Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder.

Three-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD). We generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions. Non-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations related to ASD risk. Correspondingly, target genes showed spatiotemporal expressions relevant to ASD in developing brains and enrichment in biological pathways implicated in ASD, such as histone modification. Regarding clinical features of ASD, non-coding DNMs in chromatin interactions particularly contributed to low intelligence quotient levels in ASD probands. We further validated our findings using two replication cohorts, Simons Simplex Collection (SSC) and MSSNG, and showed the consistent enrichment of non-coding DNM-disrupted chromatin interactions in ASD probands. Generating human induced pluripotent stem cells in two ASD families, we were able to demonstrate that non-coding DNMs in chromatin interactions alter the expression of target genes at the stage of early neural development. Taken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.

MPI-GWAS: a supercomputing-aided permutation approach for genomewide association studies.

Permutation testing is a robust and popular approach for significance testing in genomic research that has the advantage of reducing inflated type 1 error rates; however, its computational cost is notorious in genome-wide association studies (GWAS). Here, we developed a supercomputing-aided approach to accelerate the permutation testing for GWAS, based on the message-passing interface (MPI) on parallel computing architecture. Our application, called MPI-GWAS, conducts MPI-based permutation testing using a parallel computing approach with our supercomputing system, Nurion (8,305 compute nodes, and 563,740 central processing units [CPUs]). For 107 permutations of one locus in MPI-GWAS, it was calculated in 600 s using 2,720 CPU cores. For 107 permutations of ~30,000-50,000 loci in over 7,000 subjects, the total elapsed time was ~4 days in the Nurion supercomputer. Thus, MPI-GWAS enables us to feasibly compute the permutation-based GWAS within a reason-able time by harnessing the power of parallel computing resources.

Reconstruction of Acetogenesis Pathway Using Short-Read Sequencing of Clostridium aceticum Genome.

Clostridium aceticum is an anaerobic homoacetogen, able to reduce CO2 to multi-carbon products using the reductive acetyl-CoA pathway. This unique ability to use CO2 or CO makes the microbe a potential platform for the biotech industry. However, the development of genetically engineered homoacetogen for the large-scale production of commodity chemicals is hampered by the limited amount of their genetic and metabolic information. Here we exploited next-generation sequencing to reveal C. aceticum genome. The short-read sequencing produced 44,871,196 high quality reads with an average length of 248 bases. Following sequence trimming step, 30,256,976 reads were assembled into 12,563 contigs with 168-fold coverage and 1,971 bases in length using de Bruijn graph algorithm. Since the k-mer hash length in the algorithm is an important factor for the quality of output contigs, a window of k-mers (k-51 to k-201) was tested to obtain high quality contigs. In addition to the assembly metrics, the functional annotation of the contigs was investigated to select the k-mer optimum. Metabolic pathway mapping using the functional annotation identified the majority of central metabolic pathways, such as the glycolysis and TCA cycle. Further, these analyses elucidated the enzymes consisting of Wood-Ljungdahl pathway, in which CO2 is fixed into acetyl-CoA. Thus, the metabolic reconstruction based on the draft genome assembly provides a foundation for the functional genomics required to engineer C. aceticum.

Network Comparison of Inflammation in Colorectal Cancer and Alzheimer's Disease.

Recently, a large clinical study revealed an inverse correlation of individual risk of cancer versus Alzheimer's disease (AD). However, no explanation exists for this anticorrelation at the molecular level; however, inflammation is crucial to the pathogenesis of both diseases, necessitating a need to understand differing signaling usage during inflammatory responses distinct to both diseases. Using a subpathway analysis approach, we identified numerous well-known and previously unknown pathways enriched in datasets from both diseases. Here, we present the quantitative importance of the inflammatory response in the two disease pathologies and summarize signal transduction pathways common to both diseases that are affected by inflammation.

Effect of low-level laser therapy on osteoarthropathy in rabbit.

The aim of this study was to determine whether low-level laser therapy (LLLT) aided the recovery of damaged articular cartilage in joints with artificially induced osteoarthropathy (OA). OA was induced by injecting hydrogen peroxide (H2O2) into the articular spaces of both knees in rabbits, twice a week for 4 weeks. The induction of OA and the effect of LLLT were evaluated by biochemical, radiological and histopathological analysis. Superoxide dismutase (SOD) activity increased about 40% in the OA group, as compared to the controls. Although SOD activity in the OA group was not significantly different from the 2-week groups, it was significantly different from the 4-week control and treatment groups. There was also a significant difference between the 4-week control and treatment groups. Simple radiographs and three-dimensional computed tomographs (3D CT) did not show detectable arthropathy in the OA group, nor any particular changes in the 2-week groups. In contrast, distinct erosions were seen in the distal articular cartilage of the femur, with irregularity of the articular surface, in the 4-week control group, while the erosions were reduced and arthropathy improved slightly in the 4-week treatment group. Grossly, erosions formed on the articular surface in the OA group. In comparison, severe erosions damaged the articular cartilage in the 4-week control group, but not in the 2-week control and treatment groups. Regeneration of articular cartilage was seen in gross observations in the 4-week treatment group. Histopathologically, there was slight irregularity of the articular surface and necrosis in the OA group, and serious cartilage damage, despite slight chondrocyte regeneration, in the 4-week control group. Conversely, the 4-week treatment group showed chondrocyte replacement, with sometimes close to normal articular cartilage on the articular surface. These results suggest that LLLT was effective in the treatment of chemically-induced OA.