Genetic Effects Research Articles

Causal effects of BMI, waist circumference, and body fat percentage on the risk of bladder cancer: A Mendelian randomization study.

The causal role of body mass index (BMI) in bladder cancer (BC) by Mendelian randomization (MR) has not yet been reported. We evaluated the causal associations between the measures of obesity (BMI, waist circumference, and body fat percentage) and BC. We conducted a 2-sample MR analysis to assess the genetic effect of measures of obesity on BC. The BMI dataset (GWAS ID: ukb-b-2303) comprised 454,884 Europeans, and we identified 9,851,867 single nucleotide polymorphisms (SNPs). The waist circumference data (GWAS ID: ukb-b-9405) included 462,166 Europeans and 9,851,867 SNPs. The body fat percentage dataset (GWAS ID: ukb-a-264) contained data from 331,117 Europeans and 10,894,596 SNPs. For the outcome data, the GWAS ID was finn-b-C3_BLADDER, consisting of 1115 cases and 217,677 controls, with 16,380,466 SNPs. The inverse-variance weighted (IVW) model was used as the primary MR analysis. Cochran Q-statistic was used to identify heterogeneity between the SNPs. The MR-Egger and MR-PRESSO methods were employed to assess directional pleiotropy and outlier SNPs. We detected a decisive causal link between BMI and BC by the IVW analysis (odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.08-1.85, P = .011). The IVW analyses revealed a significant correlation between BC and waist circumference (OR = 1.55, 95% CI: 1.08-2.12, P = .016). However, the IVW method (OR = 1.49, 95% CI: 0.99-2.00, P = .05) did not report any statistical significance between body fat percentage and BC. We did not observe heterogeneity and directional pleiotropy in the 3 pairs of MR studies. The 2-sample MR analysis revealed a conceivable causal association between obesity (BMI, waist circumference) and BC.

Exploring the causal association between genetically determined circulating metabolome and hemorrhagic stroke

BackgroundHemorrhagic stroke (HS), a leading cause of death and disability worldwide, has not been clarified in terms of the underlying biomolecular mechanisms of its development. Circulating metabolites have been closely associated with HS in recent years. Therefore, we explored the causal association between circulating metabolomes and HS using Mendelian randomization (MR) analysis and identified the molecular mechanisms of effects.MethodsWe assessed the causal relationship between circulating serum metabolites (CSMs) and HS using a bidirectional two-sample MR method supplemented with five ways: weighted median, MR Egger, simple mode, weighted mode, and MR-PRESSO. The Cochran Q-test, MR-Egger intercept test, and MR-PRESSO served for the sensitivity analyses. The Steiger test and reverse MR were used to estimate reverse causality. Metabolic pathway analyses were performed using MetaboAnalyst 5.0, and genetic effects were assessed by linkage disequilibrium score regression. Significant metabolites were further synthesized using meta-analysis, and we used multivariate MR to correct for common confounders.ResultsWe finally recognized four metabolites, biliverdin (OR 0.62, 95% CI 0.40–0.96, PMVMR = 0.030), linoleate (18. 2n6) (OR 0.20, 95% CI 0.08–0.54, PMVMR = 0.001),1-eicosadienoylglycerophosphocholine* (OR 2.21, 95% CI 1.02–4.76, PMVMR = 0.044),7-alpha-hydroxy-3 -oxo-4-cholestenoate (7-Hoca) (OR 0.27, 95% CI 0.09–0.77, PMVMR = 0.015) with significant causal relation to HS.ConclusionWe demonstrated significant causal associations between circulating serum metabolites and hemorrhagic stroke. Monitoring, diagnosis, and treatment of hemorrhagic stroke by serum metabolites might be a valuable approach.

Genetic evidence strengthens the connection between gut microbiota and gingivitis: a two-sample Mendelian randomization study

IntroductionThe oral cavity and gut tract, being interconnected and rich in microbiota, may have a shared influence on gingivitis. However, the specific role of distinct gut microbiota taxa in gingivitis remains unexplored. Utilizing Mendelian Randomization (MR) as an ideal method for causal inference avoiding reverse causality and potential confounding factors, we conducted a comprehensive two-sample MR study to uncover the potential genetic causal impact of gut microbiota on gingivitis.MethodsInstrumental variables were chosen from single nucleotide polymorphisms (SNPs) strongly associated with 418 gut microbiota taxa, involving 14,306 individuals. Gingivitis, with 4,120 cases and 195,395 controls, served as the outcome. Causal effects were assessed using random-effect inverse variance-weighted, weighted median, and MR-Egger methods. For replication and meta-analysis, gingivitis data from IEU OpenGWAS were employed. Sensitivity analyses included Cochran’s Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests. This study aimed to assess the genetic correlation between the genetically predicted gut microbiota and gingivitis using linkage disequilibrium score regression (LDSC).ResultsThree gut microbiota taxa (class Actinobacteria id.419, family Defluviitaleaceae id.1924, genus Defluviitaleaceae UCG011 id.11287) are predicted to causally contribute to an increased risk of gingivitis (P< 0.05). Additionally, four gut microbiota taxa (class Actinobacteria id.419, genus Escherichia Shigella id.3504, genus Ruminococcaceae UCG002 id.11360) potentially exhibit inhibitory causal effects on the risk of gingivitis (P< 0.05). No significant evidence of heterogeneity or pleiotropy is detected. Our findings indicate a suggestive genetic correlation between class Actinobacteria id.419, class Bacteroidia id.912, family Defluviitaleaceae id.1924, genus Escherichia Shigella id.3504 and gingivitis.ConclusionOur study establishes the genetic causal effect of 418 gut microbiota taxa on gingivitis, offering insights for clinical interventions targeting gingivitis. Subsequent research endeavors are essential to corroborate the findings of our present study.

Studies on Heterozsis Breeding in Brinjal Germplasm for Growth and Yield Traits, Solanum melongena L.

Brinjal, Solanum melongena L. is one of the commercial annual vegetables grown all over India for its edible fruits. Heterosis in vegetable crops helps to exploit the superior hybrids based on its phenotypic superiority over their parents and indicates predominance of non-additive genetic effects. This research was carried out at Department of Vegetable Science, Horticultural College and Research Institute, Periyakulam. The study involves six parents and thirty hybrids laid out in Randomised Block Design with two replications. The cross CO2 × Kothampatti Kathiri, obtained significant positive heterosis (16.53%) for plant height over better parent. Significant heterosis over mid parent was observed for number of branches in Kothampatti Kathiri × Odavai Pachai Kathiri, 33.33%, fruit width in Dharmapuri Oodha Kathiri × Poiyur Purple Kathiri, 25.54%, fruit length in Kothampatti Kathiri × Gobi Pachai Kathiri, 24.33%. Significant negative heterosis over better parent for number of days to 50% flowering was observed in the cross Odavai Pachai Kathiri × Gobi Pachai Kathiri, -9.25%. Significant positive heterosis over standard check was obtained for number of fruit per plant, 35.42% in the cross Dharmapuri Oodha Kathiri × CO2 and fruit yield per plant in Dharmapuri Oodha Kathiri × Odavai Pachai Kathiri, 21.54%. Heterosis exploited could be utilized in further crop improvement program in the development of a superior hybrid.

Body mass index and all-cause mortality in HUNT and UK biobank studies: revised non-linear Mendelian randomisation analyses

ObjectivesTo estimate the shape of the causal relationship between body mass index (BMI) and mortality risk in a Mendelian randomisation framework.DesignMendelian randomisation analyses of two prospective population-based cohorts.SettingIndividuals of European...

Familial aggregation of seizure outcomes in four familial epilepsy cohorts.

To assess the possible effects of genetics on seizure outcome by estimating the familial aggregation of three outcome measures: seizure remission, history of ≥4 tonic-clonic seizures, and seizure control for individuals taking antiseizure medication. We analyzed families containing multiple persons with epilepsy in four previously collected retrospective cohorts. Seizure remission was defined as being 5 and 10 years seizure-free at last observation. Total number of tonic-clonic seizures was dichotomized at <4 and ≥4 seizures. Seizure control in patients taking antiseizure medication was defined as no seizures for 1, 2, and 3 years. We used Bayesian generalized linear mixed-effects model (GLMM) to estimate the intraclass correlation coefficient (ICC) of the family-specific random effect, controlling for epilepsy type, age at epilepsy onset, and age at last data collection as fixed effects. We analyzed each cohort separately and performed meta-analysis using GLMMs. The combined cohorts included 3644 individuals with epilepsy from 1463 families. A history of ≥4 tonic-clonic seizures showed strong familial aggregation in three separate cohorts and meta-analysis (ICC .28, 95% confidence interval [CI] .21-.35, Bayes factor 8 × 1016). Meta-analyses did not reveal significant familial aggregation of seizure remission (ICC .08, 95% CI .01-.17, Bayes factor 1.46) or seizure control for individuals taking antiseizure medication (ICC .13, 95% CI 0-.35, Bayes factor 0.94), with heterogeneity among cohorts. A history of ≥4 tonic-clonic seizures aggregated strongly in families, suggesting a genetic influence, whereas seizure remission and seizure control for individuals taking antiseizure medications did not aggregate consistently in families. Different seizure outcomes may have different underlying biology and risk factors. These findings should inform the future molecular genetic studies of seizure outcomes.

Early survival in Atlantic salmon is associated with parental genotypes at loci linked to timing of maturation.

Large effects loci often contain genes with critical developmental functions with potentially broad effects across life-stages. However, the life-stage-specific fitness consequences are rarely explored. In Atlantic salmon, variation in two large-effect loci, six6 and vgll3, is linked to age at maturity, and several physiological and behavioural traits in early life. By genotyping the progeny of wild Atlantic salmon that were planted into natural streams with nutrient manipulations, we tested if genetic variation in these loci is associated with survival in early life. We found that higher early life survival was linked to the genotype associated with late maturation in the vgll3, but with early maturation in the six6 locus. These effects were significant in high-nutrient, but not in in low-nutrient streams. The differences in early survival were not explained by additive genetic effects in the offspring generation, but by maternal genotypes in the six6 locus, and by both parents' genotypes in the vgll3 locus. Our results suggest that indirect genetic effects by large-effect loci can be significant determinants of offspring fitness. This study demonstrates an intriguing case of how large-effect loci can exhibit complex fitness associations across life stages in the wild and indicates that predicting evolutionary dynamics is difficult.

Fecal Microbial Communities of Nellore and Crossbred Beef Calves Raised at Pasture

This study aimed to investigate the effect of age and genetics on the fecal microbiota of beef calves. Ten purebred Nellore (Bos taurus indicus) and ten crossbreed 50% Nellore-50% European breed (Bos taurus taurus) calves co-habiting on the same pasture paddock had fecal samples collected on days five (5 d), 14 d, 28 d, 60 d, 90 d, 180 d, 245 d (weaning) and 260 d after birth. All calves were kept with their mothers, and six Nellore dams were also sampled at weaning. Microbiota analysis was carried out by amplification of the V4 region of the 16S rRNA gene following high-throughput sequencing with a MiSeq Illumina platform. Results revealed that bacterial richness increased with age and became more similar to adults near weaning. Differences in microbiota membership between breeds were found at 60 d and 90 d and for structure at 60 d, 90 d, 245 d, and 260 d (p &lt; 0.05). In addition, crossbreed calves presented less variability in their microbiota. In conclusion, the genetic composition significantly impacted the distal gut microbiota of calves co-habiting in the same environment, and further studies investigating food intake can reveal possible associations between microbiota composition and performance.

ComorbidPGS: an R package assessing shared predisposition between Phenotypes using Polygenic Scores.

Introduction Polygenic Score (PGS) is a valuable method for assessing the estimated genetic liability to a given outcome or genetic variability contributing to a quantitative trait. While PRSs are widely used for complex traits, their application in uncovering shared genetic predisposition between phenotypes, i.e. when genetic variants influence more than one phenotype, remains limited. Methods We developed an R package, comorbidPGS, which facilitates a systematic evaluation of shared genetic effects among (cor)related phenotypes using PGSs. The comorbidPGS package takes as input a set of Single Nucleotide Polymorphisms (SNPs) along with their established effects on the original phenotype (Po), referred to as Po-PGS. It generates a comprehensive summary of effect(s) of Po-PGS on target phenotype(s) (Pt) with customisable graphical features. Results We applied comorbidPGS to investigate the shared genetic predisposition between phenotypes defining elevated blood pressure (Systolic Blood Pressure, SBP; Diastolic Blood Pressure, DBP; Pulse Pressure, PP) and several cancers (Breast Cancer, BrC; Pancreatic Cancer, PanC; Kidney Cancer, KidC; Prostate Cancer, PrC; Colorectal Cancer, CrC) using the European ancestry UK Biobank individuals and GWAS meta-analyses summary statistics from independent set of European ancestry individuals. We report a significant association between elevated DBP and the genetic risk of PrC (β (SE)=0.066 (0.017), P-value=9.64×10^(-5)), as well as between CrC PGS and both, lower SBP (β (SE)=-0.10 [0.029], P-value=3.83×10^(-4))) and lower DBP (β (SE)=-0.055 [0.017], P-value=1.05×10^(-3)). Our analysis highlights two nominally significant relationships for individuals with genetic predisposition to elevated SBP leading to higher risk of KidC (OR [95%CI]=1.04 [1.0039-1.087], P-value=2.82×10^(-2)) and PrC (OR [95%CI]=1.02 [1.003-1.041], P-value=2.22×10^(-2)). Conclusion Using comorbidPGS, we underscore mechanistic relationships between blood pressure regulation and susceptibility to three comorbid malignancies. This package offers valuable means to evaluate shared genetic susceptibility between (cor)related phenotypes through polygenic scores.

Association between executive functions and COMT Val108/158Met polymorphism among healthy younger and older adults: A preliminary study.

Genetic variability in the dopaminergic system could contribute to age-related impairments in executive control. In this study, we examined whether genetic polymorphism for catechol-O-methyltransferase (COMT Val158Met) is related to performance on updating, shifting and inhibition tasks. We administered a battery of executive tasks assessing updating, shifting and inhibition functions to 45 older and 55 younger healthy participants, and created composite z-scores associated to each function. Six groups were created based on genetic alleles (Val/Val, Val/Met, Met/Met) derived from the COMT gene and age (younger, older). Age and genotype effects were assessed with t-test and ANOVA (p<0.05). A lower performance was observed in the older group for the three executive processes, and more particularly for inhibition. Moreover, older participants homozygous for the Val allele have a lower performance on the inhibition composite in comparison to younger Val/Val. These results confirm presence of executive performance decrease in healthy aging. With regard to genetic effect, older participants seem particularly disadvantaged when they have a lower baseline dopamine level (i.e., Val/Val homozygous) that is magnified by aging, and when the executive measure emphasize the need of stable representations (as in inhibition task requiring to maintain active the instruction to not perform an automated process).

Integrating population genetics, stem cell biology and cellular genomics to study complex human diseases.

Human pluripotent stem (hPS) cells can, in theory, be differentiated into any cell type, making them a powerful in vitro model for human biology. Recent technological advances have facilitated large-scale hPS cell studies that allow investigation of the genetic regulation of molecular phenotypes and their contribution to high-order phenotypes such as human disease. Integrating hPS cells with single-cell sequencing makes identifying context-dependent genetic effects during cell development or upon experimental manipulation possible. Here we discuss how the intersection of stem cell biology, population genetics and cellular genomics can help resolve the functional consequences of human genetic variation. We examine the critical challenges of integrating these fields and approaches to scaling them cost-effectively and practically. We highlight two areas of human biology that can particularly benefit from population-scale hPS cell studies, elucidating mechanisms underlying complex disease risk loci and evaluating relationships between common genetic variation and pharmacotherapeutic phenotypes.

From genetic mosaicism to tumorigenesis through indirect genetic effects.

Genetic mosaicism has long been linked to aging, and several hypotheses have been proposed to explain the potential connections between mosaicism and susceptibility to cancer. It has been proposed that mosaicism may disrupt tissue homeostasis by affecting intercellular communications and releasing microenvironmental constraints within tissues. The underlying mechanisms driving these tissue-level influences remain unidentified, however. Here, we present an evolutionary perspective on the interplay between mosaicism and cancer, suggesting that the tissue-level impacts of genetic mosaicism can be attributed to Indirect Genetic Effects (IGEs). IGEs can increase the level of cellular stochasticity and phenotypic instability among adjacent cells, thereby elevating the risk of cancer development within the tissue. Moreover, as cells experience phenotypic changes in response to challenging microenvironmental conditions, these changes can initiate a cascade of nongenetic alterations, referred to as Indirect non-Genetic Effects (InGEs), which in turn catalyze IGEs among surrounding cells. We argue that incorporating both InGEs and IGEs into our understanding of the process of oncogenic transformation could trigger a major paradigm shift in cancer research with far-reaching implications for practical applications.

Multiplexed bulk and single-cell RNA-seq hybrid enables cost-efficient disease modeling with chimeric organoids

Disease modeling with isogenic Induced Pluripotent Stem Cell (iPSC)-differentiated organoids serves as a powerful technique for studying disease mechanisms. Multiplexed coculture is crucial to mitigate batch effects when studying the genetic effects of disease-causing variants in differentiated iPSCs or organoids, and demultiplexing at the single-cell level can be conveniently achieved by assessing natural genetic barcodes. Here, to enable cost-efficient time-series experimental designs via multiplexed bulk and single-cell RNA-seq of hybrids, we introduce a computational method in our Vireo Suite, Vireo-bulk, to effectively deconvolve pooled bulk RNA-seq data by genotype reference, and thereby quantify donor abundance over the course of differentiation and identify differentially expressed genes among donors. Furthermore, with multiplexed scRNA-seq and bulk RNA-seq, we demonstrate the usefulness and necessity of a pooled design to reveal donor iPSC line heterogeneity during macrophage cell differentiation and to model rare WT1 mutation-driven kidney disease with chimeric organoids. Our work provides an experimental and analytic pipeline for dissecting disease mechanisms with chimeric organoids.

Lifestyle and genetic predisposition are associated with incident irritable bowel syndrome: A population-based prospective cohort study

Few prospective studies have investigated the joint effect of lifestyle factors and genetic susceptibility on the risk of irritable bowel syndrome (IBS). This study aims to evaluate the associations of lifestyle and genetic factors with incident IBS in the UK Biobank. We analyzed data from 481,057 participants (54% female) without prevalent IBS at enrollment in the UK Biobank. An overall healthy lifestyle was defined using six modifiable lifestyle factors, including smoking, body mass index (BMI), sleep duration, diet, physical activity, and alcohol consumption, and hence categorized into ‘favorable’, ‘intermediate’, and ‘unfavorable’ lifestyles. A Cox proportional hazard model was used to investigate the association between a healthy lifestyle and incident IBS. Furthermore, we constructed a polygenic risk score (PRS) for IBS and assessed whether lifestyle modified the effect of genetics on the development of IBS. During a median follow-up of 12.1 years, 8,645 incident IBS were ascertained. Specifically, among the six modifiable lifestyle factors, adequate sleep demonstrates the greatest protective effect (hazard ratio [HR]: 0.72, 95% CI: 0.69,0.75) against IBS.Compared with a favorable lifestyle, an unfavorable lifestyle was associated with a 56% (95% CI: 46%-67%) increased risk of IBS (P = 8.99×10-40). The risk of incident IBS was 12% (95% CI: 4%-21%) higher among those at high genetic risk compared with those at low genetic risk (P = 0.005). When considering the joint effect of lifestyle and genetic susceptibility, the HR nearly doubled among individuals with high genetic risk and unfavorable lifestyle (HR: 1.80; 95% CI:1.51-2.15; P = 3.50×10-11) compared to those with low genetic risk and favorable lifestyle. No multiplicative or addictive interaction was observed between lifestyle and genetics. The findings from this study indicated that lifestyle and genetic factors were independently associated with the risk of incident IBS. All these results implicated a possible clinical strategy of lowering the incidence of IBS by advocating a healthy lifestyle.

Mutational robustness and the role of buffer genes in evolvability.

Organisms rely on mutations to fuel adaptive evolution. However, many mutations impose a negative effect on fitness. Cells may have therefore evolved mechanisms that affect the phenotypic effects of mutations, thus conferring mutational robustness. Specifically, so-called buffer genes are hypothesized to interact directly or indirectly with genetic variation and reduce its effect on fitness. Environmental or genetic perturbations can change the interaction between buffer genes and genetic variation, thereby unmasking the genetic variation's phenotypic effects and thus providing a source of variation for natural selection to act on. This review provides an overview of our understanding of mutational robustness and buffer genes, with the chaperone gene HSP90 as a key example. It discusses whether buffer genes merely affect standing variation or also interact with de novo mutations, how mutational robustness could influence evolution, and whether mutational robustness might be an evolved trait or rather a mere side-effect of complex genetic interactions.

Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.

Redbay (Persea borbonia L. Spreng) Seedling and Sapling Growth and Recruitment Near Trees with and without Putative Resistance to Laurel Wilt Disease

Laurel wilt, a fungal disease (Harringtonia lauricola T.C. Harr., Fraedrich and Aghayeva) spread by the Asian redbay ambrosia beetle [Xyleborus glabratus Eichhoff (Coleoptera: Curculionidae: Scolytinae)], presents an imminent threat to North American members of the Lauraceae family, having caused extensive mortality in several species, especially redbay (Persea borbonia L. Spreng). Varying levels of disease resistance have been recorded in redbay under controlled conditions. To investigate if previously monitored putatively resistant field redbays have influenced the regeneration and survival of conspecifics within the surrounding 0.08 ha, a survey was conducted in 2018-19 and compared to similar data collected years prior (2008-09, 2013) along the coasts of Florida, Georgia, and South Carolina, United States. Plots were originally established at six disease-infested study sites around large redbay (&gt;7.5-cm diameter at breast height (1.37 m) (DBH)) that had survived the initial laurel wilt disease epidemic that began in approximately 2007. In 2018-19, a subset of 61 plots within 16 m of the original “survivor” redbay were recorded and compared to previous surveys. Among the original redbay selected for resistance, 22 of 61 (36%) survivors across all sites were alive in 2018 with survival rates varying from 0 to 70% between survey periods (average mortality 3.6%/year). Trees that died in years since 2008-09 had their plots reclassified as susceptible or “suscepts”. Changes in mean quadratic diameter at 1.37 m of redbay plots near survivors were significantly greater than those near suscepts, and in 2018-19, the average diameter of redbay near survivors was 7.62 cm vs. 4.90 cm for suscepts. The diameter distribution of dead and live redbay in the whole population showed a decrease in live individuals surviving past 8 cm DBH in 2018–2019, but 20 of 22 survivor candidate trees were larger than 8 cm DBH. Regeneration was occurring both clonally and sexually and tended to be greater near suscepts, but midstory resprouts per hectare and understory seedlings interacted significantly with the site and the latter differed between sites. These findings indicate that redbay is regenerating in these ecosystems, and disease resistance may allow for increased average tree size for some individuals, but an upper size threshold of around 8 cm DBH may still exist for much of the population. In addition, the importance of site variables in regeneration was apparent, making either local genetic or environmental effects an important topic for future research. Continuing to monitor these survivors while locating new candidates for disease screenings and breeding, preventing the introductions of new strains of H. lauricola, shedding light on the nature of resistance and its heritability, and initiating outplanting trials with resistant germplasm are instrumental steps in bringing redbay back to prominence in its historical range.

Detecting directional epistasis and dominance from cross-line analyses in alpine populations of Arabidopsis thaliana.

The contribution of non-additive genetic effects to the genetic architecture of fitness, and to the evolutionary potential of populations, has been a topic of theoretical and empirical interest for a long time. Yet, the empirical study of these effects in natural populations remains scarce, perhaps because measuring dominance and epistasis relies heavily on experimental line crosses. In this study, we explored the contribution of dominance and epistasis in natural alpine populations of Arabidopsis thaliana, for two fitness traits, the dry biomass and the estimated number of siliques, measured in a greenhouse. We found that, on average, crosses between inbred lines of A. thaliana led to mid-parent heterosis for dry biomass, but outbreeding depression for estimated number of siliques. While heterosis for dry biomass was due to dominance, we found that outbreeding depression for estimated number of siliques could be attributed to the breakdown of beneficial epistatic interactions. We simulated and discussed the implication of these results for the adaptive potential of the studied populations, as well as the use of line-cross analyses to detect non-additive genetic effects.

Disentangling genetic effects on transcriptional and post-transcriptional gene regulation through integrating exon and intron expression QTLs

Expression quantitative trait loci (eQTL) studies typically consider exon expression of genes and discard intronic RNA sequencing reads despite their information on RNA metabolism. Here, we quantify genetic effects on exon and intron levels of genes and their ratio in lymphoblastoid cell lines, revealing thousands of cis-QTLs of each type. While genetic effects are often shared between cis-QTL types, 7814 (47%) are not detected as top cis-QTLs at exon levels. We show that exon levels preferentially capture genetic effects on transcriptional regulation, while exon-intron-ratios better detect those on co- and post-transcriptional processes. Considering all cis-QTL types substantially increases (by 71%) the number of colocalizing variants identified by genome-wide association studies (GWAS). It further allows dissecting the potential gene regulatory processes underlying GWAS associations, suggesting comparable contributions by transcriptional (50%) and co- and post-transcriptional regulation (46%) to complex traits. Overall, integrating intronic RNA sequencing reads in eQTL studies expands our understanding of genetic effects on gene regulatory processes.

Fine-mapping and validation of the major quantitative trait locus QFlANG-4B for flag leaf angle in wheat.

This study precisely mapped and validated a quantitative trait locus (QTL) located on chromosome 4B for flag leaf angle in wheat. Flag leaf angle (FLANG) is closely related to crop architecture and yield. We previously identified the quantitative trait locus (QTL) QFLANG-4B for FLANG on chromosome 4B, located within a 14-cM interval flanked by the markers Xbarc20 and Xzyh357, using a mapping population of recombinant inbred lines (RILs) derived from a cross between Nongda3331 (ND3331) and Zang1817. In this study, we fine-mapped QFLANG-4B and validated its associated genetic effect. We developed a BC3F3 population using ND3331 as the recurrent parent through marker-assisted selection, as well as near-isogenic lines (NILs) by selfing BC3F3 plants carrying different heterozygous segments for the QFLANG-4B region. We obtained eight recombinant types for QFLANG-4B, narrowing its location down to a 5.3-Mb region. This region contained 76 predicted genes, 7 of which we considered to be likely candidate genes for QFLANG-4B. Marker and phenotypic analyses of individual plants from the secondary mapping populations and their progeny revealed that the FLANG of the ND3331 allele is significantly higher than that of the Zang1817 allele in multiple environments. These results not only provide a basis for the map-based cloning of QFLANG-4B, but also indicate that QFLANG-4B has great potential for marker-assisted selection in wheat breeding programs designed to improve plant architecture and yield.