Explore the vast range of titles available.

Emmanuel Mignot and colleagues report that variants in the T-cell receptor alpha ( TRA@ ) locus are strongly associated with narcolepsy. This is the first documented involvement of the TCR locus in human disease and will shed light on how HLA-TCR interactions contribute to organ-specific autoimmune targeting. Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals 1 , 2 . Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3 ) and later sublocalized to DQB1 * 0602 (ref. 4 ). Following studies in dogs 5 and mice 6 , a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported 7 , 8 . Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10 −21 , 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders 9 ; thus, narcolepsy will provide new insights on how HLA–TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders 9 .

Nat. Genet. 41, 708–711 (2009); published online 3 May 2009; corrected after print 26 June 2009 In the version of this article initially published, Seung-Chul Hong was incorrectly listed as Sheng Seung-Chul Hong. The error has been corrected in the HTML and PDF versions of the article.

The Lake County Conservation District has a creative idea for a 60,000-acre conservation forest in the Swan Valley.The fires now burning in Montana have or will burn hundreds of millions of board feet of timber and are killing and displacing hundreds of species of wildlife.

Long-term renal allograft rejection is the most common outcome in kidney transplantation. Continuing the crusade to extend allograft function after the first year post-transplantation, we attempted to associate genetic factors that might contribute to long-term allograft outcomes by sequencing the exomes of patients diagnosed with chronic allograft nephropathy/interstitial fibrosis and tubular atrophy. A variety of association analyses were employed, but these analyses failed to identify statistically significant associations. The study was underpowered to detect the association of rare genomic variants with small effect sizes. However, it confirmed previous reports of the absence of large effects from common variants. We have made both the study data and analysis workflow available for public use, and we hope that these resources will help to power future meta-analyses that may detect smaller effects.

Key Points The development of multiple myeloma is preceded by pre-malignant stages, and therefore constitutes a well-defined model of disease progression that is appropriate for studies of clonal evolution and heterogeneity Whole-exome sequencing studies have enabled the characterization of the genomic alterations underlying the pathogenesis of multiple myeloma The primary genomic events involved in multiple myeloma are the acquisition of hyperdiploidy or translocations affecting the IGH genes; these events are mutually exclusive Secondary genomic events include chromosomal translocations, copy-number variations and single-nucleotide variants Genomic events underlying multiple myeloma affect multiple signalling pathways including the MYC, NF-κB, and MAPK pathways, plasma-cell differentiation, cell-cycle regulation or DNA-damage repair In the past 5 years, results from large-scale whole-exome sequencing studies have brought new insight into the clonal heterogeneity and evolution of multiple myeloma, a genetically complex disease. Herein, the authors describe the driver gene alterations and sequential acquisition of the main genomic aberrations involved in this disease, with a focus on the clonal heterogeneity of multiple myeloma and its clinical implications. Multiple myeloma (MM) is a genetically complex disease that evolves from pre-malignant stages, such as monoclonal gammaopathy of undetermined significance and smouldering multiple myeloma, and progresses to symptomatic MM; this continuum provides a unique framework to study the sequential genomic evolution of MM. In the past 5 years, results from large-scale whole-exome sequencing studies have provided new insights into the clonal heterogeneity and evolution of the disease. Moreover, the recurrent co-occurrence of genomic events helps to dissect the genomic complexity underlying tumour progression. According to the primary genetic events involved in tumorigenesis, MM tumours are hierarchically subdivided into hyperdiploid and non-hyperdiploid subtypes; subsequently, secondary genetic events lead to tumour progression. In this Review, we describe the 'driver' gene alterations involved in the development and progression of MM, with a focus on the sequential acquisition of the main genomic aberrations. We also provide valuable insight into the clonal heterogeneity and clonal evolution of the disease, as well as into the therapeutic implications of a comprehensive understanding of the genomic complexity of MM.