Disease genetics articles within Nature

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  • News & Views |

    Neuronal networks in the brain that develop early in life underlie our ability to learn, remember and communicate. Genetic defects that perturb the fine-tuning of such neuronal connectivity can cause disease.

    • Peter Scheiffele
    •  & Asim A. Beg

  • Article |

    Analysing single cells from human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample, the evolutionary path by which different subclones have emerged, and ongoing dynamic changes associated with relapse. Leukaemia-propagating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level. This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-propagating cells.

    • Kristina Anderson
    • , Christoph Lutz
    •  & Mel Greaves

  • Letter |

    Long interspersed nuclear elements-1 (L1) retrotransposons affect gene expression and neuronal function throughout brain development. These authors show that the absence of methyl-CpG-binding protein 2, a modulator of DNA methylation implicated in several neurodevelopmental disorders, increases L1 retrotransposon activity in rodent models, with this increase in susceptibility duplicated in patients with Rett syndrome. These correlations suggest that disease-related genetic mutations may influence L1 retrotransposon activity.

    • Alysson R. Muotri
    • , Maria C. N. Marchetto
    •  & Fred H. Gage

  • Technology Feature |

    The list of human genetic variations is expanding; but an understanding of how they contribute to disease is still patchy.

    • Monya Baker

  • Letter |

    Progestins, used in contraceptives and hormone replacement therapy, have been linked to breast cancer. These authors provide a mechanistic basis for this association. They show in a mouse model that synthetic progestins can promote mammary tumour formation by inducing RANKL (receptor activator of NF-KB ligand), which acts on mammary epithelial cells through the RANKL receptor RANK.

    • Daniel Schramek
    • , Andreas Leibbrandt
    •  & Josef M. Penninger

  • Letter |

    Here, a combination of genetic studies of gene expression, cross-species network analysis and genome-wide association studies has been used to identify gene networks and the loci underlying their regulation in rats. The results show that an inflammatory network driven by interferon regulatory factor 7 contributes to susceptibility to type 1 diabetes, and implicate the innate viral-response pathway and macrophages in the aetiology of this disease.

    • Matthias Heinig
    • , Enrico Petretto
    •  & Stuart A. Cook

  • Letter |

    Mapping disease loci that underlie putative Mendelian forms of malformations of cortical development is complicated by genetic heterogeneity, small family sizes and diagnostic classifications that may not reflect molecular pathogenesis. These authors use whole-exome sequencing to identify recessive mutations in WDR62 as the cause of a wide spectrum of severe cerebral cortical malformations. WDR62's nuclear localization to germinal neuroepithelia indicates that cortical malformations can be caused by events during progenitor proliferation and neurogenesis.

    • Kaya Bilgüvar
    • , Ali Kemal Öztürk
    •  & Murat Günel

  • Letter |

    Down's syndrome is caused by trisomy of chromosome 21, and it is known that the growth of certain tumours is reduced in this genetic disorder. Using a mouse model of Down's syndrome, several individual genes on chromosome 21 are now being proposed to mediate the effect on tumour growth and angiogenesis.

    • Louise E. Reynolds
    • , Alan R. Watson
    •  & Kairbaan M. Hodivala-Dilke

  • Letter |

    The autistic spectrum disorders (ASDs) are highly heritable, yet the underlying genetic determinants remain largely unknown. Here, a genome-wide analysis of rare copy number variants (CNVs) has been carried out, revealing that ASD sufferers carry a higher load of rare, genic CNVs than do controls. Many of these CNVs are de novo and inherited. The results implicate several novel genes in ASDs, and point to the importance of cellular proliferation, projection and motility, as well as specific signalling pathways, in these disorders.

    • Dalila Pinto
    • , Alistair T. Pagnamenta
    •  & Catalina Betancur

  • Letter |

    Amyotrophic lateral sclerosis (ALS) is a disorder characterized by the degeneration of motor neurons. About 10% of cases are familial, but the mutations identified in these families account for only 20–30% of such cases. Here a new set of mutations in familial ALS is found — in the gene encoding optineurin. Given the effect of optineurin mutations on the NF-κB protein, it is suggested that inhibiting NF-κB might be useful in treating ALS.

    • Hirofumi Maruyama
    • , Hiroyuki Morino
    •  & Hideshi Kawakami

  • Letter |

    Hereditary hypotrichosis simplex is a rare form of hereditary hair loss in humans, where the hair follicle is miniaturized. Now, the gene involved has been identified, using genetic linkage analysis in three affected families. The gene, APCDD1, is expressed in human hair follicles. It encodes a previously unknown membrane-bound glycoprotein that inhibits signalling through the Wnt protein and functions upstream of β-catenin.

    • Yutaka Shimomura
    • , Dritan Agalliu
    •  & Angela M. Christiano

  • Article |

    Copy number variants (CNVs) account for a major proportion of human genetic diversity and may contribute to genetic susceptibility to disease. Here, a large, genome-wide study of association between common CNVs and eight common human diseases is presented. The study provides a wealth of technical insights that will inform future study design and analysis. The results also indicate that common CNVs that can be 'typed' on existing platforms are unlikely to contribute much to the genetic basis of common diseases.

    • Nick Craddock
    • , Matthew E. Hurles
    •  & Peter Donnelly

  • 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

  • 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

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