Enhancer Promoter Interactome and Mendelian Randomization Identify Network of Druggable Vascular Genes in Coronary Artery Disease

Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD. 3D enhancer-promoter genome mapping of CAD-genes in HCASMC was enriched in vascular eQTL genes. By using colocalization and Mendelian randomization analyses, we identified 58 causal candidate vascular genes including some druggable targets (MAP3K11, CAMK1D, PDGFD, IPO9 and CETP). A network analysis of causal candidate genes was enriched in TGF beta and MAPK pathways. The pharmacologic inhibition of causal candidate gene MAP3K11 in vascular SMC reduced the expression of athero-relevant genes and lowered cell migration, a cardinal process in CAD. Genes connected to enhancers are enriched in vascular eQTL and druggable genes causally associated with CAD.

Identification and fine mapping of qPBR10-1, a novel locus controlling panicle blast resistance in Pigm-containing P/TGMS line

Background Rice blast is one of the most widespread and devastating diseases in rice production. Tremendous success has been achieved in identification and characterization of genes and quantitative trait loci (QTLs) conferring seedling blast resistance, however, genetic studies on panicle blast resistance have lagged far behind. Results In this study, two advanced backcross inbred sister lines (MSJ13 and MSJ18) were obtained in the process of introducing Pigm into C134S, and showed significant differences in the panicle blast resistance. One F2 population derived from the crossing MSJ13/MSJ18 was used to QTL mapping for panicle blast resistance using Genotyping by Sequencing (GBS) method. A total of 7 QTLs were identified, including a major QTL qPBR10-1 on chromosome 10 that explaining 24.21% of phenotypic variance with LOD scores of 6.62. Furthermore, qPBR10-1 was verified via the BC1F2 and BC1F3 population and narrowed to a 60.6-kb region with six candidate genes predicted, including two genes encoding exonuclease family protein, two genes encoding hypothetical protein, and two genes encoding transposon protein. The nucleotide variations and the expression patterns of the candidate genes were identified and analyzed between MSJ13 and MSJ18 through sequence comparison and RT-PCR approach, and results indicated that ORF1 and ORF2 encoding exonuclease family protein might be the causal candidate genes for panicle blast resistance in the qPBR10-1 locus. Conclusions A total of 7 QTLs conferring panicle blast resistance was identified from one F2 population derived from the crossing between two advanced backcross inbred sister lines MSJ13 and MSJ18, which harbored the broad-spectrum resistance gene Pigm. A major QTL qPBR10-1 was fine mapped in a 60.6-kb region with six candidate genes predicted, and ORF1 and ORF2 encoding exonuclease family protein might be the causal candidate genes for panicle blast resistance in the qPBR10-1 locus through sequence comparison and RT-PCR approach.

Identification and fine mapping of qGR6.2, a novel locus controlling rice seed germination under salt stress

Background Rice growth is frequently affected by salinity. When exposed to high salinity, rice seed germination and seedling establishment are significantly inhibited. With the promotion of direct-seeding in Asia, improving rice seed germination under salt stress is crucial for breeding. Results In this study, an indica landrace Wujiaozhan (WJZ) was identified with high germinability under salt stress. A BC1F2 population derived from the crossing WJZ/Nip (japonica, Nipponbare)//Nip, was used to quantitative trait loci (QTL) mapping for the seed germination rate (GR) and germination index (GI) under H2O and 300 mM NaCl conditions. A total of 13 QTLs were identified, i.e. ten QTLs under H2O conditions and nine QTLs under salt conditions. Six QTLs, qGR6.1, qGR8.1, qGR8.2, qGR10.1, qGR10.2 and qGI10.1 were simultaneously identified under two conditions. Under salt conditions, three QTLs, qGR6.2, qGR10.1 and qGR10.2 for GR were identified at different time points during seed germination, which shared the same chromosomal region with qGI6.2, qGI10.1 and qGI10.2 for GI respectively. The qGR6.2 accounted for more than 20% of phenotypic variation under salt stress, as the major effective QTL. Furthermore, qGR6.2 was verified via the BC2F2 population and narrowed to a 65.9-kb region with eleven candidate genes predicted. Based on the microarray database, five candidate genes were found with high transcript abundances at the seed germination stage, of which LOC_Os06g10650 and LOC_Os06g10710 were differentially expressed after seed imbibition. RT-qPCR results showed the expression of LOC_Os06g10650 was significantly up-regulated in two parents with higher levels in WJZ than Nip during seed germination under salt conditions. Taken together, it suggests that LOC_Os06g10650, encoding tyrosine phosphatase family protein, might be the causal candidate gene for qGR6.2. Conclusions In this study, we identified 13 QTLs from a landrace WJZ that confer seed germination traits under H2O and salt conditions. A major salt-tolerance-specific QTL qGR6.2 was fine mapped to a 65.9-kb region. Our results provide information on the genetic basis of improving rice seed germination under salt stress by marker-assisted selection (MAS).

Perceiving a strong causal relation in a weak contingency: Further investigation of the evidential evaluation model of causal judgement

Contingency information is information about the occurrence or nonoccurrence of a certain effect in the presence or absence of a candidate cause. An objective measure of contingency is the δ P rule, which involves subtracting the probability of occurrence of an effect when a causal candidate is absent from the probability of occurrence of the effect when the candidate is present. Causal judgements conform closely to δ P but deviate from it under certain circumstances. Three experiments show that such deviations can be predicted by a model of causal judgement that has two components: a rule of evidence, that causal judgement is a function of the proportion of relevant instances that are judged to be confirmatory for the causal candidate, and a tendency for information about instances in which the candidate is present to have greater effect on judgement than instances in which the candidate is absent. Two experiments demonstrate how this model accounts for some recently published findings. A third experiment shows that it is possible to use the model to predict the occurrence of high causal judgements when the objective contingency is close to zero.