A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA

HIV-infected individuals are living longer on antiretro-viral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV- individuals. First,we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across \u3e80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA).We find that decreased HLA methylation is predictive of lower CD4/CD8T cell ratio, linking molecular aging, epigenetic regulation, and disease progression

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

Update on Developing and Commercializing Oil Herders for In-Situ Burning

ABSTRACT Since the 2011 Conference (Buist et al. 2011 and Buist and Nedwed 2011), work on advancing oil herding agents for in-situ burning (ISB) has focused on three areas:Obtaining regulatory approvals for their use in North America;Developing an application system for use in a helicopter; and,Researching the effectiveness of herders for rapid-response ISB in open water. Desmi-AFTI worked in conjunction with S.L. Ross Environmental Research to get approval to use herders in North American waters. The proscribed test data from an accredited laboratory in Louisiana on three candidate herding agents (also called surface collecting agents) was submitted to the U.S. EPA for approval to list them on the National Contingency Plan (NCP) Product Schedule. Two herders have been placed on the list and are now commercially available. These two can be used, with the FOSC's concurrence, for spill response operations in U.S. waters. Samples of all three herders have been sent to Environment Canada, along with all the EPA test data, for their consideration. Quantities (200 L) of the two herders listed on the NCP Product Schedule have been produced and are stockpiled at Desmi-AFTI in Buffalo, NY. An application system, consisting of a pump, controls and reservoir has been designed to be placed inside an appropriate helicopter. It incorporates a reel-able hose that is used to lower the application nozzle to the correct height above the water for herder application. Dry land, static trials were conducted in September 2013 and helicopter flight trials are planned for summer and fall 2014. A back-pack sprayer system for herder application from a small vessel is available off-the-shelf, with only minor modifications required for cold-temperature use. The US Department of the Interior's Bureau of Safety and Environmental Enforcement sponsored a series of laboratory and Ohmsett experiments to see whether herders could contract oil slicks in wave conditions in open water. The results showed that the monolayer of each of the two best herders will survive for more than 45 minutes in a calm sea. The presence of breaking or cresting waves rapidly disrupts the herder monolayer and the oil slick resulting in the production of many small slicklets from the herded slick and the re-spreading of the oil to thin slicks. The monolayer survives for considerable periods of time in a swell condition, but the constant stretching and contracting of the herded slick results in elongating the oil slick and slowly breaking the slick into smaller segments. Testing of the helicopter application system with a herding agent on a 10 m3 experimental crude oil release in drift ice is planned for spring 2015. Further laboratory study of the approved herders is also planned with the goals of better understanding their toxicity and biodegradation and the window of opportunity for their effective use on weathered, emulsified and waxy oils.</jats:p

Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA

HIV-infected individuals are living longer on antiretro-viral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV- individuals. First,we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across \u3e80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA).We find that decreased HLA methylation is predictive of lower CD4/CD8T cell ratio, linking molecular aging, epigenetic regulation, and disease progression

A cell-type deconvolution meta-analysis of whole blood EWAS reveals lineage-specific smoking-associated DNA methylation changes

AbstractHighly reproducible smoking-associated DNA methylation changes in whole blood have been reported by many Epigenome-Wide-Association Studies (EWAS). These epigenetic alterations could have important implications for understanding and predicting the risk of smoking-related diseases. To this end, it is important to establish if these DNA methylation changes happen in all blood cell subtypes or if they are cell-type specific. Here, we apply a cell-type deconvolution algorithm to identify cell-type specific DNA methylation signals in seven large EWAS. We find that most of the highly reproducible smoking-associated hypomethylation signatures are more prominent in the myeloid lineage. A meta-analysis further identifies a myeloid-specific smoking-associated hypermethylation signature enriched for DNase Hypersensitive Sites in acute myeloid leukemia. These results may guide the design of future smoking EWAS and have important implications for our understanding of how smoking affects immune-cell subtypes and how this may influence the risk of smoking related diseases.</jats:p

Fisheries 9RO1R1RYHPEHUZZZÀVKHULHVRUJ GUIDELINES AND REVIEWS AFS Completes Assessment, Issues New Guidance Regarding Hatchery Operation and the Use of Hatchery-Origin Fish

BACKGROUND The American Fisheries Society (AFS) is the oldest, larg-HVW DQGPRVW LQÀXHQWLDOSURIHVVLRQDORUJDQL]DWLRQGHYRWHG WR ¿VKHULHVFRQVHUYDWLRQDQGLQWKLVFDSDFLW\WKH$)6KDVURXWLQH-ly assessed the contributions of hatcheries to natural resource management and issued recommendations to guide natural re-VRXUFHPDQDJHUV LQEHVW XVHVRI KDWFKHU\RULJLQ¿VK)RU WKH past several decades, the Society has explored these issues in a formalized process conducted at approximately 10-year in-tervals to assess contemporary issues related to hatcheries and management of aquatic resources. Representatives of the Fish Culture and Fisheries Management Sections came together in WRDQVZHUWKHTXHVWLRQ)LVKFXOWXUH¿VKPDQDJHPHQW¶V ally? ” in a symposium entitled “The Role of Fish Culture in Fisheries Management. ” In 1994, AFS reexamined the issue

DNA methylation markers for diagnosis and prognosis of common cancers

The ability to identify a specific cancer using minimally invasive biopsy holds great promise for improving the diagnosis, treatment selection, and prediction of prognosis in cancer. Using whole-genome methylation data from The Cancer Genome Atlas (TCGA) and machine learning methods, we evaluated the utility of DNA methylation for differentiating tumor tissue and normal tissue for four common cancers (breast, colon, liver, and lung). We identified cancer markers in a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples. We replicated our findings in a separate TCGA cohort of 791 tumor samples and 93 matched adjacent normal tissue samples, as well as an independent Chinese cohort of 394 tumor samples and 324 matched adjacent normal tissue samples. The DNA methylation analysis could predict cancer versus normal tissue with more than 95% accuracy in these three cohorts, demonstrating accuracy comparable to typical diagnostic methods. This analysis also correctly identified 29 of 30 colorectal cancer metastases to the liver and 32 of 34 colorectal cancer metastases to the lung. We also found that methylation patterns can predict prognosis and survival. We correlated differential methylation of CpG sites predictive of cancer with expression of associated genes known to be important in cancer biology, showing decreased expression with increased methylation, as expected. We verified gene expression profiles in a mouse model of hepatocellular carcinoma. Taken together, these findings demonstrate the utility of methylation biomarkers for the molecular characterization of cancer, with implications for diagnosis and prognosis