Explore the vast range of titles available.

With more than 10 million genotyped customers, the consumer genomics industry is maturing and becoming a mainstream phenomenon. At last, innovations and applications, some unforeseen, are being brought to the masses.

Dense single nucleotide polymorphism testing has revolutionized forensic science, helping solve decadesold, current and future cases by overcoming the limitations of traditional short tandem repeat profiling. By embracing innovations from fields such as ancient DNA analysis, forensics can deliver long-awaited answers and justice to victims and their families.

The standardization and performance testing of analysis tools is a prerequisite to widespread adoption of genome-wide sequencing, particularly in the clinic. However, performance testing is currently complicated by the paucity of standards and comparison metrics, as well as by the heterogeneity in sequencing platforms, applications and protocols. Here we present the genome comparison and analytic testing (GCAT) platform to facilitate development of performance metrics and comparisons of analysis tools across these metrics. Performance is reported through interactive visualizations of benchmark and performance testing data, with support for data slicing and filtering. The platform is freely accessible at http://www.bioplanet.com/gcat . The standardization of clinical sequencing data generation and analysis is of critical importance. Here, the authors develop the Genome Comparison and Analytic Testing platform to facilitate the development of performance metrics and comparisons of analysis tools for clinical sequencing studies.

Purpose: To study the effects of bilateral medial rectus recession for the management of adult onset age-related distance esotropia. Methods: Ten patients with adult onset age-related distance esotropia measuring 14 prism diopters or greater underwent bilateral medial rectus recession to eliminate the need for prism glasses. Results: In all but one case, the diplopia completely resolved postoperatively, with a median residual deviation of 1 prism diopter esophoria for distance and 2 prism diopters exophoria at near. Conclusion: Bilateral medial rectus recession is a useful technique for the management of adult onset age-related distance esotropia.

Perhaps due to its negative reception by prominent scholars, Helena (1876) remains one of the least studied and appreciated novels by J. M. Machado de Assis. Roberto Schwarz, one of the most influential commentators on Machado, has dismissed the novel as a poorly written effort, even for the author's so-called first phase, that attempts to salvage the paternalistic structure of Brazilian society by appeal to Christian morality-a project the critic calls ideologically insipid (Schwarz, Ao vencedor as batatas 90). Taking somewhat more interest in the narrative, Regina Zilberman joins Schwarz in condemning the book's ideology as unacceptably \"conformista, conservadora e moralista\" (Zilberman 98). Even critics who defend the novel against such severe attacks and find value in its realism (Chalhoub 18), style and psychological depth (Fitz 49), or intertextual richness (Durand 2526), typically concede that Helena is no masterpiece. I will argue here for a new reading of the novel, one that may allow us to take greater interest in the text and to rethink its place among Machado's writings, based on a recent innovation in the theory of fictional narrative. Joshua Landy has argued that certain works of fiction are best understood as formative, in the sense that they offer opportunities for (suitably disposed) readers to engage in specific kinds of intellectual or mental training. Following Landy's theory of formative fictions, I suggest that Helena be read as a training text for skeptical readers: readers who examine critically the actions and pronouncements of fictional characters as well as narrators; who scrutinize claims, arguments, and evidence presented within narrative; and who will ultimately suspend judgment about dubious possibilities raised by fictional discourse.

Purpose: To study the effects of bilateral medial rectus recession for the management of adult onset age-related distance esotropia. Methods: Ten patients with adult onset age-related distance esotropia measuring 14 prism diopters or greater underwent bilateral medial rectus recession to eliminate the need for prism glasses. Results: In all but one case, the diplopia completely resolved postoperatively, with a median residual deviation of 1 prism diopter esophoria for distance and 2 prism diopters exophoria at near. Conclusion: Bilateral medial rectus recession is a useful technique for the management of adult onset age-related distance esotropia.

Accumulation of somatic mutations is thought to contribute to the aging process. Genomic instability has been shown to increase during aging, suggesting an aberrant function of DNA doublestrand break (DSB) repair. Surprisingly, DSB repair has not been examined with respect to cellular senescence. Therefore, we have studied the ability of young, presenescent, and senescent normal human fibroblasts to repair DSBs in transfected DNA by using a fluorescent reporter substrate. We have found that the efficiency of end joining is reduced up to 4.5 fold in presenescent and senescent cells, relative to young cells. Sequence analysis of end junctions showed that the frequency of precise ligation was higher in young cells, whereas end joining in old cells was associated with extended deletions. These results indicate that end joining becomes inefficient and more error-prone during cellular senescence. Furthermore, the ability to use microhomologies for end joining was compromised in senescent cells, suggesting that young and senescent cells may use different end joining pathways. We hypothesize that inefficient and aberrant end joining is a likely mechanism underlying the age-related genomic instability and higher incidence of cancer in the elderly.

Expanded triplet repeats have been identified as the genetic basis for a growing number of neurological and skeletal disorders. To examine the contribution of double-strand break repair to CAG·CTG repeat instability in mammalian systems, we developed zinc finger nucleases (ZFNs) that recognize and cleave CAG repeat sequences. Engineered ZFNs use a tandem array of zinc fingers, fused to the FokI DNA cleavage domain, to direct double-strand breaks (DSBs) in a site-specific manner. We first determined that the ZFNs cleave CAG repeats in vitro. Then, using our previously described tissue culture assay for identifying modifiers of CAG repeat instability, we found that transfection of ZFN-expression vectors induced up to a 15-fold increase in changes to the CAG repeat in human and rodent cell lines, and that longer repeats were much more sensitive to cleavage than shorter ones. Analysis of individual colonies arising after treatment revealed a spectrum of events consistent with ZFN-induced DSBs and dominated by repeat contractions. We also found that expressing a dominant-negative form of RAD51 in combination with a ZFN, dramatically reduced the effect of the nuclease, suggesting that DSB-induced repeat instability is mediated, in part, through homology directed repair. These studies identify a ZFN as a useful reagent for characterizing the effects of DSBs on CAG repeats in cells.

Trinucleotide repeats can be highly unstable, mutating far more frequently than point mutations. Repeats typically mutate by addition or loss of units of the repeat. CAG repeat expansions in humans trigger neurological diseases that include myotonic dystrophy, Huntington disease, and several spinocerebellar ataxias. In human cells, diverse mechanisms promote CAG repeat instability, and in mice, the mechanisms of instability are varied and tissue-dependent. Dissection of mechanistic complexity and discovery of potential therapeutics necessitates quantitative and scalable screens for repeat mutation. We describe a GFP-based assay for screening modifiers of CAG repeat instability in human cells. The assay exploits an engineered intronic CAG repeat tract that interferes with expression of an inducible GFP minigene. Like the phenotypes of many trinucleotide repeat disorders, we find that GFP function is impaired by repeat expansion, in a length-dependent manner. The intensity of fluorescence varies inversely with repeat length, allowing estimates of repeat tract changes in live cells. We validate the assay using transcription through the repeat and engineered CAG-specific nucleases, which have previously been reported to induce CAG repeat instability. The assay is relatively fast and should be adaptable to large-scale screens of chemical and shRNA libraries.

Genome sequencing technologies promise to revolutionize our understanding of genetics, evolution, and disease by making it feasible to survey a broad spectrum of sequence variation on a population scale. However, this potential can only be realized to the extent that methods for extracting and interpreting distinct forms of variation can be established. The error profiles and read length limitations of early versions of next-generation sequencing technologies rendered them ineffective for some sequence variant types, particularly microsatellites and other tandem repeats, and fostered the general misconception that such variants are inherently inaccessible to these platforms. At the same time, tandem repeats have emerged as important sources of functional variation. Tandem repeats are often located in and around genes, and frequent mutations in their lengths exert quantitative effects on gene function and phenotype, rapidly degrading linkage disequilibrium between markers and traits. Sensitive identification of these variants in large-scale next-gen sequencing efforts will enable more comprehensive association studies capable of revealing previously invisible associations. We present a population-scale analysis of microsatellite repeats using whole-genome data from 158 inbred isolates from the Drosophila Genetics Reference Panel, a collection of over 200 extensively phenotypically characterized isolates from a single natural population, to uncover processes underlying repeat mutation and to enable associations with behavioral, morphological, and life-history traits. Analysis of repeat variation from next-generation sequence data will also enhance studies of genome stability and neurodegenerative diseases.