Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction

Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes, myocardial infarction, aneurysm, vertical cup disc ratio and at least five cancers. Here we compare approaches to more comprehensively assess genetic variation in the region. We carried out targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into type 2 diabetes and myocardial infarction cohorts directly from targeted sequencing, from a genotyped reference panel derived from sequencing and from 1000 Genomes Project low-coverage data. Polymorphisms with frequency >5% were captured well by all strategies. Imputation of intermediate-frequency polymorphisms required a higher density of tag SNPs in disease samples than is available on first-generation genome-wide association study (GWAS) arrays. Our association analyses identified more comprehensive sets of variants showing equivalent statistical association with type 2 diabetes or myocardial infarction, but did not identify stronger associations than the original GWAS signals.     

Acquisition of the human adeno-associated virus type-2 rep gene by human herpesvirus type-6.

Human herpesvirus type-6 (HHV-6) is a recently isolated herpesvirus which is highly prevalent in adult populations around the world. HHV-6 was first isolated from the peripheral blood of six individuals with lymphoproliferative disorders, two of whom were also infected with human immunodeficiency virus. HHV-6, in common with other herpesviruses, transactivates the HIV long terminal repeat linked to reporter genes and has in addition been shown to accelerate HIV gene expression and CD4 cell death in cultures co-infected with both viruses. The virus is tropic for CD4+ lymphocytes and persists in the peripheral blood of most seropositive individuals. We have now identified a gene in HHV-6 encoding a 490-amino-acid polypeptide homologous to the human adeno-associated virus type-2 (AAV-2) rep gene. This gene has an essential role in AAV-2 DNA replication, can trans-regulate homologous and heterologous gene expression, and inhibits cellular transformation. The acquisition of rep by HHV-6 could be due to natural transfer of genetic information between DNA viruses of eukaryotes and is likely to have important consequences for the life-cycle of HHV-6 and for the host CD4 cell.     

Gene-target recognition among members of the myc superfamily and implications for oncogenesis

Myc and Mad family proteins regulate multiple biological processes through their capacity to influence gene expression directly. Here we show that the basic regions of Myc and Mad proteins are not functionally equivalent in oncogenesis, have separable E-box-binding activities and engage both common and distinct gene targets. Our data support the view that the opposing biological actions of Myc and Mxi1 extend beyond reciprocal regulation of common gene targets. Identification of differentially regulated gene targets provides a framework for understanding the mechanism through which the Myc superfamily governs the growth, proliferation and survival of normal and neoplastic cells.     

Evidence for a selective cytotoxic effect of carrageenan on cells of the immune system in vivo and in vitro

Summary Carrageenan suppressed antibody production to sheep erythrocytes in the mouse only when injected together with or 24 h prior to antigen. Pretreatment of sensitized spleen cell cultures with carrageenan reduced the degree of stimulation obtained using antigen but not PHA.