Variation In Genetic Background Research Articles

An Updated Review on Rat Genetics and Genomics: Understanding Complex Traits and Diseases

The study of the genetics and genomics of rats is essential to understanding the intricate mechanisms behind characteristics and illnesses. Rats are used by scientists to investigate a wide range of biological processes, including how the brain develops, how the immune system responds, and what goes wrong in diseases like cancer and metabolic disorders. Rats and humans are similar in physiology and genetics. This article provides a comprehensive analysis of the many advantages and applications of rat models in biomedical science, highlighting their significance in genetic and genomic research. Rat models are indispensable in research because of their many benefits. Numerous similarities between them and people make it simpler to research illnesses and test possible cures. Rats may be used to efficiently set up studies and obtain results rapidly because they breed quickly and have big litters. Furthermore, altering their DNA is not too difficult, which aids in the understanding of how genes affect complicated features and illnesses. Rat models have been essential in the past for achieving significant breakthroughs in biomedical research. They have contributed to medical advancements by helping to elucidate fundamental biological concepts and expanding our understanding of human illnesses. Researchers may go even farther into rat genetics with the use of cutting-edge technologies like single-cell sequencing and gene editing, which will disclose more about how genes function and impact health. Rat models are quite promising, but it's important to use them responsibly. Rats must be treated humanely and research must be conducted responsibly, thus researchers must abide by tight guidelines. Issues such as genetic background variations and environmental influences must be carefully taken into account to guarantee repeatability and accuracy of research findings. In conclusion, studies on the genetics and genomics of rats offer important new perspectives on intricate biological systems and hold enormous promise for advancing our knowledge of human health and illness. We can advance farther and improve society as a whole if we keep funding this area and use technology sensibly.

A diallel study to detect genetic background variation for FHB resistance in winter wheat

Breeding for resistance to Fusarium head blight (FHB) relies strongly on a limited number of larger-effect resistance QTL that have been mapped and associated with nearby markers. Smaller-effect (background) resistance QTL may also contribute moderate levels of resistance yet are mostly poorly characterized. Overall resistance of a genotype is determined by the combined action of both types of resistance QTL. This study aimed to identify well-adapted, advanced hard red winter (HRW) wheat breeding lines with useful background resistance QTL. A diallel trial consisting of 11 parents and 55 non-reciprocal F1 hybrids was tested for Type II FHB resistance in a replicated greenhouse experiment. Significant differences were detected among entries for disease severity (DS), general combining ability (GCA) and specific combining ability (SCA) with four parents being identified as the best general combiners with lowest DS. The ratio of GCA:SCA effects suggested that additive QTL effects were of primary importance. Overall, resistance QTL showed incomplete dominance, an excess of dominant alleles, and a greater contribution of positive effect genes. F2 of the six best F1 hybrids with the lowest DS were compared in a second greenhouse FHB trial to select possible transgressive segregates for continued evaluation and line development.

Mitochondrial DNA D-Loop Polymorphisms among the Galla Goats Reveals Multiple Maternal Origins with Implication on the Functional Diversity of the HSP70 Gene.

Despite much attention given to the history of goat evolution in Kenya, information on the origin, demographic history, dispersal route, and genetic diversity of Galla goats remains unclear. Here, we examined the genetic background, diversity, demographic history, and population genetic variation of Galla goats using mtDNA D-loop and HSP70 single-nucleotide polymorphism markers. The results revealed 90 segregating sites and 68 haplotypes in a 600-bp mtDNA D-loop sequence. The overall mean mitochondrial haplotype diversity was 0.993. The haplotype diversities ranged between 0.8939 ± 0.0777 and 1.0000 ± 0.0221 in all populations supporting high genetic diversity. Mitochondrial phylogenetic analysis revealed three Galla goat haplogroups (A, G, and D), supporting multiple maternal ancestries, of which haplogroup A was the most predominant. Analysis of molecular variance (AMOVA) showed considerable variation within populations at 94.39%, evidence of high genetic diversity. Bimodal mismatch distribution patterns were observed while most populations recorded negative results for Tajima and Fu's Fs neutrality tests supporting population expansion. Genetic variation among populations was also confirmed using HSP70 gene fragment sequences, where six polymorphic sites which defined 21 haplotypes were discovered. Analysis of molecular variance revealed a significant FST index value of 0.134 and a high FIS index value of 0.746, an indication of inbreeding. This information will pave the way for conservation strategies and informed breeding to improve Galla or other goat breeds for climate-smart agriculture.

Genetic background variation impacts microglial heterogeneity and disease progression in amyotrophic lateral sclerosis model mice

Recent single-cell analyses have revealed the complexity of microglial heterogeneity in brain development, aging, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Disease-associated microglia (DAMs) have been identified in ALS mice model, but their role in ALS pathology remains unclear. The effect of genetic background variations on microglial heterogeneity and functions remains unknown. Herein, we established and analyzed two mice models of ALS with distinct genetic backgrounds of C57BL/6 and BALB/c. We observed that the change in genetic background from C57BL/6 to BALB/c affected microglial heterogeneity and ALS pathology and its progression, likely due to the defective induction of neurotrophic factor-secreting DAMs and impaired microglial survival. Single-cell analyses of ALS mice revealed new markers for each microglial subtype and a possible association between microglial heterogeneity and systemic immune environments. Thus, we highlighted the role of microglia in ALS pathology and importance of genetic background variations in modulating microglial functions.

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular-kidney-metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.

A nematode model to evaluate microdeletion phenotype expression.

Microdeletion syndromes are genetic diseases caused by multilocus chromosomal deletions too small to be detected by karyotyping. They are typified by complex pleiotropic developmental phenotypes that depend both on the extent of the deletion and variations in genetic background. Microdeletion alleles cause a wide array of consequences involving multiple pathways. How simultaneous haploinsufficiency of numerous adjacent genes leads to complex and variable pleiotropic phenotypes is not well understood. CRISPR/Cas9 genome editing has been shown to induce microdeletion-like alleles at a meaningful rate. Here, we describe a microdeletion allele in Caenorhabditis elegans recovered during a CRISPR/Cas9 genome editing experiment. We mapped the allele to chromosome V, balanced it with a reciprocal translocation crossover suppressor, and precisely defined the breakpoint junction. The allele simultaneously removes 32 protein-coding genes, yet animals homozygous for this mutation are viable as adults. Homozygous animals display a complex phenotype including maternal effect lethality, producing polynucleated embryos that grow into uterine tumors, vulva morphogenesis defects, body wall distensions, uncoordinated movement, and a shortened life span typified by death by bursting. Our work provides an opportunity to explore the complexity and penetrance of microdeletion phenotypes in a simple genetic model system.

The impact of genetic background during laboratory evolution of Pseudomonas aeruginosa in a cystic fibrosis-like environment.

Genetic background has the potential to influence both the tempo and trajectory of adaptive change: Different genotypes of a given species may adopt varied solutions to the same environmental challenge, or they may approach the same solution at different rates. Laboratory selection has been widely used to experimentally examine the evolutionary consequences of variation in genetic background, although largely using genotypes differing by only a few mutations. Here, we leverage natural variation in the bacterium Pseudomonas aeruginosa to investigate whether different adaptive solutions are accessible from distant points of departure on an adaptive landscape. We evolved 17 diverse genotypes in a laboratory medium that partially mimics the lung sputum of cystic fibrosis patients, and we measured changes in 10 phenotypes as well as in fitness. Using phylogenetically informed analyses, we found that genetic background impacted the tempo, but not the trajectory, of phenotypic evolution: Different starting genotypes converged toward similar phenotypes, but at varying rates. Our findings add to a growing body of evidence supporting widespread diminishing return epistasis during adaptation. The importance of genetic background toward the trajectory of adaptation remains inconsistent across experimental systems and conditions.

Genetic background influences the 5XFAD Alzheimer's disease mouse model brain proteome.

There is an urgent need to improve the translational validity of Alzheimer's disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable the discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. In this study, we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in the hippocampus and cortex (n = 3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across the hippocampus and cortex in 5XFAD and non-transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress responses and neuronal synapse/signaling. The modules with the strongest relationship to human disease-neuronal synapse/signaling and lysosome/stress response-were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated with AD genotype in the hippocampus compared with the cortex. Our findings suggest that the genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD.

Ovarian Cancer Patient-Derived Organoid Models for Pre-Clinical Drug Testing.

Ovarian cancer is a fatal gynecologic cancer and the fifth leading cause of cancer death among women in the United States. Developing new drug treatments is crucial to advancing healthcare and improving patient outcomes. Organoids are in-vitro three-dimensional multicellular miniature organs. Patient-derived organoid (PDO) models of ovarian cancer may be optimal for drug screening because they more accurately recapitulate tissues of interest than two-dimensional cell culture models and are inexpensive compared to patient-derived xenografts. In addition, ovarian cancer PDOs mimic the variable tumor microenvironment and genetic background typically observed in ovarian cancer. Here, a method is described that can be used to test conventional and novel drugs on PDOs derived from ovarian cancer tissue and ascites. A luminescence-based adenosine triphosphate (ATP) assay is used to measure viability, growth rate, and drug sensitivity. Drug screens in PDOs can be completed in 7-10 days, depending on the rate of organoid formation and drug treatments.

Linking Colorimetric Variation with Non-Volatile and Volatile Components of Carob Flour

Chromatic variation was examined for its association with flour composition and quality. Carob samples from variable altitudes and genetic backgrounds were milled and assessed for colorimetric parameter L* (lightness) and analyzed for phenols, tannins, antioxidant capacity, soluble carbohydrates (HPLC-RID), organic acids and protein (IC-CD), and volatile organic compounds (VOCs; HS-SPME/GC-MS). Higher altitudes and grafted genotypes yielded lighter-colored flours of higher antioxidant potential, phenols, tannins, sucrose, and malic acid concentrations. VOCs were mainly acids, esters, aldehydes, ketones, and alcohols. Acids were the most abundant and correlated negatively with L*, though correlation for many individual acids was non-significant, including 2-methyl-propanoic acid, widely considered the carob signature aroma (cheesy acidic buttery). The compositional and quality indexing potential of L* is more robust for grafted than non-grafted material, owing putatively to a narrower genetic basis. Antioxidant capacity and concentrations of phenolics, tannins and sucrose correlated positively with L*, indicating increased levels in carob flours sourced from grafted trees at higher altitudes. These flours also have a lower content of reducing sugars, the implication of which in the darkening of carob flour warrants further investigation. Overall, L* constitutes a reliable index for ranking carob flours for key compositional attributes and may be further reinforced by multiple-year data.

Domestication and Genetic Diversity Analysis of Several Sheep Breeds in China

Sheep is the main livestock species in northern China. Under diverse climatic conditions, a gene pool of local sheep resources is now forming. There are many sheep breeds in northern China, including local breeds and hybrid breeds. However, little is known about the genetic background and genetic variation of local sheep populations in northern China. Therefore, our aims is to provide a characterization of the population structure and genetic relationship within sheep breeds in northern China, and to study its genetic relationship with other sheep breeds. We collected blood samples from 390 sheep for genetic diversity analysis using Reduced-Representation Genome Sequencing (RRGS). This study used bioinformatics methods to analyze linkage disequilibrium, population structure, evolutionary tree, selective sweep etc. The mixed model revealed in this study may be formed in the process of sheep breeding, partially overlapping with historical and archaeological findings. New information on the domestication and genetic variety of sheep is provided by this study, which will help sheep in the future be improved through genomics.

Comprehensive molecular analysis identifies eight novel variants in XY females with disorders of sex development.

Disorders of sex development (DSD) are a group of clinical conditions with variable presentation and genetic background. Females with or without development of secondary sexual characters and presenting with primary amenorrhea (PA) and a 46,XY karyotype are one of the classified groups in DSD. In this study, we aimed to determine the genetic mutations in 25 females with PA and a 46,XY karyotype to show correlations with their phenotypes. Routine Sanger sequencing with candidate genes like SRY, AR, SRD5A2, and SF1, which are mainly responsible for 46,XY DSD in adolescent females, was performed. In a cohort of 25 patients of PA with 46,XY DSD, where routine Sanger sequencing failed to detect the mutations, next-generation sequencing of a targeted gene panel with 81 genes was used for the molecular diagnosis. The targeted sequencing identified a total of 21 mutations including 8 novel variants in 20 out of 25 patients with DSD. The most frequently identified mutations in our series were in AR (36%), followed by SRD5A2 (20%), SF1 (12%), DHX37 (4%), HSD17B3 (4%), and DMRT2 (4%). We could not find any mutation in the DSD-related genes in five (20%) patients due to complex molecular mechanisms in 46,XY DSD, highlighting the possibility of new DSD genes which are yet to be discovered in these disorders. In conclusion, genetic testing, including cytogenetics and molecular genetics, is important for the diagnosis and management of 46,XY DSD cases.

Identification of Subunits for Novel Universal Vaccines against Three Predominant Serogroups and the Emerging O145 among Avian Pathogenic Escherichia coli by Pan-RV Pipeline.

Avian pathogenic Escherichia coli, a causative agent of avian colibacillosis, has been causing serious economic losses in the poultry industry. The increase in multidrug-resistant isolates and the complexity of the serotypes of this pathogen, especially the recently reported emergence of a newly predominant serogroup of O145, make the control of this disease difficult. To address this challenge, a high-throughput screening approach, called Pan-RV (Reverse vaccinology based on pangenome analysis), is proposed to search for universal protective antigens against the three traditional serogroups and the newly emerged O145. Using this approach, a total of 61 proteins regarded as probable antigens against the four important serogroups were screened from the core genome of 127 Avian pathogenic Escherichia coli (APEC) genomes, and six were verified by Western blots using antisera. Overall, our research will provide a foundation for the development of an APEC subunit vaccine against avian colibacillosis. Given the exponential growth of whole-genome sequencing (WGS) data, our Pan-RV pipeline will make screening of bacterial vaccine candidates inexpensive, rapid, and efficient. IMPORTANCE With the emergence of drug resistance and the newly predominant serogroup O145, the control of Avian pathogenic Escherichia coli is facing a serious challenge; an efficient immunological method is urgently needed. Here, for the first time, we propose a high-throughput screening approach to search for universal protective antigens against the three traditional serogroups and the newly emerged O145. Importantly, using this approach, a total of 61 proteins regarded as probable antigens against the four important serogroups were screened, and three were shown to be immunoreactive with all antisera (covering the four serogroups), thereby providing a foundation for the development of APEC subunit vaccines against avian colibacillosis. Further, our Pan-RV pipeline will provide immunological control strategies for pathogens with complex and variable genetic backgrounds such as Escherichia coli and will make screening of bacterial vaccine candidates more inexpensive, rapid, and efficient.

Neuroinflammation in retinitis pigmentosa: Therapies targeting the innate immune system.

Retinitis pigmentosa (RP) is an important cause of irreversible blindness worldwide and lacks effective treatment strategies. Although mutations are the primary cause of RP, research over the past decades has shown that neuroinflammation is an important cause of RP progression. Due to the abnormal activation of immunity, continuous sterile inflammation results in neuron loss and structural destruction. Therapies targeting inflammation have shown their potential to attenuate photoreceptor degeneration in preclinical models. Regardless of variations in genetic background, inflammatory modulation is emerging as an important role in the treatment of RP. We summarize the evidence for the role of inflammation in RP and mention therapeutic strategies where available, focusing on the modulation of innate immune signals, including TNFα signaling, TLR signaling, NLRP3 inflammasome activation, chemokine signaling and JAK/STAT signaling. In addition, we describe epigenetic regulation, the gut microbiome and herbal agents as prospective treatment strategies for RP in recent advances.

Tacrolimus induces a pro-fibrotic response in donor-derived human proximal tubule cells dependent on common variants of the CYP3A5 and ABCB1 genes.

Common genetic variants of the enzymes and efflux pump involved in tacrolimus disposition have been associated with calcineurin inhibitor nephrotoxicity, but their importance is unclear because of the multifactorial background of renal fibrosis. This study explores the pro-fibrotic response of tacrolimus exposure in relation to the differential capacity for tacrolimus metabolism in proximal tubule cells (PTCs) with a variable (pharmaco)genetic background. PTCs were obtained from protocol allograft biopsies with different combinations of CYP3A5 and ABCB1 variants and were incubated with tacrolimus within the concentration range found in vivo. Gene and protein expression, CYP3A5 and P-glycoprotein function, and tacrolimus metabolites were measured in PTC. Connective tissue growth factor (CTGF) expression was assessed in protocol biopsies of kidney allograft recipients. PTCs produce CTGF in response to escalating tacrolimus exposure, which is approximately 2-fold higher in cells with the CYP3A5*1 and ABCB1 TT combination in vitro. Increasing tacrolimus exposure results in relative higher generation of the main tacrolimus metabolite {13-O-desmethyl tacrolimus [M1]} in cells with this same genetic background. Protocol biopsies show a larger increase in in vivo CTGF tissue expression over time in TT vs. CC/CT but was not affected by the CYP3A5 genotype. Tacrolimus exposure induces a pro-fibrotic response in a PTC model in function of the donor pharmacogenetic background associated with tacrolimus metabolism. This finding provides a mechanistic insight into the nephrotoxicity associated with tacrolimus treatment and offers opportunities for a tailored immunosuppressive treatment.

P97/VCP ATPase inhibitors can rescue p97 mutation-linked motor neuron degeneration.

Mutations in p97/VCP cause two motor neuron diseases: inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia and familial amyotrophic lateral sclerosis. How p97 mutations lead to motor neuron degeneration is, however, unknown. Here we used patient-derived induced pluripotent stem cells to generate p97 mutant motor neurons. We reduced the genetic background variation by comparing mutant motor neurons to its isogenic wild type lines. Proteomic analysis reveals that p97R155H/+ motor neurons upregulate several cell cycle proteins at Day 14, but this effect diminishes by Day 20. Molecular changes linked to delayed cell cycle exit are observed in p97 mutant motor neurons. We also find that two p97 inhibitors, CB-5083 and NMS-873, restore some dysregulated protein levels. In addition, two p97 inhibitors and a food and drug administration-approved cyclin-dependent kinase 4/6 inhibitor, Abemaciclib, can rescue motor neuron death. Overall, we successfully used iPSC-derived motor neurons, identified dysregulated proteome and transcriptome and showed that p97 inhibitors rescue phenotypes in this disease model.

Real-Time Monitoring of Host-Gut Microbial Interspecies Interaction in Anticancer Drug Metabolism.

Gut microbiome can affect drug metabolism considerably, leading to modified drug response. However, quantitative estimation of host vs. microbial contributions in a living host-gut microbiome system has been challenging. Using the interspecies system of Caenorhabditis elegans and gut bacteria, we developed a real-time approach for monitoring their metabolic interaction in vivo during anticancer drug 5-fluorouracil (5-FU) metabolism. The fluorine NMR-based approach yielded the quantitative contributions to the host 5-FU metabolism made by human gut-microbial species of variable genetic backgrounds. It also experimentally confirmed a bacterial gene-metabolism relationship. Differential 5-FU catabolism among bacterial substrains and the contributions to the host metabolism, unobservable by conventional 16S rRNA metagenomic sequencing, were also found. The metabolic contributions could be correlated with phenotypic developmental toxicity of 5-FU to the host fed with different substrains. Our convenient platform should help to reveal heterogeneity in host-gut microbiome interactions for many drugs in a living symbiotic system.

Primary immunodeficiency and the microbiome.

The current understanding of the relationship of the microbiota to clinical manifestation in patients with primary immunodeficiency, specifically the inflammatory processes caused by or that result in microbial dysbiosis, and their potential therapeutic options in primary immunodeficiency diseases (PID), is the basis of this review. PIDs are heterogeneous diseases with variable presentations, genetic backgrounds, complications, and severity. The immune-mediators may be extrinsic, such as therapeutic regimens that patients are on, including immunoglobin, biologics, antibiotics and diet, or intrinsic, like cytokines, microRNA and microbiome. The microbiome in PID, in particular, appears to play a crucial role in helping the host's immune system maintain hemostatic control in the intestine. Many of the clinical manifestations and complications of PID may be attributed to inflammatory and immune dysregulatory processes connected to the imbalances of the diet-microbiota-host-immunity axis, as shown by data pointing to the loss of microbial diversity, dysbiosis, in PID. The gut microbiome is a promising area of study in PID. Although the connection of the microbiome to humoral immunodeficiency is evident, the possibility of utilizing the association of humoral and cellular immunodeficiency and the microbiome for therapeutic benefit is still under investigation.

IMPDH2: a new gene associated with dominant juvenile-onset dystonia-tremor disorder

The aetiology of dystonia disorders is complex, and next-generation sequencing has become a useful tool in elucidating the variable genetic background of these diseases. Here we report a deleterious heterozygous truncating variant in the inosine monophosphate dehydrogenase gene (IMPDH2) by whole-exome sequencing, co-segregating with a dominantly inherited dystonia-tremor disease in a large Finnish family. We show that the defect results in degradation of the gene product, causing IMPDH2 deficiency in patient cells. IMPDH2 is the first and rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders. We report IMPDH2 as a new gene to the dystonia disease entity. The evidence underlines the important link between guanine metabolism, dopamine biosynthesis and dystonia.

Challenges and Opportunities in Understanding Genetics of Fungal Diseases: Towards a Functional Genomics Approach.

Infectious diseases are a leading cause of morbidity and mortality worldwide, and human pathogens have long been recognized as one of the main sources of evolutionary pressure, resulting in a high variable genetic background in immune-related genes. The study of the genetic contribution to infectious diseases has undergone tremendous advances over the last decades. Here, focusing on genetic predisposition to fungal diseases, we provide an overview of the available approaches for studying human genetic susceptibility to infections, reviewing current methodological and practical limitations. We describe how the classical methods available, such as family-based studies and candidate gene studies, have contributed to the discovery of crucial susceptibility factors for fungal infections. We will also discuss the contribution of novel unbiased approaches to the field, highlighting their success but also their limitations for the fungal immunology field. Finally, we show how a systems genomics approach can overcome those limitations and can lead to efficient prioritization and identification of genes and pathways with a critical role in susceptibility to fungal diseases. This knowledge will help to stratify at-risk patient groups and, subsequently, develop early appropriate prophylactic and treatment strategies.