Autism Genes, Again and Again Despite recent advances in sequencing technologies and their lowered costs—effective, highly sensitive, and specific sequencing of multiple genes of interest from large cohorts remains expensive. O'Roak et al. (p. 1619 ; published online 15 November) modified molecular inversion probe methods for target-specific capture and sequencing to resequence candidate genes in thousands of patients. The technique was applied to 44 candidate genes to identify de novo mutations in a large cohort of individuals with and without autism spectrum disorder. The analysis revealed several de novo mutations in genes that together contribute to 1% of sporadic autism spectrum disorders, supporting the notion that multiple genes underlie autism-spectrum disorders.

No abstract

Intra-individual tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases within an individual, we analyzed multiple tumors from men with disseminated prostate cancer by whole exome sequencing, array CGH and RNA transcript profiling and compared the genomic diversity within and between individuals. In contrast to substantial heterogeneity between men, there was limited diversity comparing metastases within an individual. Numbers of somatic mutations, the burden of genomic copy number alterations, and aberrations in known oncogenic drivers were highly concordant as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA) complex genes correlated with elevated cell cycle progression, E2F1 expression and RB1 loss. Men with somatic aberrations in FA complex genes or ATM exhibited significantly longer treatment response durations to carboplatin compared to men without defects in genes encoding DNA repair proteins. Collectively, these data indicate that though exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations present in disseminated tumors within an individual, and may be useful for selecting treatments based on predicted molecular vulnerabilities.

The aging population is at an increased risk of tendon injury and tendinopathy. Elucidating the molecular basis of tendon aging is crucial to understanding the age-related changes in structure and function in this vulnerable tissue. In this study, the structural and functional features of tendon aging are investigated. In addition, the roles of decorin and biglycan in the aging process were analyzed using transgenic mice at both mature and aged time points. Our hypothesis is that the increase in tendon injuries in the aging population is the result of altered structural properties that reduce the biomechanical function of the tendon and consequently increase susceptibility to injury. Decorin and biglycan are important regulators of tendon structure and therefore, we further hypothesized that decreased function in aged tendons is partly the result of altered decorin and biglycan expression. Biomechanical analyses of mature (day 150) and aged (day 570) patellar tendons revealed deteriorating viscoelastic properties with age. Histology and polarized light microscopy demonstrated decreased cellularity, alterations in tenocyte shape, and reduced collagen fiber alignment in the aged tendons. Ultrastructural analysis of fibril diameter distributions indicated an altered distribution in aged tendons with an increase of large diameter fibrils. Aged wild type tendons maintained expression of decorin which was associated with the structural and functional changes seen in aged tendons. Aged patellar tendons exhibited altered and generally inferior properties across multiple assays. However, decorin-null tendons exhibited significantly decreased effects of aging compared to the other genotypes. The amelioration of the functional deficits seen in the absence of decorin in aged tendons was associated with altered tendon fibril structure. Fibril diameter distributions in the decorin-null aged tendons were comparable to those observed in the mature wild type tendon with the absence of the subpopulation containing large diameter fibrils. Collectively, our findings provide evidence for age-dependent alterations in tendon architecture and functional activity, and further show that lack of stromal decorin attenuates these changes.