Missing heritability in genome-wide association studies defines a major problem in genetic analyses of complex biological traits
. The solution to this problem is to identify all causal genetic ...variants and to measure their individual contributions
. Here we report a graph pangenome of tomato constructed by precisely cataloguing more than 19 million variants from 838 genomes, including 32 new reference-level genome assemblies. This graph pangenome was used for genome-wide association study analyses and heritability estimation of 20,323 gene-expression and metabolite traits. The average estimated trait heritability is 0.41 compared with 0.33 when using the single linear reference genome. This 24% increase in estimated heritability is largely due to resolving incomplete linkage disequilibrium through the inclusion of additional causal structural variants identified using the graph pangenome. Moreover, by resolving allelic and locus heterogeneity, structural variants improve the power to identify genetic factors underlying agronomically important traits leading to, for example, the identification of two new genes potentially contributing to soluble solid content. The newly identified structural variants will facilitate genetic improvement of tomato through both marker-assisted selection and genomic selection. Our study advances the understanding of the heritability of complex traits and demonstrates the power of the graph pangenome in crop breeding.
Summary The poor prognosis and rising incidence of esophageal cancer highlight the need for improved detection and prediction methods that are essential prior to treatment. Esophageal cancer is one ...of the most fatal malignancies worldwide, with a dramatic increase in incidence in the Western world occurring over the past few decades. Despite improvements in the management and treatment of esophageal cancer patients, the general outcome remains very poor for overall 5-year survival rates (∼10%) and 5-year postesophagectomy survival rates (∼15–40%). Esophageal cancer is often diagnosed during its advanced stages, the main reason being the lack of early clinical symptoms. In an attempt to improve the outcome of patients after surgery, such patients are often treated with neoadjuvent concurrent chemoradiotherapy (CCRT) in order to decrease tumor size. However, CCRT may enhance toxicity levels and possibly cause a delay in surgery for patients who respond poorly to CCRT. Thus, precise biomarkers that could predict or identify patients who may or may not respond well to CCRT can assist physicians in choosing the appropriate therapy for patients. Identifying susceptible gene and biomarkers can help in predicting the treatment response of patients while improving their survival rates.
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression ...features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R
= 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R
of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
Summary
The intestinal tract of mammals is colonized by a large number of microorganisms including trillions of bacteria that are referred to collectively as the gut microbiota. These indigenous ...microorganisms have co‐evolved with the host in a symbiotic relationship. In addition to metabolic benefits, symbiotic bacteria provide the host with several functions that promote immune homeostasis, immune responses, and protection against pathogen colonization. The ability of symbiotic bacteria to inhibit pathogen colonization is mediated via several mechanisms including direct killing, competition for limited nutrients, and enhancement of immune responses. Pathogens have evolved strategies to promote their replication in the presence of the gut microbiota. Perturbation of the gut microbiota structure by environmental and genetic factors increases the risk of pathogen infection, promotes the overgrowth of harmful pathobionts, and the development of inflammatory disease. Understanding the interaction of the microbiota with pathogens and the immune system will provide critical insight into the pathogenesis of disease and the development of strategies to prevent and treat inflammatory disease.
Genetic factors of chronic pancreatitis in Russian population Litvinova, Maria M.; Khafizov, Kamil; Speranskaya, Anna S. ...
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... et al.,
June 2019, 2019-06-00, 20190601, Letnik:
19
Journal Article
Exposures to adverse environments, both psychosocial and physicochemical, are prevalent and consequential across a broad range of childhood populations. Such adversity, especially early in life, ...conveys measurable risk to learning and behavior and to the foundations of both mental and physical health. Using an interactive gene-environment-time (GET) framework, we survey the independent and interactive roles of genetic variation, environmental context, and developmental timing in light of advances in the biology of adversity and resilience, as well as new discoveries in biomedical research. Drawing on this rich evidence base, we identify 4 core concepts that provide a powerful catalyst for fresh thinking about primary health care for young children: (1) all biological systems are inextricably integrated, continuously "reading" and adapting to the environment and "talking back" to the brain and each other through highly regulated channels of cross-system communication; (2) adverse environmental exposures induce alterations in developmental trajectories that can lead to persistent disruptions of organ function and structure; (3) children vary in their sensitivity to context, and this variation is influenced by interactions among genetic factors, family and community environments, and developmental timing; and (4) critical or sensitive periods provide unmatched windows of opportunity for both positive and negative influences on multiple biological systems. These rapidly moving frontiers of investigation provide a powerful framework for new, science-informed thinking about health promotion and disease prevention in the early childhood period.
Globally, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death. Arising through three major pathways, including adenoma-carcinoma ...sequence, serrated pathway and inflammatory pathway, CRC represents an aetiologically heterogeneous disease according to subtyping by tumour anatomical location or global molecular alterations. Genetic factors such as germline MLH1 and APC mutations have an aetiologic role, predisposing individuals to CRC. Yet, the majority of CRC is sporadic and largely attributable to the constellation of modifiable environmental risk factors characterizing westernization (for example, obesity, physical inactivity, poor diets, alcohol drinking and smoking). As such, the burden of CRC is shifting towards low-income and middle-income countries as they become westernized. Furthermore, the rising incidence of CRC at younger ages (before age 50 years) is an emerging trend. This Review provides a comprehensive summary of CRC epidemiology, with emphasis on modifiable lifestyle and nutritional factors, chemoprevention and screening. Overall, the optimal reduction of CRC incidence and mortality will require concerted efforts to reduce modifiable risk factors, to leverage chemoprevention research and to promote population-wide and targeted screening.
During the peak of hospitalizations of patients with severe Covid-19 in Italy and Spain in March, a group of researchers in these and other countries obtained and analyzed samples, resulting in the ...identification of two chromosomal loci associated with the disorder.
The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogeneous. Studies have reported that males and some ...ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors.
In this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS fails to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations.
We find 8 super variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV-2.
Eight genetic variants are identified to significantly increase the risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely clues and potential directions for better understanding the molecular pathogenesis of COVID-19 and the genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.
Adolescence and mental health Blakemore, Sarah-Jayne
The Lancet,
05/2019, Letnik:
393, Številka:
10185
Journal Article
Recenzirano
Odprti dostop
...there is evidence of adolescent-typical behaviour across species. ...adolescent-typical behaviours are documented across history. Photo: Alex Brenner Puberty is characterised by rapid increases in ...oestrogen in girls and testosterone in boys, and this is when sex differences in mental health problems start to emerge. ...while genetic factors are a key mechanism of risk transmission for mental health problems, the social environment also has an important role and, furthermore, nature and nurture do not work in isolation.
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