Genetic Interaction Analysis Research Articles

Using Synthetic Genetic Interactions in Candida glabrata as a Novel Method to Detect Genes with Roles in Antifungal Drug Resistance.

Synthetic genetic interaction analysis is a powerful genetic strategy that analyzes the fitness and phenotypes of single- and double-gene mutant cells in order to dissect the interactions between genes, categorize into biological pathways, and characterize genes of unknown function. It has been extensively employed in model organisms for fundamental, systems-level assessment of the interactions between genes. However, more recently, genetic interaction mapping has been applied to fungal pathogens and has been instrumental for the study of clinically important infectious organisms. This protocol herein explains in the detail the methodology and analysis that can be employed to develop interaction maps in microbial pathogens. Such techniques can aid in bridging our understanding of complex genetic networks, with applications to diverse microbial pathogens to further our understanding of virulence, the use of antimicrobial therapies, and host-pathogen interactions.

Regulation of axon pruning of mossy fiber projection in hippocampus by CRMP2 and CRMP4.

Axon pruning facilitates the removal of ectopic and misguided axons and plays an important role in neural circuit formation during brain development. Sema3F and its receptor neuropilin-2 (Nrp2) have been shown to be involved in the stereotyped pruning of the infrapyramidal bundle (IPB) of mossy fibers of the dentate gyrus (DG) in the developing hippocampus. Collapsin response mediator proteins (CRMPs) were originally identified as an intracellular mediator of semaphorin signaling, and the defective pruning of IPB was recently reported in CRMP2-/- and CRMP3-/- mice. CRMP1 and CRMP4 have high homology to CRMP2 and CRMP3, and their expression in the developing mouse brain overlaps; however, their role in IPB pruning has not yet been examined. In this study, we report that CRMP4, but not CRMP1, is involved in IPB pruning during neural circuit formation in the hippocampus. Our genetic interaction analyses indicated that CRMP2 and CRMP4 have distinct functions and that CRMP2 mediates IPB pruning via Nrp2. We also observed the altered synaptic terminals of mossy fibers in CRMP2 and CRMP4 mutant mice. These results suggest that CRMP family members have a distinct function in the axon pruning and targeting of mossy fibers of the hippocampal DG in the developing mouse brain.

HIF-1α Is Associated with Resistance to Hypoxia-Induced Apoptosis in Ameloblastoma.

Background Ameloblastoma (AMB) is a benign odontogenic tumour, with an aggressive local behaviour and a high rate of recurrence. Previous studies have demonstrated that hypoxia-induced factor alpha 1 (HIF-1α) and activated caspase-3 contribute to tumour invasiveness and cytogenesis in ameloblastoma. Hypoxia increases HIF-1α levels, which triggers a number of signalling pathways. This paper aimed to present data in the study of hypoxia-activated signalling pathways that modulate proapoptotic and antiapoptotic events in AMB. Methods Twenty cases of AMB and ten cases of dental follicle (DF) were used to analyse the immunoexpression of HIF-1α, p53, BNIP3, Bcl-2, IAP-2, GLUT1, and Bax. To contribute to the study, an analysis of expression and genetic interaction was performed using the cell line AME-1. Results AMB and DF expressed the studied proteins. These proteins showed significantly greater immunoexpression in AMB compared with the DF (p < 0.05). HIF-1α showed an important association with GLUT1, and a positive correlation was observed among p53, Bcl-2, and IAP-2. Transcriptomic analysis showed the significant expression of the studied proteins, and the network generated showed a direct association of HIF-1αF with GLUT1 (SLC2A1), TP53, and LDHA. Interestingly, GLUT1 also exhibited direct interaction with TP53 and LDHA. Conclusion In AMB tumorigenesis, hypoxia is possibly related to antiapoptotic events, which suggests an important role for HIF-1α, GLUT1, Bcl-2, IAP-2, and possibly p53.

Conducting genetic interaction analysis with CRISPR-Cas9-based strategies in Candida albicans

Candida albicans is an opportunistic fungal pathogen found in the oral mucosa, the gut, the vaginal mucosa, and humans' skin. While C. albicans can cause superficial infections, severe invasive infections can occur in immunocompromised individuals. Understanding the survival mechanisms and pathogenesis of C. albicans is critical for novel antifungal drug discovery. Determining the relationships between different genes can create a genetic interaction map, which can identify complementary gene sets, central to C. albicans survival, as potential drug targets in combination therapy. A genetic approach using the CRISPR-Cas9-based genome editing platform will focus on genetic interaction analysis of C. albicans stress response genes. The ultimate goal is to create a stress response gene deletion library to study its pathogen survival role. This library of single and double stress response gene mutants will be screened under diverse growth conditions to assess their relative fitness. Genetic interaction analysis will help map out epistatic interactions between fungal genes involved in growth, survival, and pathogenesis and uncover putative targets for combination antifungal therapy based on negative or synthetic lethal genetic interactions.

Bioinformatic Analysis of Prognostic Value, Genetic Interaction, and Immune Infiltration of Chromobox Family Proteins in Breast Cancer.

IntroductionBreast cancer (BC) has become the malignant tumor with the highest incidence worldwide. As a critical components of epigenetic regulation complexes, chromobox (CBX) family members inhibit the transcription of target genes through chromatin modification, leading to the progression of various human diseases and cancers. So far, little is known about the role of different CBX members in BC, especially their association with immune cells.MethodsWe conducted the analysis of differential expression of CBXs using Oncomine and GEPIA, prognostic value of CBXs using GEPIA and Kaplan-Meier, genetic interaction of CBXs using cBioPortal and GeneMANIA, and immune cell infiltration of CBXs in BC patients using TIMER.ResultsThe CBX2/3/4/8 expression levels were increased significantly, while the CBX6/7 expression levels were decreased. We found that CBX3 was significantly correlated with clinicopathological staging and short DFS in BC patients. High CBX3/5 expression was correlated with short OS in BC patients, while high expression of CBX4 was correlated with long OS in BC patients. In addition, the functions of CBXs family members mainly focus on methylated histone residue binding and chromatin organization. The CBXs expressions were closely related to the infiltration level of a variety of immune cells, including CD4/8+ T cells, B cells, neutrophils, macrophages and dendritic cells in BC cancers. The correlation between CBXs and immune cell infiltration was more common in Luminal BC than in Basal and Her-2 type.ConclusionThis study may provide a new understanding for selection of molecular typing, therapeutic and prognostic biomarkers of CBX family in BC.

The Arabidopsis HDZIP class II transcription factor ABA INSENSITIVE TO GROWTH 1 functions in leaf development.

Leaf laminar growth and adaxial-abaxial boundary formation are fundamental outcomes of plant development. Boundary and laminar growth coordinate the further patterning and growth of the leaf, directing the differentiation of cell types within the top and bottom domains and promoting initiation of lateral organs along their adaxial or abaxial axis. Leaf adaxial-abaxial polarity specification and laminar outgrowth are regulated by two transcription factors, REVOLUTA (REV) and KANADI (KAN). ABA INSENSITIVE TO GROWTH 1 (ABIG1) encodes a HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIP) class II transcription factor and is a direct target of the adaxial-abaxial regulators REV and KAN. To investigate the role of ABIG1 in leaf development and in the establishment of polarity, we examined the phenotypes of both gain-of-function and loss-of-function mutants. Through genetic interaction analysis with REV and KAN mutants, we determined that ABIG1 plays a role in leaf laminar growth as well as in adaxial-abaxial polarity establishment. Genetic and physical interaction assays showed that ABIG1 interacts with the transcriptional TOPLESS corepressor. This study provides new evidence that ABIG1, another HD-ZIP II, facilitates growth through the corepressor TOPLESS.

Three novel structural variations at the major histocompatibility complex and IL12B predispose to psoriasis.

Structural variations (SVs; defined as DNA variants ≥ 50 base pairs) have been associated with various complex human diseases. However, research to screen the whole genome for SVs predisposing to psoriasis is lacking. To investigate the association of SVs and psoriasis. Using imputation, we performed a genome-wide screen of SVs on five independent cohorts with 45 386 participants from the Han Chinese population. Fine-mapping analysis, genetic interaction analysis and RNA expression analysis were conducted to explore the mechanism of SVs. In total, we obtained 4535 SVs and identified two novel deletions [esv3608550, odds ratio (OR) 2·73 (P < 2·00 × 10-308 ); esv3608542, OR 0·47 (P = 7·40 × 10-28 )] at 6q21·33 (major histocompatibility complex), one novel Alu element insertion [esv3607339; OR 1·22 (P = 1·18 × 10-35 )] at 5q33·3 (IL12B) and confirmed one previously reported deletion [esv3587563; OR 1·30 (P = 9·52 × 10-60 )] at 1q21·2 (late cornified envelope) for psoriasis. Fine-mapping analysis including single-nucleotide polymorphisms (SNPs) and small insertions/deletions revealed that esv3608550 and esv3608542 were independently associated with psoriasis, and a novel independent SNP [rs9378188; OR, 1·65 (P = 3·46 × 10-38 )] was identified at 6q21·33. By genetic interaction analysis and RNA expression analysis, we speculate that the association of two deletions at 6q21·33 with psoriasis might relate to their influence on the expression of HLA-C. We have constructed the most comprehensive SV map for psoriasis thus far and enriched the genetic architecture and pathogenesis of psoriasis, and highlight the non-negligible impact of SVs on complex diseases.

Noncanonical protease-activated receptor 1 regulates lymphatic differentiation in zebrafish

SummaryThe differentiation of lymphatic progenitors is a crucial step in lymphangiogenesis. However, its underlying mechanism remains unclear. Here, we found that noncanonical protease-activated receptor 1 (par1) regulates the differentiation of lymphatic progenitors in zebrafish embryos. Loss of par1 function impaired lymphatic differentiation by downregulating prox1a expression in parachordal lymphangioblasts and caused compromised thoracic duct formation in zebrafish. Meanwhile, the G protein gnai2a, a par1 downstream effector, was selectively required for lymphatic development in zebrafish, and its mutation mimicked the lymphatic phenotype observed in par1 mutants. Interestingly, mmp13, but not thrombin, was required for lymphatic development in zebrafish. Furthermore, analyses of genetic interactions confirmed that mmp13b serves as a par1 upstream protease to regulate lymphatic development in zebrafish embryos. Mechanistically, par1 promotes flt4 expression and phospho-Erk1/2 activity in the posterior cardinal vein. Taken together, our findings highlight a function of par1 in the regulation of lymphatic differentiation in zebrafish embryos.

Genetic landscape of T cells identifies synthetic lethality for T-ALL

To capture the global gene network regulating the differentiation of immature T cells in an unbiased manner, large-scale forward genetic screens in zebrafish were conducted and combined with genetic interaction analysis. After ENU mutagenesis, genetic lesions associated with failure of T cell development were identified by meiotic recombination mapping, positional cloning, and whole genome sequencing. Recessive genetic variants in 33 genes were identified and confirmed as causative by additional experiments. The mutations affected T cell development but did not perturb the development of an unrelated cell type, growth hormone-expressing somatotrophs, providing an important measure of cell-type specificity of the genetic variants. The structure of the genetic network encompassing the identified components was established by a subsequent genetic interaction analysis, which identified many instances of positive (alleviating) and negative (synthetic) genetic interactions. Several examples of synthetic lethality were subsequently phenocopied using combinations of small molecule inhibitors. These drugs not only interfered with normal T cell development, but also elicited remission in a model of T cell acute lymphoblastic leukaemia. Our findings illustrate how genetic interaction data obtained in the context of entire organisms can be exploited for targeted interference with specific cell types and their malignant derivatives.

A systematic analysis of genetic interactions and their underlying biology in childhood cancer

Childhood cancer is a major cause of child death in developed countries. Genetic interactions between mutated genes play an important role in cancer development. They can be detected by searching for pairs of mutated genes that co-occur more (or less) often than expected. Co-occurrence suggests a cooperative role in cancer development, while mutual exclusivity points to synthetic lethality, a phenomenon of interest in cancer treatment research. Little is known about genetic interactions in childhood cancer. We apply a statistical pipeline to detect genetic interactions in a combined dataset comprising over 2,500 tumors from 23 cancer types. The resulting genetic interaction map of childhood cancers comprises 15 co-occurring and 27 mutually exclusive candidates. The biological explanation of most candidates points to either tumor subtype, pathway epistasis or cooperation while synthetic lethality plays a much smaller role. Thus, other explanations beyond synthetic lethality should be considered when interpreting genetic interaction test results.

A standard knockout procedure alters expression of adjacent loci at the translational level

The Saccharomyces cerevisiae gene deletion collection is widely used for functional gene annotation and genetic interaction analyses. However, the standard G418-resistance cassette used to produce knockout mutants delivers strong regulatory elements into the target genetic loci. To date, its side effects on the expression of neighboring genes have never been systematically assessed. Here, using ribosome profiling data, RT-qPCR, and reporter expression, we investigated perturbations induced by the KanMX module. Our analysis revealed significant alterations in the transcription efficiency of neighboring genes and, more importantly, severe impairment of their mRNA translation, leading to changes in protein abundance. In the ‘head-to-head’ orientation of the deleted and neighboring genes, knockout often led to a shift of the transcription start site of the latter, introducing new uAUG codon(s) into the expanded 5′ untranslated region (5′ UTR). In the ‘tail-to-tail’ arrangement, knockout led to activation of alternative polyadenylation signals in the neighboring gene, thus altering its 3′ UTR. These events may explain the so-called neighboring gene effect (NGE), i.e. false genetic interactions of the deleted genes. We estimate that in as much as ∼1/5 of knockout strains the expression of neighboring genes may be substantially (>2-fold) deregulated at the level of translation.

Two galacturonosyltransferases function in plant growth, stomatal development, and dynamics.

The mechanical properties of guard cell (GC) walls are important for stomatal development and stomatal response to external stimuli. However, the molecular mechanisms of pectin synthesis and pectin composition controlling stomatal development and dynamics remain poorly explored. Here, we characterized the role of two Arabidopsis (Arabidopsis thaliana) galacturonosyltransferases, GAUT10 and GAUT11, in plant growth, stomatal development, and stomatal dynamics. GAUT10 and GAUT11 double mutations reduced pectin synthesis and promoted homogalacturonan (HG) demethylesterification and demethylesterified HG degradation, resulting in larger stomatal complexes and smaller pore areas, increased stomatal dynamics, and enhanced drought tolerance of plants. In contrast, increased GAUT10 or GAUT11 expression impaired stomatal dynamics and drought sensitivity. Genetic interaction analyses together with immunolabeling analyses suggest that the methylesterified HG level is important in stomatal dynamics, and pectin abundance with the demethylesterified HG level controls stomatal dimension and stomatal size. Our results provide insight into the molecular mechanism of GC wall properties in stomatal dynamics, and highlight the role of GAUT10 and GAUT11 in stomatal dimension and dynamics through modulation of pectin biosynthesis and distribution in GC walls.

Multi-objective design optimization of battery thermal management system for electric vehicles

• Genetic programming shows reliable surrogate modelling. • Properties of liquid-based battery thermal management system are analyzed. • Cooling plate design and inlet coolant velocity are the main factors affect the temperature uniformity and pressure drop. • The pressure drop has been significantly optimized with the proposed optimization framework. Lithium batteries are commonly used as the primary power storage unit for electric vehicles, and their performance is sensitive to temperature. Thus, the battery thermal management system is crucially needed to allow the EVs to work safely and efficiently. This paper mainly focuses on the performance analysis and design optimization of the battery thermal management system with a U-shaped cooling channel. A Computational fluid dynamics model of a battery thermal management system is built to study the battery temperature distribution and pressure distribution. Through the establishment of the genetic programming model, sensitivity analysis and parameter interaction analysis are carried out to analyze the influence of cooling plate thickness, cooling plate wall thickness, inlet coolant temperature and flow velocity on the comprehensive performance of the battery thermal management system. A new surrogate-assisted multi-objective optimization scheme is proposed by introducing an integrated AI system that includes a surrogate battery model built with genetic programming (GP) and a design optimizer driven by the second-generation non-dominated sorting genetic algorithm (NSGA-II). Results show that the inlet coolant temperature has the most significant influence on the rise of battery temperature (59.87%) but has no influence on the pressure drop. The structural parameters of the cooling plate and the velocity of the inlet coolant have apparent effects on the uniformity of the battery temperature distribution and the pressure drop. The battery thermal management system achieves an ideal comprehensive performance when the thickness of the cooling plate is 4.50 mm, the thickness of the cooling plate wall is 1.49 mm, the inlet coolant temperature is 298.15 K, and the inlet coolant velocity is 0.29 m/s. Under such optimized parameter settings, the max temperature rise of the battery reduces from 7.72 K to 7.69 K, the standard deviation of the temperature distribution 2.54 K (a drop of 0.02 K), and the pressure drop decrease from 1022.1 Pa to 436.43 Pa (decrease by 57.3%). Such results have guiding significance for the design of the battery thermal management system with a U-shaped channel and the application of genetic programming in system performance analysis and optimization.

Zinc-finger protein MdBBX7/MdCOL9, a target of MdMIEL1 E3 ligase, confers drought tolerance in apple.

Water deficit is one of the main challenges for apple (Malus × domestica) growth and productivity. Breeding drought-tolerant cultivars depends on a thorough understanding of the drought responses of apple trees. Here, we identified the zinc-finger protein B-BOX 7/CONSTANS-LIKE 9 (MdBBX7/MdCOL9), which plays a positive role in apple drought tolerance. The overexpression of MdBBX7 enhanced drought tolerance, whereas knocking down MdBBX7 expression reduced it. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis identified one cis-element of MdBBX7, CCTTG, as well as its known binding motif, the T/G box. ChIP-seq and RNA-seq identified 1,197 direct targets of MdBBX7, including ETHYLENE RESPONSE FACTOR (ERF1), EARLY RESPONSIVE TO DEHYDRATION 15 (ERD15), and GOLDEN2-LIKE 1 (GLK1) and these were further verified by ChIP-qPCR and electronic mobility shift assays. Yeast two-hybrid screen identified an interacting protein of MdBBX7, RING-type E3 ligase MYB30-INTERACTING E3 LIGASE 1 (MIEL1). Further examination revealed that MdMIEL1 could mediate the ubiquitination and degradation of MdBBX7 by the 26S proteasome pathway. Genetic interaction analysis suggested that MdMIEL1 acts as an upstream factor of MdBBX7. In addition, MdMIEL1 was a negative regulator of the apple drought stress response. Taken together, our results illustrate the molecular mechanisms by which the MdMIEL1-MdBBX7 module influences the response of apple to drought stress.

Construction of Synaptic Neural Network for Genetic Interaction Analysis

Contribution by a single gene to the association with trait may be either independent or through interactions with other genes. Examining all available genes for the main effect should be carried out without the time constraint. However the number of possible interacting combinations would soon become formidably large with the growing number of genes. Therefore it is often coerced to identify a group of candidate genes for the interaction and investigate only within it. Such an identification process should be able to select the group of genes having possibilities to interact with each other. Main effect of each gene should not necessarily be the criterion for the selection. We devised a neural network process that was quite sensitive to the interaction of a particular gene to the remaining ones. Contribution of each gene to the association by the genes as a whole was estimated. Selection was made based on the statistical significance for the existence of such contribution. It was demonstrated that this process might perform reliable candidate gene selection for the interaction even when the selected genes did not show significant main effect, through single scan of each individual gene.

Actin-Related Protein 6 (Arp6) Influences Double-Strand Break Repair in Yeast

DNA double-strand breaks (DSBs) are the most deleterious form of DNA damage and are repaired through non-homologous end-joining (NHEJ) or homologous recombination (HR). Repair initiation, regulation and communication with signaling pathways require several histone-modifying and chromatin-remodeling complexes. In budding yeast, this involves three primary complexes: INO80-C, which is primarily associated with HR, SWR1-C, which promotes NHEJ, and RSC-C, which is involved in both pathways as well as the general DNA damage response. Here we identify ARP6 as a factor involved in DSB repair through an RSC-C-related pathway. The loss of ARP6 significantly reduces the NHEJ repair efficiency of linearized plasmids with cohesive ends, impairs the repair of chromosomal breaks, and sensitizes cells to DNA-damaging agents. Genetic interaction analysis indicates that ARP6, MRE11 and RSC-C function within the same pathway, and the overexpression of ARP6 rescues rsc2∆ and mre11∆ sensitivity to DNA-damaging agents. Double mutants of ARP6, and members of the INO80 and SWR1 complexes, cause a significant reduction in repair efficiency, suggesting that ARP6 functions independently of SWR1-C and INO80-C. These findings support a novel role for ARP6 in DSB repair that is independent of the SWR1 chromatin remodeling complex, through an apparent RSC-C and MRE11-associated DNA repair pathway.

Fat body Ire1 regulates lipid homeostasis through the Xbp1s-FoxO axis in Drosophila

SummaryThe endoplasmic reticulum (ER)-resident transmembrane protein kinase/RNase Ire1 is a conserved sensor of the cellular unfolded protein response and has been implicated in lipid homeostasis, including lipid synthesis and transport, across species. Here we report a novel catabolic role of Ire1 in regulating lipid mobilization in Drosophila. We found that Ire1 is activated by nutrient deprivation, and, importantly, fat body-specific Ire1 deficiency leads to increased lipid mobilization and sensitizes flies to starvation, whereas fat body Ire1 overexpression results in the opposite phenotypes. Genetic interaction and biochemical analyses revealed that Ire1 regulates lipid mobilization by promoting Xbp1s-associated FoxO degradation and suppressing FoxO-dependent lipolytic programs. Our results demonstrate that Ire1 is a catabolic sensor and acts through the Xbp1s-FoxO axis to hamper the lipolytic response during chronic food deprivation. These findings offer new insights into the conserved Ire1 regulation of lipid homeostasis.

Improving grain appearance of erect-panicle japonica rice cultivars by introgression of the null gs9 allele

The panicle architecture and grain size of rice affect not only grain yield but also grain quality, especially grain appearance. The erect-panicle (EP) trait controlled by the qpe9-1/dep1 allele has been widely used in high-yielding japonica rice breeding, but usually accompanied with moderate appearance of milled rice. The null gs9 allele shows a good potential for improving grain shape and appearance. However, GS9 and qPE9-1/DEP1 loci are tightly linked, and their interaction is unclear, which obviously restricts their utilization in modern rice breeding. In the present study, comparative analyses of protein and mRNA levels revealed that GS9 and qPE9-1 function independently. Three near-isogenic lines (NILs) carrying various allelic combinations of these two loci, NIL (gs9/qpe9-1), NIL (GS9/qPE9-1) and NIL (gs9/qPE9-1), in the EP japonica cultivar 2661 (GS9/qpe9-1) background were developed for genetic interaction analysis. GS9 and qPE9-1 had additive effects on determining grain size, and the null gs9 allele could decrease grain chalkiness and improve grain appearance without affecting plant and panicle architecture in EP japonica cultivars. Additionally, introgression lines (ILs) developed in another released EP japonica cultivar Wuyujing 27 (WYJ27) background showed the same additive effect and the feasibility of utilizing the gs9 allele to improve grain appearance quality in high-yielding EP cultivars. This study provides an effective strategy for rice breeders to improve rice grain appearance in EP japonica and related cultivars.

Mutation Profiling and Associated Clinical Features in Chinese Cytogenetically Normal Acute Myeloid Leukemia Patients

AML without abnormal karyotypes (CN-AML), which accounted for nearly half of total AML patients, is a highly heterogeneous subset of AML. Here we used deep sequencing technology to describe the spectrum of mutations in 39 genes and clinical features of CN-AML in 152 patients.We identified 503 mutations in 145 (95.39%) patients, with the median number of 3 mutations per case. Nine genes (NPM1, CEBPAbi, DNMT3A, GATA2, NRAS, TET2, FLT3-ITD, IDH2, WT1) mutated in more than 10% patients. Function groups of myeloid transcription factors, activated signaling and DNA methylation mutated most. Three sets of co-occurrence and seven sets of mutual exclusivities existed in genes, three sets of overlapping and incompatibility in function groups were observed in genetic interaction analysis. The distribution of variant allele frequencies (VAF) of recurrent genes was different among functional groups, and obvious diversities of VAF existed in same genes among different mutation points were also observed.Compared with the western studies, the mutation frequencies of NPM1 and DNMT3A genes were lower in Asian CN-AML patients. High mutation rates of CEBPA and GATA2 together with the low frequency of FLT3-ITD mutation seemed to be the distinct characteristics of Chinese patients. Obviously, the mutation distribution differed significantly among different regions and ethnicities.Correlation were shown between genotype and clinical features. There were significant distinctions in the distribution of genotypes in FAB subtypes. NPM1 and DNMT3A mutated most in M5 while CEBPAbi and GATA2 mutated most in M2. In M4, leukemia cells are composed of both myeloid and monocytic blasts, the mutation pattern was uniformly distributed.Prognosis analysis identified CEBPAmo mutation as an inferior factor. Combined with NCCN guidelines, the FLT3-ITD, TP53, DNMT3A, CEBPAmo and WT1 mutations were selected as high-risk markers, which could further differentiate the patients with poor prognosis of CN-AML, suggesting the potential application of guidance in clinical treatment.In conclusion, we reported here a comprehensive study of gene mutations in 152 CN-AML patients, gained insights into unique genetic profile and better risk consultation in CN-AML patients, providing valuable information for clinical practice. DisclosuresNo relevant conflicts of interest to declare.

Computational Methods Dedicated to Neurological Disorder Detection through Epistasis Analysis: A Review

Neurological disorders, such as ALS, Alzheimer’s, epilepsy, Parkinson’s Disease, Autism, Atrial Fibrillation, and Sclerosis, affect the central nervous system, including the brain, nerves, spinal cords, muscles, and Neuromuscular joint. These disorders are investigated by detecting the genetic variations in Single Nucleotide Polymorphism (SNP) in Genome-Wide Association Studies (GWAS). In the human genome sequence, one SNP influences the effects of another SNP. These SNP-SNP interactions or Gene-Gene interaction (Epistasis) significantly increase the risk of disease susceptibility to neurological disorders. The manual analyses of various genetic interactions related to neurological diseases are cumbersome. Hence, the computational system is effective for the discovery of Epistasis effects in neurological syndromes. This study aims to explore various techniques of statistical, machine learning, optimization so far applied to find the epistasis effect for neurological disorders. This study finds several genetic interaction models involving different loci, various candidate genes, and SNP interactions involved in numerous neurological diseases. The gene APOE and its polymorphism increase Alzheimer's disease pathology. The gene GAB2 and its SNPs play a vital role in Alzheimer’s disease. The genes GABRA4, ITGB3, and SLC64A highly influence the genetic interactions for Autism disorder. In schizophrenia, the SNPs of NRG1 increase the disease risk. The benefits, limitations, and issues of the various computational techniques implemented for epistasis evaluation of neurological disease are deeply discussed.