Accelerating Discovery for Complex Neurological and Behavioral Disorders Through Systems Genetics and Integrative Genomics in the Laboratory Mouse

Recent advances in systems genetics and integrative functional genomics have greatly improved the study of complex neurological and behavioral traits. The methods developed for the integrated characterization of new, high-resolution mouse genetic reference populations and systems genetics enable behavioral geneticists an unprecedented opportunity to address questions of the molecular basis of neurological and psychiatric disorders and their comorbidities. Integrative genomics augment these strategies by enabling rapid informatics-assisted candidate gene prioritization, cross-species translation, and mechanistic comparison across related disorders from a wealth of existing data in mouse and other model organisms. Ultimately, through these complementary approaches, finding the mechanisms and sources of genetic variation underlying complex neurobehavioral disease related traits is becoming tractable. Furthermore, these methods enable categorization of neurobehavioral disorders through their underlying biological basis. Together, these model organism-based approaches can lead to a refinement of diagnostic categories and targeted treatment of neurological and psychiatric disease

Caretaker Brca1: keeping the genome in the straight and narrow

Inheritance of germline BRCA1 mutations is associated with a high risk of breast and ovarian cancers. A multitude of cellular functions has been ascribed to BRCA1, including transcription activation and various aspects of DNA repair. So far, indirect evidence has indicated a role for BRCA1 in the repair of double-strand breaks. Recently, an elegant gene targeting design was used to provide definitive evidence that BRCA1 promotes homologous recombination and limits nonhomologous mutagenic repair processes. This reaffirms the role of BRCA1 as caretaker in preserving genomic integrity

Phylogenetic and environmental context of a Tournaisian tetrapod fauna

The end-Devonian to mid-Mississippian time interval has long been known for its depauperate palaeontological record, especially for tetrapods. This interval encapsulates the time of increasing terrestriality among tetrapods, but only two Tournaisian localities previously produced tetrapod fossils. Here we describe five new Tournaisian tetrapods ($\textit{Perittodus apsconditus}$, $\textit{Koilops herma}$, $\textit{Ossirarus kierani}$, $\textit{Diploradus austiumensis}$ and $\textit{Aytonerpeton microps}$) from two localities in their environmental context. A phylogenetic analysis retrieved three taxa as stem tetrapods, interspersed among Devonian and Carboniferous forms, and two as stem amphibians, suggesting a deep split among crown tetrapods. We also illustrate new tetrapod specimens from these and additional localities in the Scottish Borders region. The new taxa and specimens suggest that tetrapod diversification was well established by the Tournaisian. Sedimentary evidence indicates that the tetrapod fossils are usually associated with sandy siltstones overlying wetland palaeosols. Tetrapods were probably living on vegetated surfaces that were subsequently flooded. We show that atmospheric oxygen levels were stable across the Devonian/Carboniferous boundary, and did not inhibit the evolution of terrestriality. This wealth of tetrapods from Tournaisian localities highlights the potential for discoveries elsewhere.NERC consortium grants NE/J022713/1 (Cambridge), NE/J020729/1 (Leicester), NE/J021067/1 (BGS), NE/J020621/1 (NMS) and NE/J021091/1 (Southampton

A search for quantitative trait loci controlling within-individual variation of physical activity traits in mice

<p>Abstract</p> <p>Background</p> <p>In recent years it has become increasingly apparent that physical inactivity can predispose individuals to a host of health problems. While many studies have analyzed the effect of various environmental factors on activity, we know much less about the genetic control of physical activity. Some studies in mice have discovered quantitative trait loci (QTL) influencing various physical activity traits, but mostly have analyzed inter-individual variation rather than variation in activity within individuals over time. We conducted a genome scan to identify QTLs controlling the distance, duration, and time run by mice over seven consecutive three-day intervals in an F₂population created by crossing two inbred strains (C57L/J and C3H/HeJ) that differed widely (average of nearly 300%) in their activity levels. Our objectives were (a) to see if we would find QTLs not originally discovered in a previous investigation that assessed these traits over the entire 21-day period and (b) to see if some of these QTLs discovered might affect the activity traits only in the early or in the late time intervals.</p> <p>Results</p> <p>This analysis uncovered 39 different QTLs, over half of which were new. Some QTLs affected the activity traits only in the early time intervals and typically exhibited significant dominance effects whereas others affected activity only in the later age intervals and exhibited less dominance. We also analyzed the regression slopes of the activity traits over the intervals, and found several QTLs affecting these traits that generally mapped to unique genomic locations.</p> <p>Conclusions</p> <p>It was concluded that the genetic architecture of physical activity in mice is much more complicated than has previously been recognized, and may change considerably depending on the age at which various activity measures are assessed.</p

Design-time formal verification for smart environments: an exploratory perspective

Smart environments (SmE) are richly integrated with multiple heterogeneous devices; they perform the operations in intelligent manner by considering the context and actions/behaviors of the users. Their major objective is to enable the environment to provide ease and comfort to the users. The reliance on these systems demands consistent behavior. The versatility of devices, user behavior and intricacy of communication complicate the modeling and verification of SmE's reliable behavior. Of the many available modeling and verification techniques, formal methods appear to be the most promising. Due to a large variety of implementation scenarios and support for conditional behavior/processing, the concept of SmE is applicable to diverse areas which calls for focused research. As a result, a number of modeling and verification techniques have been made available for designers. This paper explores and puts into perspective the modeling and verification techniques based on an extended literature survey. These techniques mainly focus on some specific aspects, with a few overlapping scenarios (such as user interaction, devices interaction and control, context awareness, etc.), which were of the interest to the researchers based on their specialized competencies. The techniques are categorized on the basis of various factors and formalisms considered for the modeling and verification and later analyzed. The results show that no surveyed technique maintains a holistic perspective; each technique is used for the modeling and verification of specific SmE aspects. The results further help the designers select appropriate modeling and verification techniques under given requirements and stress for more R&D effort into SmE modeling and verification researc

Clustered Gene Expression Changes Flank Targeted Gene Loci in Knockout Mice

Gene expression profiling using microarrays is a powerful technology widely used to study regulatory networks. Profiling of mRNA levels in mutant organisms has the potential to identify genes regulated by the mutated protein.Using tissues from multiple lines of knockout mice we have examined genome-wide changes in gene expression. We report that a significant proportion of changed genes were found near the targeted gene.The apparent clustering of these genes was explained by the presence of flanking DNA from the parental ES cell. We provide recommendations for the analysis and reporting of microarray data from knockout mice

IL-2 Immunotherapy to Recently HIV-1 Infected Adults Maintains the Numbers of IL-17 Expressing CD4+ T (TH17) Cells in the Periphery

Little is known about the manipulation of IL-17 producing CD4+ T cells (TH17) on a per-cell basis in humans in vivo. Previous studies on the effects of IL-2 on IL-17 secretion in non-HIV models have shown divergent results. We hypothesized that IL-2 would mediate changes in IL-17 levels among recently HIV-1-infected adults receiving anti-retroviral therapy. We measured cytokine T cell responses to CD3/CD28, HIV-1 Gag, and CMV pp65 stimulation, and changes in multiple CD4+ T cell subsets. Those who received IL-2 showed a robust expansion of naive and total CD4+ T cell counts and T-reg counts. However, after IL-2 treatment, the frequency of TH17 cells declined, while counts of TH17 cells did not change due to an expansion of the CD4+ naïve T cell population (CD27+CD45RA+). Counts of HIV-1 Gag-specific T cells declined modestly, but CMV pp65 and CD3/CD28 stimulated populations did not change. Hence, in contrast with recent studies, our results suggest IL-2 is not a potent in vivo regulator of TH17 cell populations in HIV-1 disease. However, IL-2-mediated T-reg expansions may selectively reduce responses to certain antigen-specific populations, such as HIV-1 Gag

Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J × 129S1/SvImJ inbred mouse cross

Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication. To gain insight into genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia, and loss of righting reflex (LORR) duration in a B6 × S1 F2 population. We confirmed that S1 showed greater EtOH-induced hypothermia (specifically at a high dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex. QTLs for different EtOH phenotypes were largely non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies. The architecture of the traits we examined was complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found. Uncovering candidate genes associated with variation in these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans

Role of BRCA gene dysfunction in breast and ovarian cancer predisposition

Tumor suppressor genes that perform apparently generic cellular functions nonetheless cause tissue-specific syndromes in the human population when they are mutated in the germline. The two major hereditary breast/ovarian cancer predisposition genes, BRCA1 and BRCA2, appear to participate in a common pathway that is involved in the control of homologous recombination and in the maintenance of genomic integrity. How might such functions translate into the specific suppression of cancers of the breast and ovarian epithelia? Recent advances in the study of BRCA1 and BRCA2, discussed herein, have provided new opportunities to address this question