• 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 |

    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 |

    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 |

    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
  • 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 |

    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
  • 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 |

    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 |

    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
  • 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
  • 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
    | 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
  • Letter
    | Open Access

    Until now, fully sequenced human genomes of the indigenous hunter-gatherer peoples of southern Africa have been limited to recently diverged populations. The complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and of a Bantu from southern Africa are now presented. The extent of whole-genome and exome diversity is characterized; the observed genomic differences may help to pinpoint genetic adaptations to an agricultural lifestyle.

    • Stephan C. Schuster
    • , Webb Miller
    •  & Vanessa M. Hayes
  • Article |

    The transcriptome of Helicobacter pylori, an important human pathogen involved in gastric ulcers and cancer, is presented. The approach establishes a model for mapping and annotating the primary transcriptomes of many living species.

    • Cynthia M. Sharma
    • , Steve Hoffmann
    •  & Jörg Vogel
  • Letter |

    Here, iPS cell technology is used to study the mechanisms underlying dyskeratosis congenita in humans. Reprogramming restores telomere elongation in dyskeratosis congenita cells despite genetic lesions affecting telomerase. The reprogrammed cells were able to overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal, and multiple telomerase components are targeted by pluripotency-associated transcription factors.

    • Suneet Agarwal
    • , Yuin-Han Loh
    •  & George Q. Daley
  • Article |

    Local adaptations are often governed by several interacting genes scattered throughout the genome. Here a novel type of multi–locus genetic variation is described that has been maintained within a species over a vast period of time. A balanced unlinked gene network polymorphism is dissected that involves galactose utilization in a close relative of baker's yeast.

    • Chris Todd Hittinger
    • , Paula Gonçalves
    •  & Antonis Rokas
  • Article
    | Open Access

    The first genome sequence of an ancient human is reported. It comes from an approximately 4,000-year-old permafrost-preserved hair from a male from the first known culture to settle in Greenland. Functional single-nucleotide polymorphism (SNP) assessment is used to assign possible phenotypic characteristics and high-confidence SNPs are compared to those of contemporary populations to find those most closely related to the individual.

    • Morten Rasmussen
    • , Yingrui Li
    •  & Eske Willerslev
  • Article |

    The genome of the wild grass Brachypodium distachyon (Brachypodium), a member of the Pooideae subfamily, is sequenced. The Pooideae are one of three subfamilies of grasses that provide the bulk of human nutrition and may become major sources of renewable energy. Availability of the genome sequence should help establish Brachypodium as a model for developing new energy and food crops.

    • John P. Vogel
    • , David F. Garvin
    •  & Ivan Baxter
  • Letter |

    Recently, numerous single nucleotide polymorphisms have been identified as being associated with obesity, but these loci together account for only a small fraction of the known heritable component. Here, an association is reported between rare deletions of at least 593 kilobases at 16p11.2 and a highly penetrant form of obesity. The strategy used of combining study of extreme phenotypes with targeted follow-up is promising for identifying missing heritability in obesity.

    • R. G. Walters
    • , S. Jacquemont
    •  & J. S. Beckmann
  • Letter |

    Heterozygous mutations in the gene encoding CHD7, an ATP-dependent chromatin-remodelling protein, result in CHARGE syndrome — a disorder characterized by malformations of the craniofacial structures, peripheral nervous system, ears, eyes and heart. In humans and Xenopus, CHD7 is now shown to be essential for the formation of multipotent migratory neural crest and for activating the transcriptional circuitry of the neural crest; shedding light on the pathoembryology of CHARGE syndrome.

    • Ruchi Bajpai
    • , Denise A. Chen
    •  & Joanna Wysocka
  • Article |

    The integrase protein of retroviruses such as HIV-1 catalyses insertion of the viral genome into that of the host. Here, the long-awaited structure of the full-length integrase complex is predicted, revealing not only details of the biochemistry of the integration reaction, but also the means by which current inhibitors affect this process.

    • Stephen Hare
    • , Saumya Shree Gupta
    •  & Peter Cherepanov
  • Letter |

    Although cyclin D1 is frequently overexpressed in human cancers, the full range of its functions in normal development and oncogenesis is unclear. Here, tagged cyclin D1 knock-in mouse strains are developed to allow a search for cyclin D1-binding proteins in different mouse organs using high-throughput mass spectrometry. The results show that, in addition to its established cell cycle roles, cyclin D1 has an in vivo transcriptional function in mouse development.

    • Frédéric Bienvenu
    • , Siwanon Jirawatnotai
    •  & Piotr Sicinski
  • Letter |

    If robustness is the opposite of evolvability, we might expect that a robust population would have difficulty adapting to environmental change; however, some studies have suggested that genetic robustness facilitates adaptation. Here, using a general population genetics model, mutational robustness is found to either impede or facilitate adaptation depending on the population size, the mutation rate and the structure of the fitness landscape.

    • Jeremy A. Draghi
    • , Todd L. Parsons
    •  & Joshua B. Plotkin
  • Letter |

    Antimicrobial peptides (AMPs) are an important class of immune effector molecules which fight pathogen infections. AMP induction in Drosophila is regulated through the activation of the Toll and immune deficiency pathways; it is now shown that AMP activation can be achieved independently of these pathways by the transcription factor FOXO. In non-infected animals, AMP genes are activated in response to nuclear FOXO activity when induced by starvation.

    • Thomas Becker
    • , Gerrit Loch
    •  & Michael Hoch
  • Letter |

    Sperm can increase their swimming velocity and gain a competitive advantage over sperm from another male by forming cooperative groups, such that selection should favour cooperation of the most closely related sperm. Sperm of deer mice are now shown to aggregate more often with conspecific than heterospecific sperm, in accordance with this theory, whereas in a monogamous species lacking sperm competition, sperm indiscriminately group with unrelated conspecific sperm.

    • Heidi S. Fisher
    •  & Hopi E. Hoekstra
  • Letter |

    Much of the mammalian genome is derived from retroelements, a significant proportion of which are endogenous retroviruses (ERVs). ERVs are transcriptionally silenced during early embryogenesis by histone and DNA methylation, but the initiators of this process are largely unknown. Here, deletion of KAP1 is shown to lead to a marked upregulation of a range of ERVs in mouse embryonic stem cells and in early embryos.

    • Helen M. Rowe
    • , Johan Jakobsson
    •  & Didier Trono
  • Article
    | Open Access

    Soybean is an important crop plant, providing seed protein and oil and fixing atmospheric nitrogen through symbioses with soil-borne microorganisms. Using a whole-genome shotgun approach, its 1.1-gigabase genome is now sequenced and integrated with physical and high-density genetic maps to create a chromosome-scale draft sequence assembly.

    • Jeremy Schmutz
    • , Steven B. Cannon
    •  & Scott A. Jackson
  • Letter |

    Immune homeostasis relies on tight control over the size of a population of regulatory T cells (Treg) that can suppress over-exuberant immune responses. Cells commit to the Treg lineage by upregulating the transcription factor Foxp3. Conserved non-coding DNA sequence elements at the Foxp3 locus are now shown to control the composition, size and maintenance of the Treg cell population.

    • Ye Zheng
    • , Steven Josefowicz
    •  & Alexander Y. Rudensky
  • Letter |

    Phenotypic robustness in the face of genetic and environmental perturbations — known as canalization — relies on buffering mechanisms. Hsp90 chaperone machinery has been proposed to be an evolutionarily conserved buffering mechanism of phenotypic variance. Here, an additional, perhaps alternative, mechanism whereby Hsp90 influences phenotypic variation is proposed; Hsp90 mutations can generate new variation by transposon-mediated mutagenesis.

    • Valeria Specchia
    • , Lucia Piacentini
    •  & Maria P. Bozzetti
  • Letter |

    Until now, retroviruses have been the only group of viruses known to have left a fossil record, in the form of endogenous proviruses; those elements make up approximately 8% of the human genome. Elements homologous to the nucleoprotein gene of the non-retroviral bornavirus are now shown to exist in the genomes of several mammalian species; the results give insights into the role of bornavirus as a source of genetic novelty to its host.

    • Masayuki Horie
    • , Tomoyuki Honda
    •  & Keizo Tomonaga
  • Letter |

    Clear cell renal carcinoma, the most common form of adult kidney cancer, is often characterized by the presence of inactivating mutations in the VHL gene. A large survey for somatic mutations now identifies inactivating mutations in two genes encoding enzymes involved in histone modification, highlighting the role of mutations in components of the chromatin modification machinery in human cancer.

    • Gillian L. Dalgliesh
    • , Kyle Furge
    •  & P. Andrew Futreal
  • Letter |

    After fertilization in mammals, the maternal and paternal genomes undergo epigenetic reprogramming to prepare for the transition from germ cell to somatic cell transcription programs. One of the events that takes place is the demethylation of the paternal genome. To identify the factors involved in this process, a live cell imaging system is now used to monitor the paternal DNA methylation state in zygotes; Elp3, a component of the elongator complex, is found to have an important role.

    • Yuki Okada
    • , Kazuo Yamagata
    •  & Yi Zhang