Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

/pdf/integrative-genomics-viewer-b637hdfl11.pdf

Integrative genomics viewer

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

An integrated encyclopedia of DNA elements in the human genome.

Data visualization is an essential component of genomic data analysis. However, the size and diversity of the data sets produced by today’s sequencing and array-based profiling methods present major challenges to visualization tools. The Integrative Genomics Viewer (IGV) is a high-performance viewer that efficiently handles large heterogeneous data sets, while providing a smooth and intuitive user experience at all levels of genome resolution. A key characteristic of IGV is its focus on the integrative nature of genomic studies, with support for both array-based and next-generation sequencing data, and the integration of clinical and phenotypic data. Although IGV is often used to view genomic data from public sources, its primary emphasis is to support researchers who wish to visualize and explore their own data sets or those from colleagues. To that end, IGV supports flexible loading of local and remote data sets, and is optimized to provide high-performance data visualization and exploration on standard desktop systems. IGV is freely available for download from http://www.broadinstitute.org/igv, under a GNU LGPL open-source license.

/pdf/integrative-genomics-viewer-igv-high-performance-genomics-3wp9qtayn5.pdf

Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration

Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

/pdf/a-haplotype-map-of-the-human-genome-2oc85odzud.pdf

A haplotype map of the human genome

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

/pdf/identification-and-analysis-of-functional-elements-in-1-of-2o640l8ikl.pdf

Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

S2077 Almost Half of the Chronic Hepatitis B (CHB) Patients with Positive HBeAg Have Confirmed Precore and/or Basal Core Promoter (PREC/BCP) Mutations

Tu1632 – Association Between Bowel Movements and Diverticulitis in Women

BACKGROUND
Mechanistic data indicate the benefit of short-chain fatty acids (SCFAs) produced by gut microbial fermentation of fiber on colorectal cancer (CRC), but direct epidemiological evidence is limited. A recent study identified single nucleotide polymorphisms (SNPs) for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits.


METHODS
We conducted a two-sample Mendelian randomization (MR) analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to CRC risk in three large European genetic consortia of 58,131 CRC cases and 67,347 controls. We estimated the risk of overall CRC and conducted subgroup analyses by sex, age, and anatomical subsites of CRC.


RESULTS
We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall CRC, CRC by sex, or early-onset CRC (CRC diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD=0.95, 95% CI=0.91-0.99; P=0.03) but it did not surpass multiple testing of subgroup analysis.


CONCLUSIONS
Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with CRC risk.


IMPACT
Fecal propionate and PWY-5022 may not have a substantial influence on CRC risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on CRC risk.

Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis.

Long H. Nguyen

Papers

S2077 Almost Half of the Chronic Hepatitis B (CHB) Patients with Positive HBeAg Have Confirmed Precore and/or Basal Core Promoter (PREC/BCP) Mutations

Tu1632 – Association Between Bowel Movements and Diverticulitis in Women

Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis.

689 aspirin and non-steroidal anti-inflammatory drug use and risk of precursorsof early-onset colorectal cancer

1244 population-level impact of a metabolically- and microbiallyinformed diet on weight change and obesity-related complications