Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia

The exponential expansion of genomic data coupled with the lack of appropriate clinical categorization of the variants is posing a major challenge to conventional medications for many common and rare diseases. To narrow this gap and achieve the goals of personalized medicine, a collaborative effort should be made to characterize the genomic variants functionally and clinically with a massive global genomic sequencing of “healthy” subjects from several ethnicities. Familial-based clustered diseases with homogenous genetic backgrounds are amongst the most beneficial tools to help address this challenge. This review will discuss the diagnosis, management, and clinical monitoring of familial hypercholesterolemia patients from a wide angle to cover both the genetic mutations underlying the phenotype, and the pharmacogenomic traits unveiled by the conventional and novel therapeutic approaches. Achieving a drug-related interactive genomic map will potentially benefit populations at risk across the globe who suffer from dyslipidemia.

Construction of a Quantitative Genomic Map Gives Insight on Rapeseed Genetic Characteristics and Direction for Future Breeding

Background Rapeseed is the second most important oil crop in the world. Improving seed yield and seed oil content are the two main highlights for researches. Unfortunately, rapeseed development is frequently affected by different diseases. Extensive researches have been made through many years to develop elite cultivars which could produce high oil, high yield or be resistant to disease. QTL analysis has been one of the most important strategy in genetic deciphering of agronomic characteristics. In order to comprehend the distribution of these QTLs and to uncover the key regions that could simultaneously control multiple traits, 4555 QTLs that have been identified during the last 25 years were aligned in one unique map, and a quantitative genomic map which involved 128 traits from 79 populations developed in 12 countries was constructed. Results The present study revealed 517 regions of overlapping QTLs which harbored 2744 candidate genes and might affect multiple traits, simultaneously. They could be selected to customize super-rapeseed cultivars, including the cultivars which produce high oil content for biofuels production. The gene ontology and the interaction network of those candidates revealed genes which highly interacted with the other genes and might have strong influence on them. The expression and structure of these candidate genes were compared in eight rapeseed accessions and revealed genes of similar structure which were expressed differently. Conclusion The present study enriches our knowledge on rapeseed genome characteristic and diversity, and it also provided indications for rapeseed molecular breeding improvement in the future.

Method to obtain homozygous introgressing segments in Drosophila to identify the presence of hybrid sterility genes of the reproductive isolation

Here, we present for the first time, a method to generate homozygous segmental introgressions, by means of crosses between a pair of synmorphic species. The introgressions were monitored by the cytogenetic method of polygenic chromosome asynapses. Later the introgressions were evaluated in their capacity to produce sterility in segmental males. Also, the smallest segment with the capacity to produce sterility in segmental males was mapped by in situ hybridization of polythene chromosomes, using 8 sequences of BACs clones as probes. Finally, a bioinformatic analysis was carried out to identify the presence of particular genes. From 2 parental strains, D. buzzatii and D. koepferae, 6 simple segmental hybrid lines were generated, whose introgressing segments are distributed along chromosome 4 of these species. From the 6 simple segmental lines and by means of a new crossing strategy, the 6 respective homozygous segmental hybrid offspring were obtained, each of them carrying a specific homozygous introgression. None of the 6 heterozygous introgressions was capable of producing sterility in segmental males, while 4 of the same homozygous introgressions produced total sterility in segmental males, including in this group the two smallest introgressive segments, one of 5.03 % and the other 7.87% with respect to the total length of chromosome 4, which are located in the region F2 to F4 of the standard cytological map based on polythene chromosomes of the Drosophila Repleta group. In situ hybridization, using 8 clones from contig 1065 located along the F2 to F4 region of the physical map of D. buzzattii constructed in BACs, confirmed the precise location of the 6 clones in the chromosomal region F2 to F4 of chromosome 4 of the polygenic chromosomes of both D. buzzatii and D. mojavensis. The bioinformatic analysis of the F2 to F4 region, using the complete genetic sequence of the contig 1065 of D. buzzatti shows the presence of two predicted genes in the genomic map of D. buzzatii (g.1313.t1 and g.1314.t1), and the orthologous association of these 2 genes both with the D. moj_GI22766 gene of D. mojavensis and with the Trivet gene of D. melanogaster.

Global Analysis of Small Non-Coding RNA Populations across Tissues in the Malaria Vector, Anopheles gambiae

Malaria is a major global health problem, where the anautogenous female mosquito Anopheles gambiae serves as a major vector. In order to combat this devastating disease, understanding mosquito physiology is paramount. Numerous studies in the vector field demonstrate that small non-coding RNAs (ncRNAs) play essential roles in numerous aspects of mosquito physiology. While our previous miRNA annotation work demonstrated expression dynamics across differing tissues, miRNAs represented less than 20% of all small ncRNAs in our small RNA-Seq libraries. To this end, we systematically classified multiple small ncRNA groups across mosquito tissues. Here we (i) determined a new enriched-midgut miRNA, (ii) updated the piRNA annotation in ovaries with a genomic map of unique-mapping piRNAs, (iii) identified pan-tissue and tissue-enriched mRNA-derived small ncRNAs, and (iv) assessed AGO1- and AGO2- loading of candidate small ncRNAs. Continued research will broaden our view of small ncRNAs and greatly aide in our understanding on how these molecules contribute to mosquito physiology.

Resolving complex structures at oncovirus integration loci with conjugate graph

ABSTRACTOncovirus integrations cause complex structural variations (SVs) on host genomes. We propose a conjugate graph model to reconstruct the rearranged local genomic map (LGM) at integrated loci. Simulation tests prove the reliability and credibility of the algorithm. Applications of the algorithm to whole-genome sequencing data of Human papillomavirus (HPV) and hepatitis B virus (HBV)-infected cancer samples gained biological insights on oncovirus integrations. We observed five affection patterns of oncovirus integrations from the HPV and HBV-integrated cancer samples, including the exon loss, promoter gain, hyper-amplification of tumor gene, the viral cis-regulation inserted at the single intron and at the intergenic region. We found that the focal duplicates and host SVs are frequent in the HPV-integrated LGMs, while the focal deletions and complex virus SVs are prevalent in HBV-integrated LGMs. Furthermore, with the results yields from our method, we found the enhanced microhomology-mediated end joining (MMEJ) might lead to both HPV and HBV integrations, and conjectured that the HPV integrations might mainly occur during the DNA replication process.

Development and Validation of a Bordetella pertussis Whole-Genome Screening Strategy

The immune response elicited by the protective whole-cell pertussis (wP) versus the less-protective acellular pertussis (aP) vaccine has been well characterized; however, important clinical problems remain unsolved, as the inability of the currently administered aP vaccine is resulting in the reemergence of clinical disease (i.e., whooping cough). Strong evidence has shown that original, childhood aP and wP priming vaccines provide a long-lasting imprint on the CD4+ T cells that impacts protective immunity. However, aP vaccination might prevent disease but not infection, which might also affect the breadth of responses to Bordetella pertussis (BP) antigens. Thus, characterizing and defining novel targets associated with T cell reactivity are of considerable interest. Here, we compare the T cell reactivity of original aP and wP priming for different antigens contained or not contained in the aP vaccine and define the basis of a full-scale genomic map of memory T cell reactivity to BP antigens in humans. Our data show that the original priming after birth with aP vaccines has higher T cell reactivity than originally expected against a variety of BP antigens and that the genome-wide mapping of BP using an ex vivo screening methodology is feasible, unbiased, and reproducible. This could provide invaluable knowledge towards the direction of a new and improved pertussis vaccine design.