Quantile-specific heritability of plasma fibrinogen concentrations

Background Fibrinogen is a moderately heritable blood protein showing different genetic effects by sex, race, smoking status, pollution exposure, and disease status. These interactions may be explained in part by “quantile-dependent expressivity”, where the effect size of a genetic variant depends upon whether the phenotype (e.g. plasma fibrinogen concentration) is high or low relative to its distribution. Purpose Determine whether fibrinogen heritability (h2) is quantile-specific, and whether quantile-specific h2 could account for fibrinogen gene-environment interactions. Methods Plasma fibrinogen concentrations from 5689 offspring-parent pairs and 1932 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (βOP, h2 = 2βOP/(1+rspouse)) and full-sib regression slopes (βFS, h2 = {(1+8rspouseβFS)0.05–1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. Results Quantile-specific h2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted fibrinogen distribution when estimated from βOP (Ptrend = 5.5x10-6): 0.30±0.05 at the 10th, 0.37±0.04 at the 25th, 0.48±0.05 at the 50th, 0.61±0.06 at the 75th, and 0.65±0.08 at the 90th percentile, and when estimated from βFS (Ptrend = 0.008): 0.28±0.04 at the 10th, 0.31±0.04 at the 25th, 0.36±0.03 at the 50th, 0.41±0.05 at the 75th, and 0.50±0.06 at the 90th percentile. The larger genetic effect at higher average fibrinogen concentrations may contribute to fibrinogen’s greater heritability in women than men and in Blacks than Whites, and greater increase from smoking and air pollution for the FGB -455G>A A-allele. It may also explain greater fibrinogen differences between: 1) FGB -455G>A genotypes during acute phase reactions than usual conditions, 2) GTSM1 and IL-6 -572C>G genotypes in smokers than nonsmokers, 3) FGB -148C>T genotypes in untreated than treated diabetics, and LPL PvuII genotypes in macroalbuminuric than normoalbuminuric patients. Conclusion Fibrinogen heritability is quantile specific, which may explain or contribute to its gene-environment interactions. The analyses do not disprove the traditional gene-environment interpretations of these examples, rather quantile-dependent expressivity provides an alternative explanation that warrants consideration.

MOROCCAN STRAWBERRY TREE (Arbutus Unedo L.) LEAVES: COMPARATIVE STUDY OF THE NUTRITIONAL VALUE AND MINERAL COMPOSITION

Strawberry tree (Arbutus Unedo L.) is one of the evergreen trees that grow spontaneously in Moroccan forests. This tall shrub is traditionally used in grazing zones of some Moroccan areas, especially during the dry season, but its value in Morocco has still been underestimated. In this paper, the nutritional composition of A. unedo leaves sample collected from seven Moroccan regions has been assessed. For this, the leaves were dried, crushed, and chemically analyzed for their proximate composition, energetic value, total and reducing sugar, and mineral composition. Results of this study suggested that samples from BniAarouse (BA) region showed the highest contents of essential nutrients such as proteins, dietary fiber, ashes, and fat with average values of 7.53, 17.89, 4.14, and 8.05 g/ 100 g of dry weight, respectively, which positively influences its consumption by small ruminants. Cluster analysis based on surveyed parameters separated the strawberries individuals into four distinct groups, providing a high variability among and within studied locations. That could be related to the diversity of the edaphoclimatic conditions between regions and to the genetic effect. The results of the present study highlighted the potential use of leaves as livestock feed, with intermediate quality, and promotes their optimal cultivation and subsequent domestication in Morocco.

Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer

Transposable elements (TEs) are interspersed repeats that contribute to more than half of the human genome, and TE-embedded regulatory sequences are increasingly recognized as major components of the human regulome. Perturbations of this system can contribute to tumorigenesis, but the impact of TEs on gene expression in cancer cells remains to be fully assessed. Here, we analyzed 275 normal colon and 276 colorectal cancer (CRC) samples from the SYSCOL colorectal cancer cohort and discovered 10,111 and 5,152 TE expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively. Amongst the latter, 376 were exclusive to CRC, likely driven by changes in methylation patterns. We identified that transcription factors are more enriched in tumor-specific TE-eQTLs than shared TE-eQTLs, indicating that TEs are more specifically regulated in tumor than normal. Using Bayesian Networks to assess the causal relationship between eQTL variants, TEs and genes, we identified that 1,758 TEs are mediators of genetic effect, altering the expression of 1,626 nearby genes significantly more in tumor compared to normal, of which 51 are cancer driver genes. We show that tumor-specific TE-eQTLs trigger the driver capability of TEs subsequently impacting expression of nearby genes. Collectively, our results highlight a global profile of a new class of cancer drivers, thereby enhancing our understanding of tumorigenesis and providing potential new candidate mechanisms for therapeutic target development.

Efecto de dos estrategias de agrupación de padres fantasmas en la evaluación genética de rasgos de crecimiento en el ganado Braunvieh mexicano

The study aimed to compare two grouping strategies for unknown parents or phantom parent groups (PPG) on the genetic evaluation of growth traits for Mexican Braunvieh cattle. Phenotypic data included birth (BW), weaning (WW) and yearling (YW) weights. Pedigree included 57,341 animals. The first strategy involved 12 PPG (G12) based on the birth year of the unknown parent’s progeny and the sex of the unknown parent, while the second involved 24 PPG (G24) based on the birth year of the unknown parent’s progeny and 4-selection pathways. The animal models included fixed effects and the random direct additive genetic effect; WW also included random maternal genetic and maternal permanent environmental effects. Product-moment correlations between EBV from G0 (no PPG) and G12 were 0.96, 0.77 and 0.69 for BW, WW and YW, respectively, and between EBV from G0 and G24 were 0.91, 0.54, and 0.53, respectively. Corresponding rank correlations between G0 and G12 were 0.94, 0.77, and 0.72, and between G0 and G24 were 0.89, 0.61, and 0.60. Genetic trends showed a base deviation from the genetic trend of G0, except for BW of G12. The results did not support the use of the two grouping strategies on the studied population and traits, and further research is required. Introducing PPG to the model, enough phenotype contribution from descendants to PPG, and avoiding collinearity between PPG and fixed effects are important. Genetic groups should reflect changes in the genetic structure of the population to the unknown parents, including different sources of genetic materials, and changes made by selection over time.

Genetic-Quantitative Uni- and Bi-Trait Analysis for Growth Traits in the Colombian Creole Breed Blanco Orejinegro (BON)

The Blanco Orejinegro (BON) is a Colombian creole cattle breed that is not genetically well characterized for growth traits. The aim of this work was to estimate genetic parameters for birth weight (BW), weaning weight (WW), yearling weight (YW), daily weight gain between birth and weaning (DWG), time to reach 120 kg of live weight (T120), and time to reach 60% of adult weight (T60%), and establish the selection criteria for growth traits in the BON population of Colombia. Genealogical and phenotypic information for BW, WW, YW, DWG, T120, and T60% traits of BON animals from 14 Colombian herds were used. These traits were analyzed with the AIREML method in a uni- and bi-trait animal model including the maternal effect for BW, WW, DWG, and T120. The direct heritability estimates values were 0.22 ± 0.059 (BW), 0.20 ± 0.057 (WW), 0.20 ± 0.153 (YW), 0.17 ± 0.07 (DWG), 0.26 (T120), and 0.44 ± 0.03 (T60%). The maternal heritability estimates values were 0.14 ± 0.040 (BW), 0.15 ± 0.039 (WW), 0.25 ± 0.06 (DWG), and 0.16 (T120). The direct genetic correlations were high (>|0.60|) among all the traits, except between T60% with BW, WW, YW, and DWG (ranged from -0.02 to -0.51), all in a favorable direction. The results showed that there is genetic variation in the growth traits associated with the additive genetic effect and they might respond to selection processes. Furthermore, genetic gains would improve through selection, especially for YW and T60% when WW is used as criterion.

Host Genetic Associations with Salivary Microbiome in Oral Cancer

Despite the growing recognition of a host genetic effect on shaping gut microbiota composition, the genetic determinants of oral microbiota remain largely unexplored, especially in the context of oral diseases. Here, we performed a microbiome genome-wide association study in 2 independent cohorts of patients with oral squamous cell carcinoma (OSCC, n = 144 and 67) and an additional group of noncancer individuals ( n = 104). Besides oral bacterial dysbiosis and signatures observed in OSCC, associations of 3 loci with the abundance of genus-level taxa and 4 loci with β diversity measures were detected ( q < 0.05) at the discovery stage. The most significant hit (rs10906082 with the genus Lachnoanaerobaculum, P = 3.55 × 10–9 at discovery stage) was replicated in a second OSCC cohort. Moreover, the other 2 taxonomical associations, rs10973953 with the genus Kingella ( P = 1.38 × 10–9) and rs4721629 with the genus Parvimonas ( P = 3.53 × 10–8), were suggestive in the meta-analysis combining 2 OSCC cohorts. Further pathway analysis revealed that these loci were enriched for genes in regulation of oncogenic and angiogenic responses, implicating a genetic anchor to the oral microbiome in estimation of casual relationships with OSCC. Our findings delineate the role of host genotypes in influencing the structure of oral microbial communities.

Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes

Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells. Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced β-like cells, and improved glucose tolerance in Ins2Akita/+ mice. This genetic effect was phenocopied by small molecule FoxO1 inhibitor, Cpd10. Cpd10 induced β-like cells that released insulin in response to glucose in mouse gut organoids, and this effect was strengthened by the Notch inhibitor, DBZ. In Ins2Akita/+ mice, a five-day course of either Cpd10 or DBZ induced insulin-immunoreactive β-like cells in the gut, lowered glycemia, and increased plasma insulin levels without apparent adverse effects. These results provide proof of principle of gut cell conversion into β-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications.

Cryptic local adaptation is pervasive across environmental and evolutionary gradients

Cryptic local adaptation—where an environmental effect masks the magnitude of the genetic contribution to a phenotype—has long been a topic of interest in ecology and evolution. Here, we systematically document the magnitude and drivers of two common forms of cryptic local adaptation—counter- and cogradient variation. Using a hierarchical Bayesian meta-analysis, we calculated the overall effect size as 1.03 for countergradient variation and 0.90 for cogradient variation. This result indicates that the genetic effect of cryptic local adaptation is approximately equal to a one standard deviation change in trait value between the most disparate populations. We also found that the abiotic and biotic covariates with the largest mean effects were temperature (2.50) and gamete size (2.78), although there was substantial variance. Our results demonstrate the pervasiveness and large effect of cryptic local adaptation in wild populations and underscores the importance of accounting for these effects in future studies.

Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer

ABSTRACTTransposable elements (TEs) are interspersed repeats that contribute to more than half of the human genome, and TE-embedded regulatory sequences are increasingly recognized as major components of the human regulome. Perturbations of this system can contribute to tumorigenesis, but the impact of TEs on gene expression in cancer cells remains to be fully assessed. Here, we analyzed 275 normal colon and 276 colorectal cancer (CRC) samples from the SYSCOL colorectal cancer cohort and discovered 10,111 and 5,152 TE expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively. Amongst the latter, 376 were exclusive to CRC, likely driven by changes in methylation patterns. We identified that transcription factors are more enriched in tumor-specific TE-eQTLs than shared TE-eQTLs, indicating that TEs are more specifically regulated in tumor than normal. Using Bayesian Networks to assess the causal relationship between eQTL variants, TEs and genes, we identified that 1,758 TEs are mediators of genetic effect, altering the expression of 1,626 nearby genes significantly more in tumor compared to normal, of which 51 are cancer driver genes. We show that tumor-specific TE-eQTLs trigger the driver capability of TEs subsequently impacting expression of nearby genes. Collectively, our results highlight a global profile of a new class of cancer drivers, thereby enhancing our understanding of tumorigenesis and providing potential new candidate mechanisms for therapeutic target development.