The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes.

Graphical Abstract Highlights d Expanded CD8CD38 high T cells in SLE patients identify patients with infections d CD8CD38 high T cells express decreased amounts of cytotoxic molecules d CD38 decreases NAD + and SIRT1 activity and releases the activity of EZH2 d Inhibition of EZH2 restores the degranulation capacity of CD8CD38 high T cells In Brief Katsuyama et al. find that an expanded CD8CD38 high T cell population in SLE patients is linked to infections. CD8CD38 high T cells display decreased cytotoxic capacity by suppressing the expression of related molecules through an NAD + /Sirtuin1/EZH2 pathway. EZH2 inhibitors increase cytotoxicity offering a means to mitigate infection rates in SLE. SUMMARYPatients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38 high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38 high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38 high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

Study Design. A retrospective cohort study of a nationwide sample database. Objective. The objective of the present study was to compare the long-term incidence of reoperation for lumbar herniated intervertebral disc disease (HIVD) after major surgical techniques (open discectomy, OD; laminectomy; percutaneous endoscopic lumbar discectomy, PELD; fusion). Summary of Background Data. HIVD is a major spinal affliction; if the disease is intractable, surgery is recommended. Considering both the aging of patients and the chronicity of lumbar degenerative disease, the effect of surgical treatment for the lumbar spine should be durable for as long as possible. Methods. The National Health Insurance Service-National Sample Cohort (NHIS-NSC) of Republic of Korea was utilized to establish a cohort of adult patients (N = 1856) who underwent first surgery for lumbar HIVD during 2005 to 2007. Patients were followed for 8 to 10 years. Considering death before reoperation as a competing event, reoperation hazards were compared among surgical techniques using the Fine and Gray regression model after adjustment for age, gender, Charlson comorbidity score, osteoporosis, diabetes, the severity of disability, insurance type, and hospital type. Results. The overall cumulative incidences of reoperation were 4% at 1 year, 6% at 2 years, 8% at 3 years, 11% at 5 years, and 16% at 10 years. The cumulative incidences of reoperation were 16%, 14%, 16%, and 10% after OD, laminectomy, PELD, and fusion, respectively, at 10 years postoperation, with no difference among the surgical techniques. However, the distribution of reoperation types was significantly different according to the first surgical technique (P < 0.01). OD was selected as the reoperation surgical technique in 80% of patients after OD and in 81% of patients after PELD. Conclusion. The probability of reoperation did not differ among OD, laminectomy, PELD, and fusion during the 10-year follow-up period. However, OD was the most commonly used technique in reoperation. Level of Evidence: 4

Background: Abalones are large marine snails in the family Haliotidae and the genus Haliotis belonging to the class Gastropoda of the phylum Mollusca. The family Haliotidae contains only one genus, Haliotis, and this single genus is known to contain several species of abalone. With 18 additional subspecies, the most comprehensive treatment of Haliotidae considers 56 species valid [1]. Abalone is an economically important fishery and aquaculture animal that is considered a highly prized seafood delicacy. The total global supply of abalone has increased 5-fold since the 1970s and farm production increased explosively from 50 mt to 103 464 mt in the past 40 years. Additionally, researchers have recently focused on abalone given their reported tumor suppression effect. However, despite the valuable features of this marine animal, no genomic information is available for the Haliotidae family and related research is still limited. To construct the H. discus hannai genome, a total of 580-G base pairs using Illumina and Pacbio platforms were generated with 322-fold coverage based on the 1.8-Gb estimated genome size of H. discus hannai using flow cytometry. The final genome assembly consisted of 1.86 Gb with 35 450 scaffolds (>2 kb). GC content level was 40.51%, and the N50 length of assembled scaffolds was 211 kb. We identified 29 449 genes using Evidence Modeler based on the gene information from ab initio prediction, protein homology with known genes, and transcriptome evidence of RNA-seq. Here we present the first Haliotidae genome, H. discus hannai, with sequencing data, assembly, and gene annotation information. This will be helpful for resolving the lack of genomic information in the Haliotidae family as well as providing more opportunities for understanding gastropod evolution.

Colorful clones in the blood Stem cells in regenerating tissues such as the blood can acquire mutations that enable a growth advantage, increasing the chance of developing cancer. It is unclear how such diverse mutations promote clonal fitness. Avagyan et al . generated a platform in zebrafish to label clones with unique hues while inducing mutations in genes implicated in human blood disorders. Mutations in some genes caused clones to expand over time, resulting in clonal dominance. Progenitors in the dominant clone expressed anti-inflammatory factors to resist the inflammatory environment produced by their own mature progeny, leading to a self-perpetuating cycle promoting clonal fitness. Targeting these resistance pathways may be used to abate clonal hematopoiesis and prevent its associated pathology. —BAP

Many recent RNA-seq studies were focused mainly on detecting the differentially expressed genes (DEGs) between two or more conditions. In contrast, only a few attempts have been made to detect genes associated with quantitative traits, such as obesity index and milk yield, on RNA-seq experiment with large number of biological replicates. This study illustrates the linear model application on trait associated genes (TAGs) detection in two real RNA-seq datasets: 89 replicated human obesity related data and 21 replicated Holsteins’ milk production related RNA-seq data. Based on these two datasets, the performance between suggesting methods, such as ordinary regression and robust regression, and existing methods: DESeq2 and Voom, were compared. The results indicate that suggesting methods have much lower false discoveries compared to the precedent two group comparisons based approaches in our simulation study and qRT-PCR experiment. In particular, the robust regression outperforms existing DEG finding method as well as ordinary regression in terms of precision. Given the current trend in RNA-seq pricing, we expect our methods to be successfully applied in various RNA-seq studies with numerous biological replicates that handle continuous response traits.

Since domestication, the genome landscape of cattle has been changing due to natural and artificial selection forces resulting in several general and specialized cattle breeds of the world. Identifying genomic regions affected due to these forces in livestock gives an insight into the history of selection for economically important traits and genetic adaptation to specific environments of the populations under consideration. This study explores the genes/genomic regions under selection in relation to the phenotypes of Holstein, Hanwoo, and N'Dama cattle breeds using Tajima's D, XP-CLR, and XP-EHH population statistical methods. The whole genomes of 10 Holstein (South Korea), 11 Hanwoo (South Korea), and 10 N'Dama (West Africa-Guinea) cattle breeds re-sequenced to ~11x coverage and retained 37 million SNPs were used for the study. Selection signature analysis revealed 441, 512, and 461 genes under selection from Holstein, Hanwoo, and N'Dama cattle breeds, respectively. Among all these, seven genes including ARFGAP3, SNORA70, and other RNA genes were common between the breeds. From each of the gene lists, significant functional annotation cluster terms including milk protein and thyroid hormone signaling pathway (Holstein), histone acetyltransferase activity (Hanwoo), and renin secretion (N'Dama) were enriched. Genes that are related to the phenotypes of the respective breeds were also identified. Moreover, significant breed-specific missense variants were identified in CSN3, PAPPA2 (Holstein), C1orf116 (Hanwoo), and COMMD1 (N'Dama) genes. The genes identified from this study provide an insight into the biological mechanisms and pathways that are important in cattle breeds selected for different traits of economic significance.

Results of recent studies on gut microbiota have suggested that obesogenic bacteria exacerbate obesity and metabolic dysfunction in the host when fed a high fat diet (HFD). In order to explore obesity-associated bacterial candidates and their response to diet, the composition of faecal bacterial communities was investigated by analyzing 16S rRNA gene sequences in mice. Dietary intervention with probiotics and Garcinia cambogia extract attenuated weight gain and adipocyte size in HFD-fed mice. To identify obesity-causative microbiota, two statistical analyses were performed. Forty-eight bacterial species were found to overlap between the two analyses, indicating the commonly identified species as diet-driven and obesity-associated, which would make them strong candidates for host-microbiome interaction on obesity. Finally, correlation based network analysis between diet, microbe, and host revealed that Clostridium aminophilum, a hyper-ammonia-producing bacterium, was highly correlated with obesity phenotypes and other associated bacteria, and shown to be suppressed by the combination of probiotics and Garcinia cambogia extract. Results of the present study suggest that probiotics and Garcinia cambogia extract alleviate weight gain and adiposity, in part via differentially modulating the composition of gut microbiota in HFD fed mice.