| 1. |
- Broeckx, Bart J. G., et al.
(författare)
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An exome sequencing based approach for genome-wide association studies in the dog
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits. However, a disadvantage of GWAS is that it always requires subsequent fine-mapping or sequencing to pinpoint causal mutations. Here, we performed whole exome sequencing (WES) and canine high-density (cHD) SNP genotyping of 28 dogs from 3 breeds to compare the SNP and linkage disequilibrium characteristics together with the power and mapping precision of exome-guided GWAS (EG-GWAS) versus cHD-based GWAS. Using simulated phenotypes, we showed that EG-GWAS has a higher power than cHD to detect associations within target regions and less power outside target regions, with power being influenced further by sample size and SNP density. We analyzed two real phenotypes (hair length and furnishing), that are fixed in certain breeds to characterize mapping precision of the known causal mutations. EG-GWAS identified the associated exonic and 3'UTR variants within the FGF5 and RSPO2 genes, respectively, with only a few samples per breed. In conclusion, we demonstrated that EG-GWAS can identify loci associated with Mendelian phenotypes both within and across breeds.
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| 2. |
- Broeckx, Bart J. G., et al.
(författare)
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Improved canine exome designs, featuring ncRNAs and increased coverage of protein coding genes
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- By limiting sequencing to those sequences transcribed as mRNA, whole exome sequencing is a cost-efficient technique often used in disease-association studies. We developed two target enrichment designs based on the recently released annotation of the canine genome: the exome-plus design and the exome-CDS design. The exome-plus design combines the exons of the CanFam 3.1 Ensembl annotation, more recently discovered protein-coding exons and a variety of non-coding RNA regions (microRNAs, long non-coding RNAs and antisense transcripts), leading to a total size of approximate to 152 Mb. The exome-CDS was designed as a subset of the exome-plus by omitting all 3' and 5' untranslated regions. This reduced the size of the exome-CDS to approximate to 71 Mb. To test the capturing performance, four exome-plus captures were sequenced on a NextSeq 500 with each capture containing four pre-capture pooled, barcoded samples. At an average sequencing depth of 68.3x, 80% of the regions and well over 90% of the targeted base pairs were completely covered at least 5 times with high reproducibility. Based on the performance of the exome-plus, we estimated the performance of the exome-CDS. Overall, these designs provide flexible solutions for a variety of research questions and are likely to be reliable tools in disease studies.
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| 3. |
- Joosten, Myrthe, et al.
(författare)
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Divergence between the highly virulent zoonotic pathogen Helicobacter heilmannii and its closest relative, the low virulent Helicobacter ailurogastricus sp. nov.
- 2016
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Ingår i: Infection and immunity. - 1098-5522. ; 84:1, s. 293-306
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter heilmannii naturally colonizes the stomach of dogs and cats, and has been associated with gastric disorders in humans. Nine feline Helicobacter strains, classified as H. heilmannii based on ureAB and 16S rRNA gene sequences, were divided into a highly virulent and a low virulent group. The genomes of these strains were sequenced to investigate their phylogenetic relationships, to define their gene content and diversity and to determine if the differences in pathogenicity were associated with the presence/absence of potential virulence genes. The binding capacity of these helicobacters to the gastric mucosa was investigated as well.Our analyses revealed that the low virulent strains do not belong to the H. heilmannii species, but to a novel, closely related species for which we propose the name H. ailurogastricus. Several homologs of H. pylori virulence factors, such as IceA1, HrgA and jhp0562-like glycosyltransferase, are present in H. heilmannii but absent in H. ailurogastricus. Both species contain a VacA-like autotransporter, from which the passenger domain is remarkably larger for H. ailurogastricus compared to H. heilmannii. In addition, H. ailurogastricus shows clear differences in binding to the gastric mucosa compared to H. heilmannii. These findings highlight the low virulent character of this novel Helicobacter species.
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| 4. |
- Roels, Juliette, et al.
(författare)
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Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia
- 2020
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Ingår i: Blood cancer discovery. - : American Association for Cancer Research. - 2643-3249. ; 1:3, s. 274-289
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding. In addition, we revealed that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in pre-leukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, we here provide conceptual evidence for the involvement of a pre-leukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL.
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