Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice

Congenital anomalies of the kidney and urinary tract (CAKUT) are some of the most common developmental defects and have a complicated etiology, indicating an interaction of (epi-) genetic and environmental factors. Single gene mutations and copy number variations (CNVs) do not explain most cases of CAKUT, and simultaneous contributions of more than one gene (di-, oligo-, or polygenic effects; i.e., complex genetics) may lead to the pathogenesis of CAKUT. Robo2 plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations leading to supernumerary kidneys. Gen1 is a candidate gene associated with CAKUT because of its important role in early metanephric development in mice. We established a mouse model with double disruption of Robo2 and Gen1 using a piggyBac transposon and found that double gene mutation led to significantly increased CAKUT phenotypes in Robo2PB/+Gen1PB/+ mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the Robo2PB/+Gen1PB/+ mice during the embryonic period. Robo2 and Gen1 exert synergistic effects on mouse kidney development, promoting cell proliferation by activating the GDNF/RET pathway and downstream MAPK/ERK signaling. Our findings provide a disease model for CAKUT as an oligogenic disorder.

Epistatic genetic interactions govern morphogenesis during sexual reproduction and infection in a global human fungal pathogen

Cellular development is orchestrated by evolutionarily conserved signaling pathways, which are often pleiotropic and involve intra- and inter-pathway epistatic interactions that form intricate, complex regulatory networks. Cryptococcus species are a group of closely-related human fungal pathogens that grow as yeasts yet transition to hyphae during sexual reproduction. Additionally, during infection they can form large, polyploid titan cells that evade immunity and develop drug resistance. Multiple known signaling pathways regulate cellular development, yet how these are coordinated and interact with genetic variation is less well understood. Here, we conducted quantitative trait locus (QTL) analyses of a mapping population generated by sexual reproduction of two parents, only one of which is unisexually fertile. We observed transgressive segregation of the unisexual phenotype among progeny, as well as a novel large-cell phenotype under mating-inducing conditions. These large-cell progeny were found to produce titan cells both in vitro and in infected animals. Two major QTLs and corresponding quantitative trait genes (QTGs) were identified: RIC8 (encoding a guanine-exchange factor) and CNC06490 (encoding a putative Rho-GTPase activator), both involved in G-protein signaling. The two QTGs interact epistatically with each other and with the mating-type locus in phenotypic determination. These findings provide insights into the complex genetics of morphogenesis during unisexual reproduction and pathogenic titan cell formation and illustrate how QTL analysis can be applied to identify epistasis between genes. This study shows that phenotypic outcomes are influenced by the genetic background upon which mutations arise, implicating dynamic, complex genotype-to-phenotype landscapes in fungal pathogens and beyond.

Genetic Factors Underlying Single Fiber Quality in A-Genome Donor Asian Cotton (Gossypium arboreum)

The study of A-genome Asian cotton as a potential fiber donor in Gossypium species may offer an enhanced understanding of complex genetics and novel players related to fiber quality traits. Assessment of individual fibers providing classified fiber quality information to the textile industry is Advanced Fiber Information System (AFIS) in the recent technological era. Keeping the scenario, a diverse collection of 215 Asiatic cotton accessions were evaluated across three agro-ecological zones of China. Genome-Wide Association Studies (GWAS) was performed to detect association signals related to 17 AFIS fiber quality traits grouped into four categories viz: NEPs, fiber length, maturity, and fineness. Significant correlations were found within as well as among different categories of various traits related to fiber quality. Fiber fineness has shown a strong correlation to all other categories, whereas these categories are shown interrelationships via fiber-fineness. A total of 7,429 SNPs were found in association with 17 investigated traits, of which 177 were selected as lead SNPs. In the vicinity of these lead SNPs, 56 differentially expressed genes in various tissues/development stages were identified as candidate genes. This compendium connecting trait-SNP-genes may allow further prioritization of genes in GWAS loci to enable mechanistic studies. These identified quantitative trait nucleotides (QTNs) may prove helpful in fiber quality improvement in Asian cotton through marker-assisted breeding as well as in reviving eroded genetic factors of G. hirsutum via introgression breeding.

Massive QTL analysis identifies pleiotropic genetic determinants for stress resistance, aroma formation, and ethanol, glycerol and isobutanol production in Saccharomyces cerevisiae

Background The brewer’s yeast Saccharomyces cerevisiae is exploited in several industrial processes, ranging from food and beverage fermentation to the production of biofuels, pharmaceuticals and complex chemicals. The large genetic and phenotypic diversity within this species offers a formidable natural resource to obtain superior strains, hybrids, and variants. However, most industrially relevant traits in S. cerevisiae strains are controlled by multiple genetic loci. Over the past years, several studies have identified some of these QTLs. However, because these studies only focus on a limited set of traits and often use different techniques and starting strains, a global view of industrially relevant QTLs is still missing. Results Here, we combined the power of 1125 fully sequenced inbred segregants with high-throughput phenotyping methods to identify as many as 678 QTLs across 18 different traits relevant to industrial fermentation processes, including production of ethanol, glycerol, isobutanol, acetic acid, sulfur dioxide, flavor-active esters, as well as resistance to ethanol, acetic acid, sulfite and high osmolarity. We identified and confirmed several variants that are associated with multiple different traits, indicating that many QTLs are pleiotropic. Moreover, we show that both rare and common variants, as well as variants located in coding and non-coding regions all contribute to the phenotypic variation. Conclusions Our findings represent an important step in our understanding of the genetic underpinnings of industrially relevant yeast traits and open new routes to study complex genetics and genetic interactions as well as to engineer novel, superior industrial yeasts. Moreover, the major role of rare variants suggests that there is a plethora of different combinations of mutations that can be explored in genome editing.

The complex genetics of symbiotic extended phenotypes across environments in a model mutualism

A goal of modern biology is to develop the genotype-phenotype (G-P) map, a predictive understanding of how genomic information generates the organismal trait variation that forms the basis of both natural and managed communities. As microbiome research advances, however, it has become clear that many of these traits are governed by genetic variation encoded not only by the host's own genome, but also by the genomes of myriad cryptic symbionts. Thus many ecologically-important traits are likely symbiotic extended phenotypes, and this recognition adds even more complexity to our conceptions of the G-P map. In model symbioses such as the legume-rhizobium mutualism, host growth and fitness often depend on genetic variation in symbiont partner quality, and our ability to manipulate host and symbiont genotype combinations, combined with increasingly precise sequencing and mapping approaches, provides an opportunity to characterize the genetic nature of these symbiotic extended phenotypes. Here we use naturally-occurring genetic variation in 191 strains of the nitrogen-fixing symbiont Ensifer meliloti in four mapping experiments to study the genomic architecture of symbiotic partner quality within and across environmental contexts and host genotypes. We demonstrate the quantitative genetic nature of symbiotic extended phenotypes, including extensive context-dependency in both the identity and functions of symbiont loci that control host growth. We additionally resolve a core set of universal loci from populations in the native range that are likely important in all or most environments, and thus, serve as excellent targets both for genetic engineering and future coevolutionary studies of symbiosis.

Analysis of Genetic Variants Associated with Levels of Immune Modulating Proteins for Impact on Alzheimer’s Disease Risk Reveal a Potential Role for SIGLEC14

Genome-wide association studies (GWAS) have identified immune-related genes as risk factors for Alzheimer’s disease (AD), including TREM2 and CD33, frequently passing a stringent false-discovery rate. These genes either encode or signal through immunomodulatory tyrosine-phosphorylated inhibitory motifs (ITIMs) or activation motifs (ITAMs) and govern processes critical to AD pathology, such as inflammation and amyloid phagocytosis. To investigate whether additional ITIM and ITAM-containing family members may contribute to AD risk and be overlooked due to the stringent multiple testing in GWAS, we combined protein quantitative trait loci (pQTL) data from a recent plasma proteomics study with AD associations in a recent GWAS. We found that pQTLs for genes encoding ITIM/ITAM family members were more frequently associated with AD than those for non-ITIM/ITAM genes. Further testing of one family member, SIGLEC14 which encodes an ITAM, uncovered substantial copy number variations, identified an SNP as a proxy for gene deletion, and found that gene expression correlates significantly with gene deletion. We also found that SIGLEC14 deletion increases the expression of SIGLEC5, an ITIM. We conclude that many genes in this ITIM/ITAM family likely impact AD risk, and that complex genetics including copy number variation, opposing function of encoded proteins, and coupled gene expression may mask these AD risk associations at the genome-wide level.

Plant-Derived Natural Compounds for the treatment of Amyotrophic Lateral Sclerosis: An Update

Background: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease (MND) that typically causes death within 3-5 years after diagnosis. Regardless of the substantial scientific knowledge accrued from more than a century ago, truly effective therapeutic strategies remain distant. Various conventional drugs are being used but are having several adverse effects. Objective/Aim: The current study aims to thoroughly review plant-derived compounds with well-defined ALS activities and their structure-activity relationships. Moreover, the review also focuses on complex genetics, clinical trials, and the use of natural products that might decrypt the future and novel therapeutics in ALS. Methods: The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct. Results: Results showed that phytochemicals like-Ginkgolides, Protopanaxatriol, Genistein, epigallocatechingallate, resveratrol, cassoside, and others possess Amyotrophic lateral sclerosis (ALS) activity by various mechanisms. Conclusion: These plant-derived compounds may be considered as supplements to conventional (ALS). Moreover, further preclinical and clinical studies are required to understand the structure-activity relationships, metabolism, absorption, and mechanisms of plant-derived natural agents.