Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension

Treatment of hypertension-mediated cardiac damage with left ventricular (LV) hypertrophy (LVH) and heart failure remains challenging. To identify novel targets, we performed comparative transcriptome analysis between genetic models derived from stroke-prone spontaneously hypertensive rats (SHRSP). Here, we identified carboxypeptidase X 2 (Cpxm2) as a genetic locus affecting LV mass. Analysis of isolated rat cardiomyocytes and cardiofibroblasts indicated Cpxm2 expression and intrinsic upregulation in genetic hypertension. Immunostaining indicated that CPXM2 associates with the t-tubule network of cardiomyocytes. The functional role of Cpxm2 was further investigated in Cpxm2-deficient (KO) and wild-type (WT) mice exposed to deoxycorticosterone acetate (DOCA). WT and KO animals developed severe and similar systolic hypertension in response to DOCA. WT mice developed severe LV damage, including increases in LV masses and diameters, impairment of LV systolic and diastolic function and reduced ejection fraction. These changes were significantly ameliorated or even normalized (i.e., ejection fraction) in KO-DOCA animals. LV transcriptome analysis showed a molecular cardiac hypertrophy/remodeling signature in WT but not KO mice with significant upregulation of 1234 transcripts, including Cpxm2, in response to DOCA. Analysis of endomyocardial biopsies from patients with cardiac hypertrophy indicated significant upregulation of CPXM2 expression. These data support further translational investigation of CPXM2.

New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1–3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent–offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.

Genome-wide association and functional interrogation identified a variant at 3p26.1 modulating ovarian cancer survival among Chinese women

Ovarian cancer survival varies considerably among patients, to which germline variation may also contribute in addition to mutational signatures. To identify genetic markers modulating ovarian cancer outcome, we performed a genome-wide association study in 2130 Chinese ovarian cancer patients and found a hitherto unrecognized locus at 3p26.1 to be associated with the overall survival (Pcombined = 8.90 × 10−10). Subsequent statistical fine-mapping, functional annotation, and eQTL mapping prioritized a likely casual SNP rs9311399 in the non-coding regulatory region. Mechanistically, rs9311399 altered its enhancer activity through an allele-specific transcription factor binding and a long-range interaction with the promoter of a lncRNA BHLHE40-AS1. Deletion of the rs9311399-associated enhancer resulted in expression changes in several oncogenic signaling pathway genes and a decrease in tumor growth. Thus, we have identified a novel genetic locus that is associated with ovarian cancer survival possibly through a long-range gene regulation of oncogenic pathways.

Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator

Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.

Genetic mapping of the tomato quality traits brix and blossom-end rot under supplemental LED and HPS lighting conditions

LED lighting has emerged as alternative to the current HPS standard in greenhouse production. However little is known about the impact on fruit quality under the different light spectra. We grew a biparental tomato RIL population between September 2019 and January 2020 under two commercial greenhouse supplemental lighting conditions, i.e. HPS, and 95% red/5% blue- LED, of about 220 µmol m−2 s−1 at maximum canopy height for 16 h per day. Differences in Brix and blossom-end rot (BER) between the two light conditions were observed and we studied the genetic influences on those traits, separating genetics located on chromosomes from genetics located in plastids. The Brix value was on average 11% lower under LED than under HPS supplemental lighting. A LED-light specific QTL for Brix was identified on chromosome 6. This QTL can be of interest for breeding for tomato varieties cultivated under LED supplemental lighting. A Brix-QTL on chromosome 2 was found for both light conditions. In our study fewer plants developed BER under LED supplemental lighting than under HPS. We identified a novel genetic locus on chromosome 11 for the incidence of BER that lead to a difference in about 20% of fruits with BER. This genetic component was independent of the light.

Interaction of Alcohol Consumption and ABCG2 rs2231142 Variant Contributes to Hyperuricemia in a Taiwanese Population

Background: ABCG2 rs2231142 is an important genetic factor that contributes to the development of gout and hyperuricemia (HUA). Epidemiologic studies have demonstrated that lifestyle risk factors of HUA (e.g., alcohol consumption) and genetic predisposition (e.g., ABCG2 gene) together, contribute to enhanced serum uric acid levels. However, the interaction between ABCG2 rs2231142, alcohol consumption, and HUA in the Taiwanese population is still unclear. Therefore, this study investigated whether the risk of HUA is associated with ABCG2 rs2231142 variants and how this is affected by alcohol consumption. Method: study subjects were selected from the participants of the Taiwan Biobank database. Overall, 114,540 participants aged 30 to 70 years were enrolled in this study. The interaction between ABCG2 rs2231142, alcohol consumption, and serum uric acid (sUA) levels was analyzed by multiple logistic regression models. Results: the prevalence of HUA was 32.7% and 4.4 % in the male and female populations, respectively. In the whole study population, the minor T allele of ABCG2 rs2231142 was significantly associated with HUA risk, and the occurrence of HUA was high in TT genotype and TG genotype. The risk of HUA was significantly increased by the combined association of ABCG2 rs2231142 and alcohol consumption for TG/TT genotype compared to the GG genotype (wild-type genotype), especially among women. Conclusion: the ABCG2 rs2231142 is a crucial genetic locus for sUA levels in the Taiwanese population and our findings revealed that alcohol consumption combined with the ABCG2 rs2231142 risk allele contributes to increased HUA risk.

Characterization of a Common S Haplotype BnS-6 in the Self-Incompatibility of Brassica napus

Self-incompatibility (SI) is a pollen-stigma recognition system controlled by a single and highly polymorphic genetic locus known as the S-locus. The S-locus exists in all Brassica napus (B. napus, AACC), but natural B. napus accessions are self-compatible. About 100 and 50 S haplotypes exist in Brassica rapa (AA) and Brassica oleracea (CC), respectively. However, S haplotypes have not been detected in B. napus populations. In this study, we detected the S haplotype distribution in B. napus and ascertained the function of a common S haplotype BnS-6 through genetic transformation. BnS-1/BnS-6 and BnS-7/BnS-6 were the main S haplotypes in 523 B. napus cultivars and inbred lines. The expression of SRK in different S haplotypes was normal (the expression of SCR in the A subgenome affected the SI phenotype) while the expression of BnSCR-6 in the C subgenome had no correlation with the SI phenotype in B. napus. The BnSCR-6 protein in BnSCR-6 overexpressed lines was functional, but the self-compatibility of overexpressed lines did not change. The low expression of BnSCR-6 could be a reason for the inactivation of BnS-6 in the SI response of B. napus. This study lays a foundation for research on the self-compatibility mechanism and the SI-related breeding in B. napus.

Polygenic sex determination produces modular sex polymorphism in an African cichlid fish

For many vertebrates, a single genetic locus initiates a cascade of developmental sex differences in the gonad and throughout the organism, resulting in adults with two, phenotypically distinct sexes. Species with polygenic sex determination (PSD) have multiple interacting sex determination alleles segregating within a single species, allowing for more than two genotypic sexes, and scenarios where sex genotype at a given locus can be decoupled from gonadal sex. Here we investigate the effects of PSD on secondary sexual characteristics in the cichlid fish Metriaclima mbenjii, where one female (W) and one male (Y) sex determination allele interact to produce siblings with four possible sex classes: ZZXX females, ZWXX females, ZWXY females, and ZZXY males. We find that PSD in M. mbenjii produces an interplay of sex-linkage and sex-limitation resulting in modular variation in morphological and behavioral traits. Further, the evolution or introgression of a novel sex determiner creates additional axes of phenotypic variation for varied traits, including genital morphology, craniofacial morphology, gastrointestinal morphology, and home tank behaviors. In contrast to single-locus sex determination, which broadly results in sexual dimorphism, polygenic sex determination can induce higher-order sexual polymorphism. The modularity of secondary sexual characteristics produced by PSD provides novel context for understanding the evolutionary causes and consequences of maintenance, gain, or loss of sex determination alleles in populations.

Quantitative traits loci mapping and molecular marker development for total glutenin and glutenin fraction contents in wheat

Background Glutenin contents and compositions are crucial factors influencing the end-use quality of wheat. Although the composition of glutenin fractions is well known, there has been relatively little research on the genetic basis of glutenin fractions in wheat. Results To elucidate the genetic basis for the contents of glutenin and its fractions, a population comprising 196 recombinant inbred lines (RILs) was constructed from two parents, Luozhen No.1 and Zhengyumai 9987, which differ regarding their total glutenin and its fraction contents (except for the By fraction). Forty-one additive Quantitative Trait Loci (QTL) were detected in four environments over two years. These QTL explained 1.3% - 53.4% of the phenotypic variation in the examined traits. Forty-three pairs of epistatic QTL (E-QTL) were detected in the RIL population across four environments. The QTL controlling the content of total glutenin and its seven fractions were detected in clusters. Seven clusters enriched with QTL for more than three traits were identified, including a QTL cluster 6AS-3, which was revealed as a novel genetic locus for glutenin and related traits. Kompetitive Allele-Specific PCR (KASP) markers developed from the main QTL cluster 1DL-2 and the previously developed KASP marker for the QTL cluster 6AS-3 were validated as significantly associated with the target traits in the RIL population and in natural varieties. Conclusions This study identified novel genetic loci related to glutenin and its seven fractions. Additionally, the developed KASP markers may be useful for the marker-assisted selection of varieties with high glutenin fraction content and for identifying individuals in the early developmental stages without the need for phenotyping mature plants. On the basis of the results of this study and the KASP markers described herein, breeders will be able to efficiently select wheat lines with favorable glutenin properties and develop elite lines with high glutenin subunit contents.