Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases

Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study

BACKGROUND: This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD). METHODS: In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. RESULTS: Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. CONCLUSIONS: Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

peer reviewe

Better characterization of operation for ulcerative colitis through the National surgical quality improvement program: A 2-year audit of NSQIP-IBD

IntroductionThere is little consensus of quality measurements for restorative proctocolectomy with ileal pouch-anal anastomosis(RPC-IPAA) performed for ulcerative colitis(UC). The National Surgical Quality Improvement Program(NSQIP) cannot accurately classify RPC-IPAA staged approaches. We formed an IBD-surgery registry that added IBD-specific variables to NSQIP to study these staged approaches in greater detail.MethodsWe queried our validated database of IBD surgeries across 11 sites in the US from March 2017 to March 2019, containing general NSQIP and IBD-specific perioperative variables. We classified cases into delayed versus immediate pouch construction and looked for independent predictors of pouch delay and postoperative Clavien-Dindo complication severity.Results430 patients received index surgery or completed pouches. Among completed pouches, 46(28%) and 118(72%) were immediate and delayed pouches, respectively. Significant predictors for delayed pouch surgery included higher UC surgery volume(p = 0.01) and absence of colonic dysplasia(p = 0.04). Delayed pouch formation did not significantly predict complication severity.ConclusionsOur data allows improved classification of complex operations. Curating disease-specific variables allows for better analysis of predictors of delayed versus immediate pouch construction and postoperative complication severity.Short summaryWe applied our previously validated novel NSIP-IBD database for classifying complex, multi-stage surgical approaches for UC to a degree that was not possible prior to our collaborative effort. From this, we describe predictive factors for delayed pouch formation in UC RPC-IPAA with the largest multicenter effort to date