Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign.

BackgroundMany genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced.MethodsPublicly available data from the Exome Variant Project were analyzed, focusing on 36 genes known to harbor mutations causing autosomal dominant macular dystrophy.ResultsRates of rare (minor allele frequency ≤0.1%) and private missense variants within autosomal dominant retinal dystrophy genes were found to occur at a high frequency in unaffected individuals, while nonsense variants were not.ConclusionsWe conclude that rare missense variations in most of these genes identified in individuals with retinal dystrophy cannot be confidently classified as disease-causing in the absence of additional information such as linkage or functional validation

High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene.

Chromosome 17q11-q21 is a region of the genome likely to harbor susceptibility to autism (MIM(209850)) based on earlier evidence of linkage to the disorder. This linkage is specific to multiplex pedigrees containing only male probands (MO) within the Autism Genetic Resource Exchange (AGRE). Earlier, Stone et al.(1) completed a high-density single nucleotide polymorphism association study of 13.7 Mb within this interval, but common variant association was not sufficient to account for the linkage signal. Here, we extend this single nucleotide polymorphism-based association study to complete the coverage of the two-LOD support interval around the chromosome 17q linkage peak by testing the majority of common alleles in 284 MO trios. Markers within an interval containing the gene, CACNA1G, were found to be associated with Autism Spectrum Disorder at a locally significant level (P=1.9 × 10(-5)). While establishing CACNA1G as a novel candidate gene for autism, these alleles do not contribute a sufficient genetic effect to explain the observed linkage, indicating that there is substantial genetic heterogeneity despite the clear linkage signal. The region thus likely harbors a combination of multiple common and rare alleles contributing to the genetic risk. These data, along with earlier studies of chromosomes 5 and 7q3, suggest few if any major common risk alleles account for Autism Spectrum Disorder risk under major linkage peaks in the AGRE sample. This provides important evidence for strategies to identify Autism Spectrum Disorder genes, suggesting that they should focus on identifying rare variants and common variants of small effect

Creating transplant tolerance by taming adverse intragraft innate immunity

Certain forms of inflammation of an allograft are highly detrimental to the induction and maintenance of transplant tolerance as they foster stable commitment to graft-destructive, not graft-protective, forms of T-cell immunity. Hence, a reduction in adverse tissue inflammation may prove crucial in facilitating the induction and maintenance of a long-lasting state of transplant tolerance

RELBET 4.0 user's guide

This manual describes the operation and use of RELBET 4.0 implemented on the Hewlett Packard model 9000. The RELBET System is an integrated collection of computer programs which support the analysis and post-flight reconstruction of vehicle to vehicle relative trajectories of two on-orbit free-flying vehicles: the Space Shuttle Orbiter and some other free-flyer. The manual serves both as a reference and as a training guide. Appendices provide experienced users with details and full explanations of program usage. The body of the manual introduces new users to the system by leading them through a step by step example of a typical production. This should equip the new user both to execute a typical production process and to understand the most significant variables in that process

Detection of Molecular Hydrogen Orbiting a "Naked" T Tauri Star

Astronomers have established that for a few million years newborn stars possess disks of orbiting gas and dust. Such disks, which are likely sites of planet formation, appear to disappear once these stars reach ages of 5-10 times 10^6 yr; yet, >= 10^7 yr is thought necessary for giant planet formation. If disks dissipate in less time than is needed for giant planet formation, such planets may be rare and those known around nearby stars would be anomalies. Herein, we report the discovery of H_2 gas orbiting a weak-lined T Tauri star heretofore presumed nearly devoid of circumstellar material. We estimate that a significant amount of H_2 persists in the gas phase, but only a tiny fraction of this mass emits in the near-infrared. We propose that this star possesses an evolved disk that has escaped detection thus far because much of the dust has coagulated into planetesimals. This discovery suggests that the theory that disks are largely absent around such stars should be reconsidered. The widespread presence of such disks would indicate that planetesimals can form quickly and giant planet formation can proceed to completion before the gas in circumstellar disks disperses.Comment: latex 12 pages, including 1 figur