms for essential compounds.

    • H. James Tripp
    • , Shellie R. Bench
    •  & Jonathan P. Zehr
  • Letter |

    Genomic instability has been implicated in tumour development. Here, a new mouse model of Kras-driven lung tumours has been developed, in which genomic instability is caused by overexpression of the mitotic checkpoint protein Mad2. In this model, inhibiting Kras leads to tumour regression, as shown previously. But tumours recur at a much higher rate.

    • Rocio Sotillo
    • , Juan-Manuel Schvartzman
    •  & Robert Benezra
  • Letter |

    Worldwide, 170 million people are infected with the hepatitis C virus, which is a significant cause of liver-related illnesses and deaths. Standard treatment combines pegylated interferon alpha and ribavirin (RBV), but has some negative effects, notably RBV-induced haemolytic anaemia. Here, a genome-wide study shows that a deficiency in the enzyme inosine triphosphatase protects against haemolytic anaemia in patients receiving RBV.

    • Jacques Fellay
    • , Alexander J. Thompson
    •  & David B. Goldstein
  • Letter |

    Sequence variations in a 58-kilobase interval on human chromosome 9p21 have been associated with an increased risk of coronary artery disease. However, this interval contains no protein-coding genes and the mechanism underlying the increased risk has been unclear. Here, the corresponding interval has been deleted from mouse chromosome 4, revealing that this part of the chromosome regulates the cardiac expression of two nearby genes, Cdkn2a and Cdkn2b, and the proliferation dynamics of vascular cells.

    • Axel Visel
    • , Yiwen Zhu
    •  & Len A. Pennacchio
  • Letter |

    The vertebrate body plan shows marked bilateral symmetry, although this can be disrupted in conditions such as scoliosis. Here, a mutation in Rere is found that leads to the formation of asymmetrical somites in mouse embryos; furthermore, Rere is shown to control retinoic acid signalling, which is required to maintain somite symmetry by interacting with Fgf8. The results provide insight into how bilateral symmetry is maintained.

    • Gonçalo C. Vilhais-Neto
    • , Mitsuji Maruhashi
    •  & Olivier Pourquié
  • Article |

    Even genetically identical organisms in homogeneous environments vary, indicating that randomness in developmental processes such as gene expression may generate phenotypic diversity. Intestinal specification in the nematode Caenorhabditis elegans, in which wild-type cell fate is invariant and controlled by a small transcriptional network, is now studied. The results demonstrate that mutations in developmental networks can expose stochastic variability in gene expression, leading to phenotypic variation.

    • Arjun Raj
    • , Scott A. Rifkin
    •  & Alexander van Oudenaarden
  • Article
    | Open Access

    Homozygous gene deletions in cancer cells occur over recessive cancer genes (where they can confer selective growth advantage) or over genes at fragile sites of the genome (where they are thought to reflect increased DNA breakage). Here, a large number of homozygous deletions in a collection of cancer cell lines are identified and analysed to derive structural signatures for the two different types of deletion. More deletions are found in inherently fragile regions, and fewer overlying recessive genes.

    • Graham R. Bignell
    • , Chris D. Greenman
    •  & Michael R. Stratton
  • Article |

    One way of discovering genes with key roles in cancer development is to identify genomic regions that are frequently altered in human cancers. Here, high-resolution analyses of somatic copy-number alterations (SCNAs) in numerous cancer specimens provide an overview of regions of focal SCNA that are altered at significant frequency across several cancer types. An oncogenic function is also found for the anti-apoptosis genes MCL1 and BCL2L1, which reside in amplified genome regions in many cancers.

    • Rameen Beroukhim
    • , Craig H. Mermel
    •  & Matthew Meyerson