Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.     

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.     

Topological domains in mammalian genomes identified by analysis of chromatin interactions

The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories, and numerous models have been proposed for how chromosomes fold within chromosome territories. These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid advances in the study of three-dimensional genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide. Here we investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term 'topological domains', as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes. Finally, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome.     

Optimal traffic organization in ants under crowded conditions

Efficient transportation, a hot topic in nonlinear science, is essential for modern societies and the survival of biological species. Biological evolution has generated a rich variety of successful solutions, which have inspired engineers to design optimized artificial systems. Foraging ants, for example, form attractive trails that support the exploitation of initially unknown food sources in almost the minimum possible time. However, can this strategy cope with bottleneck situations, when interactions cause delays that reduce the overall flow? Here, we present an experimental study of ants confronted with two alternative routes. We find that pheromone-based attraction generates one trail at low densities, whereas at a high level of crowding, another trail is established before traffic volume is affected, which guarantees that an optimal rate of food return is maintained. This bifurcation phenomenon is explained by a nonlinear modelling approach. Surprisingly, the underlying mechanism is based on inhibitory interactions. It points to capacity reserves, a limitation of the density-induced speed reduction, and a sufficient pheromone concentration for reliable trail perception. The balancing mechanism between cohesive and dispersive forces appears to be generic in natural, urban and transportation systems.     

Pathogenic mutation in the ALS/FTD gene, <Emphasis Type="Italic">CCNF,</Emphasis> causes elevated Lys48-linked ubiquitylation and defective autophagy

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase (SCF^{cyclin F}) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin F^S621G caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin F^WT. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin F^S621G-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin F^S621G revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin F^S621G disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis.     

A mid-level approach to modeling scientific communities

This paper provides an account of mid-level models which calibrate highly theoretical agent-based models of scientific communities by incorporating empirical information from real-world systems. As a result, these models more closely correspond with real-world communities, and are better suited for informing policy decisions than extant how-possibly models. I provide an exemplar of a mid-level model of science funding allocation that incorporates bibliometric data from scientific publications and data generated from empirical studies of peer review into an epistemic landscape model. The results of my model show that on a dynamic epistemic landscape, allocating funding by modified and pure lottery strategies performs comparably to a perfect selection funding allocation strategy. These results support the idea that introducing randomness into a funding allocation process may be a tractable policy worth exploring further through pilot studies. My exemplar shows that agent-based models need not be restricted to the abstract and the apriori; they can also be informed by empirical data.     

Root tip contact with low-phosphate media reprograms plant root architecture

Plant roots are able to sense soil nutrient availability. In order to acquire heterogeneously distributed water and minerals, they optimize their root architecture. One poorly understood plant response to soil phosphate (P(i)) deficiency is a reduction in primary root growth with an increase in the number and length of lateral roots. Here we show that physical contact of the Arabidopsis thaliana primary root tip with low-P(i) medium is necessary and sufficient to arrest root growth. We further show that loss-of-function mutations in Low Phosphate Root1 (LPR1) and its close paralog LPR2 strongly reduce this inhibition. LPR1 was previously mapped as a major quantitative trait locus (QTL); the molecular origin of this QTL is explained by the differential allelic expression of LPR1 in the root cap. These results provide strong evidence for the involvement of the root cap in sensing nutrient deficiency, responding to it, or both. LPR1 and LPR2 encode multicopper oxidases (MCOs), highlighting the essential role of MCOs for plant development.