Epistasis-aware genome-wide association studies provide insights into the efficient breeding of high-yield and high-quality rice

Marker-assisted selection(MAS)and genomic selection(GS)breeding have greatly improved the efficiency of rice breeding.Due to the influences of epistasis and gene pleiotropy,ensuring the actual breeding effect of MAS and GS is still a difficult challenge to overcome.In this study,113 indica rice varieties(V)and their 565 testcross hybrids(TC)were used as the materials to investigate the genetic basis of 12 quality traits and nine agronomic traits.The original traits and general combining ability of the parents,as well as the original traits and midparent heterosis of TC,were subjected to genome-wide association analysis.In total,381 primary significantly associated loci(SAL)and 1,759 secondary SALs that had epistatic interactions with these primary SALs were detected.Among these loci,322 candidate genes located within or nearby the SALs were screened,204 of which were cloned genes.A total of 39 MAS molecular modules that are beneficial for trait improvement were identified by pyramiding the superior haplotypes of candidate genes and desirable epistatic alleles of the secondary SALs.All the SALs were used to construct genetic networks,in which 91 pleiotropic loci were investigated.Additionally,we estimated the accuracy of genomic prediction in the parent V and TC by incorporating either no SALs,primary SALs,secondary SALs or epistatic effect SALs as covariates.Although the prediction accuracies of the four models were generally not significantly different in the TC dataset,the incorporation of primary SALs,secondary SALs,and epistatic effect SALs significantly improved the prediction accuracies of 5(26%),3(16%),and 11(58%)traits in the V dataset,respectively.These results suggested that SALs and epistatic effect SALs identified based on an additive genotype can provide considerable predictive power for the parental lines.They also provide insights into the genetic basis of complex traits and valuable information for molecular breeding in rice.

Genetic Pleiotropy Test by Quasi p-Value with Application to Typhoon Data in China

To test genetic pleiotropy,the main difficulty lies in the failure to find a test statistic and calculate its p-value for determining whether to reject the null hypothesis or not.To deal with this issue,the authors propose a quasi p-value,which plays the similar role as the usual p-value in genetic pleiotropy test.In the formula of the quasi p-value,the main task is to determine the weights.In this paper,the authors present two weighted methods based on the Bayesian rule and extend the proposed methods to study a single binary trait using a data-driven EM algorithm.Extensive simulation studies are conducted for the assessment of the two proposed methods and illustrate that the proposed methods improve the performance of power by comparing with the two-stage method.In addition,the authors apply the proposed methods to the data of tropical storms that occurred on the mainland of China since 1949,investigating the relationship between the landing site and predictive features of tropical storms,and showing that the landing site has a large influence on at least two features of typhoon.

CCT family genes in cereal crops: A current overview

Control of flowering time is crucial for reproductive success of cereal crops, and has a significant impact on grain yield as well as adaptation to diverse environmental conditions.Plants integrate signals from both environmental cues and endogenous regulatory pathways to fine-tune flowering time. The CCT domain originally described to a 43-amino acid sequence at the C-terminus of three Arabidopsis proteins, namely CONSTANS(CO),CO-LIKE, and TIMING OF CAB1(TOC1). The CCT domain-containing genes(CCT genes),which encode transcription co-factors, are the major genetic determinants that modulate flowering time, and this in turn enables plants to effectively expand their territory to take advantage of favorable habitats. Moreover, certain CCT genes have pleiotropic effects on morphological traits and confer resistance/tolerance to biotic/abiotic stresses. CCT genes can be classified into three families, namely COL(CONSTANS-like), PRR(Pseudo-response regulator), and CMF(CCT motif family),based on their non-CCT domains. During domestication, natural and artificial selection resulted in reduced nucleotide diversity of CCT genes in modern cultivated cereals than their wild types. Here, we review the features and functions of CCT genes in cereal crops and propose future research to focus on CCT genes and their utilization in crop breeding.

Application of computational methods in genetic study ofinflammatory bowel disease

Genetic factors play an important role in the etiology of inflammatory bowel disease(IBD). The launch of genome-wide association study(GWAS) represents a landmark in the genetic study of human complex disease. Concurrently, computational methods have undergone rapid development during the past a few years, which led to the identification of numerous disease susceptibility loci. IBD is one of the successful examples of GWAS and related analyses. A total of 163 genetic loci and multiple signaling pathways have been identified to be associated with IBD. Pleiotropic effects were found for many of these loci; and risk prediction models were built based on a broad spectrum of genetic variants. Important gene-gene, gene-environment interactions and key contributions of gut microbiome are being discovered. Here we will review the different types of analyses that have been applied to IBD genetic study, discuss the computational methods for each type of analysis, and summarize the discoveries made in IBD research with the application of these methods.

Diabetes mellitus susceptibility with varied diseased phenotypes and its comparison with phenome interactome networks

An emerging area of interest in understanding disease phenotypes is systems genomics.Complex diseases such as diabetes have played an important role towards understanding the susceptible genes and mutations.A wide number of methods have been employed and strategies such as polygenic risk score and allele frequencies have been useful,but understanding the candidate genes harboring those mutations is an unmet goal.In this perspective,using systems genomic approaches,we highlight the application of phenome-interactome networks in diabetes and provide deep insights.LINC01128,which we previously described as candidate for diabetes,is shown as an example to discuss the approach.

Theory of pleiotropic action of biologically active compounds and medicines—Basic principles and practical application

This article represents the main positions of the theory of pleiotropic action of biologically active compounds (BACs) and medicines, which has been designed by the author based on her own experimental researches. The term “pleiotropy” means the ability of the BACs and medicines to implement more than one mechanism of action resulting in the specific biological (pharmacological) effect. The interaction of these mechanisms forms a distinct pattern of biological response (pleiotropic pattern), which reflects the change in his character with the increased dose (concentration)-dependent efficacy of BACs and medicines. The article consists of description of different pleiotropic patterns established in experiments on the model of reactive oxygen species (ROS) generation by macrophages dependent on activity of specialized enzyme called Nox2-NAD(P)H oxidase (Nox2, EC 1.6.3.1). Moreover, it consists of explanation of pharmacodynamic nature of pleiotropic patterns by means of application Chou-Talalay median effect equalization and combination index (CI) theory. The novel theory explains unsolved until now universal aspects of activity BACs and medicines, such as slope angles of “dose-effect” dependences in the conditions relevant in vivo, and it is of fundamental interest. However, it has applications in experimental pharmacology, as it allows defining the choice of the individual compounds and combinations, modulating the trust effect selectively and efficiently. This knowledge opens up new approaches to medicines discovery and evaluation, their rational dosing and combining.

Overlap of genetic influences in phenotypes classically categorized as psychiatric vs medical disorders

Psychiatric disorders have traditionally been segregated from medical disorders in terms of drugs,treatment,insurance coverage and training of clinicians.This segregation is consistent with the long-standing observation that there are inherent differences between psychiatric disorders(diseases relating to thoughts,feelings and behavior)and medical disorders(diseases relating to physical processes).However,these differences are growing less distinct as we improve our understanding of the roles of epistasis and pleiotropy in medical genetics.Both psychiatric and medical disorders are predisposed in part by genetic variation,and psychiatric disorders tend to be comorbid with medical disorders.One hypothesis on this interaction posits that certain combinations of genetic variants(epistasis)influence psychiatric disorders due to their impact on the brain,but the associated genes are also expressed in other tissues so the same groups of variants influence medical disorders(pleiotropy).The observation that psychiatric and medical disorders may interact is not novel.Equally,both epistasis and pleiotropy are fundamental concepts in medical genetics.However,we are just beginning to understand how genetic variation can influence both psychiatric and medical disorders.In our recent work,we have discovered gene networks significantly associated with psychiatric and substance use disorders.Invariably,these networks are also significantly associated with medical disorders.Recognizing how genetic variation can influence both psychiatric and medical disorders will help us to understand the etiology of the individual and comorbid disease phenotypes,predict and minimize side effects in drug and other treatments,and help to reduce stigma associated with psychiatric disorders.

Systematic Exploration of Optimized Base Editing gRNA Design and Pleiotropic Effects with BExplorer

Base editing technology is being increasingly applied in genome engineering,but the current strategy for designing guide RNAs(gRNAs)relies substantially on empirical experience rather than a dependable and efficient in silico design.Furthermore,the pleiotropic effect of base editing on disease treatment remains unexplored,which prevents its further clinical usage.Here,we presented BExplorer,an integrated and comprehensive computational pipeline to optimize the design of gRNAs for 26 existing types of base editors in silico.Using BExplorer,we described its results for two types of mainstream base editors,BE3 and ABE7.10,and evaluated the pleiotropic effects of the corresponding base editing loci.BExplorer revealed 524 and 900 editable pathogenic single nucleotide polymorphism(SNP)loci in the human genome together with the selected optimized gRNAs for BE3 and ABE7.10,respectively.In addition,the impact of 707 edited pathogenic SNP loci following base editing on 131 diseases was systematically explored by revealing their pleiotropic effects,indicating that base editing should be carefully utilized given the potential pleiotropic effects.Collectively,the systematic exploration of optimized base editing gRNA design and the corresponding pleiotropic effects with BExplorer provides a computational basis for applying base editing in disease treatment.

A Post-domestication Mutation, Dt2, Triggers Systemic Modification of Divergent and Convergent Pathways Modulating Multiple Agronomic Traits in Soybean

The semi-determinate stem growth habit in leguminous crops,similar to the“green revolution”semi-dwarf trait in cereals,is a key plant architecture trait that affects several other traits determining grain yield.In soybean semi-determinacy is modulated by a post-domestication gain-of-function mutation in the gene,Dt2,which encodes an MADS-box transcription factor.However,its role in systemic modification of stem growth and other traits is unknown.In this study,we show that Dt2 functions not only as a direct repressor of Dt1,which prevents terminal flowering,but also as a direct activator of putative floral integrator/identity genes including GmSOC1,GmAP1,and GmFUL,which likely promote flowering.We also demonstrate that Dt2 functions as a direct repressor of the putative drought-responsive transcription factor gene GmDREB1D,and as a direct activator of GmSPCH and GmGRP7,which are potentially associated with asymmetric division of young epidermal cells and stomatal opening,respectively,and may affect the plant's water-use efficiency(WUE).Intriguingly,Dt2 was found to be a direct activator or repressor of the precursors of eight microRNAs targeting genes potentially associated with meristem maintenance,flowering time,stomatal density,WUE,and/or stress responses.This study thus reveals the molecular basis of pleiotropy associated with plant productivity,adaptability,and environmental resilience.

The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies:a review

The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms.It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder.The advent of next generation sequencing(NGS)has allowed for a system-wide,unbiased approach to identify all gene variants in the genome simultaneously.With the plethora of new genes being identified,genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia(SCA),hereditary spastic paraplegia(HSP)and Charcot-Marie-Tooth disease(CMT)has become widely accepted.It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease(PD)and amyotrophic lateral sclerosis(ALS).The observation of pleiotropy has emerged,with mutations in the same gene giving rise to diverse phenotypes,which further increases the complexity of phenotype-genotype correlation.Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene,presence of modifier genes,and oligogenic inheritance.Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms,translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies,and ultimately finding disease-modifying therapies for neurodegenerative disorders.

Genetic hypothesis for the developmental origins of health and disease theory

The developmental origins of health and disease theory states that environmental stresses during the early stages of life influence health and risk of developing non-communicable diseases throughout the lifespan of an individual.Developmental plasticity is thought to be a possible underlying mechanism.Here,I discuss a contrasting but complementary genetic hypothesis regarding the developmental origins of health and disease theory:crosstalk between the genomes of the parents and offspring is responsible for shaping and adapting responses to environmental stresses,regulating early growth and predisposition to non-communicable diseases.Genetic variants that are beneficial in terms of responses to early life stresses may have pleiotropic detrimental effects on health later in life,which may change the allele frequencies driven by selection on a population level.Genetic studies on the cohort of children born after assisted reproduction could provide insight regarding the genetic mechanisms of the developmental origins of health and disease theory.