SVEP1 IS IMPORTANT FOR MORPHOGENESIS OF LYMPHATIC SYSTEM: POSSIBLE IMPLICATIONS IN LYMPHEDEMA

SVEP1, also known as Polydom, is a large extracellular mosaic protein with functions in protein interactions and adhesion. Since Svep1 knockout animals show severe edema and lymphatic system malformations, the aim of this study is to evaluate the presence of SVEP1 variants in patients with lymphedema. We analyzed DNA from 246 lymphedema patients for variants in known lymphedema genes, 235 of whom tested negative and underwent a second testing for new candidate genes, including SVEP1, as reported here. We found three samples with rare heterozygous missense single-nucleotide variants in the SVEP1 gene. In one family, healthy members were found to carry the same variants and reported some subclinical edema. Based on our findings and a review of the literature, we propose SVEP1 as a candidate gene that should be sequenced in patients with lymphatic malformations, with or without lymphedema, in order to investigate and add evidence on its possible involvement in the development of lymphedema.

Librator, a platform for optimized sequence editing, design, and expression of influenza virus proteins

Artificial mutagenesis and chimeric/mosaic protein engineering have laid the foundation for antigenic characterization1 and universal vaccine design2–4 for influenza viruses. However, many methods used for influenza research and vaccine development require sequence editing and protein expression, limiting their applicability and the progress of related research to specialists. Rapid tools allowing even novice influenza researchers to properly analyze and visualize influenza protein sequences with accurate nomenclature are needed to expand the research field. To address this need, we developed Librator, a system for analyzing and designing protein sequences of influenza virus Hemagglutinin (HA) and Neuraminidase (NA). With Librator’s graphical user interface (GUI) and built-in sequence editing functions, biologists can easily analyze influenza sequences and phylogenies, automatically port sequences to visualize structures, then readily mutate target residues and design sequences for antigen probes and chimeric/mosaic proteins efficiently and accurately. This system provides optimized fragment design for Gibson Assembly5 of HA and NA expression constructs based on peptide conservation of all historical HA and NA sequences, ensuring fragments are reusable and compatible, allowing for significant reagent savings. Use of Librator will significantly facilitate influenza research and vaccine antigen design.

Mosaic Mutations in Blood DNA Sequence Are Associated with Solid Tumor Cancers

Recent findings in understanding the causal role of blood-detectable somatic protein-truncating DNA variants in leukemia prompt questions about generalizability of such observations for other cancer types. We used exome sequencing to compare 22 different cancer phenotypes from TCGA data (~8,000 samples) with more than 6,000 controls using a case-control study design and demonstrate that mosaic protein truncating variants in these genes are also associated with solid-tumor cancers. We analyzed tumor DNA samples from TCGA and observed that the cancer-associated mosaic variants are absent from the tumors.Through analysis of different cancer phenotypes we observe gene-specificity for mosaic mutations. PPM1D in previous reports has been linked to breast and ovarian cancer, which our analysis confirms as a specifically associated to ovarian cancer. Additionally, glioblastoma, melanoma and lung cancers show gene specific burden of the mosaic protein truncating mutations. Taken together, these results extend existing observations broadly and link solid-tumor cancers to somatic blood DNA changes.

Hepatitis C Genotype 1 Mosaic Vaccines Are Immunogenic in Mice and Induce Stronger T-Cell Responses than Natural Strains

ABSTRACTDespite improved hepatitis C virus (HCV) treatments, vaccines remain an effective and economic option for curtailing the epidemic. Mosaic protein HCV genotype 1 vaccine candidates designed to address HCV diversity were immunogenic in mice. They elicited stronger T-cell responses to NS3-NS4a and E1-E2 proteins than did natural strains, as assessed with vaccine-matched peptides.