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Results for “Phenotype modifier”

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PubMed2025

The evolution of separate sexes in waterhemp is associated with surprising chromosomal diversity and complexity.

The evolution of separate sexes is hypothesized to occur through distinct pathways involving few large-effect or many small-effect alleles. However, we lack empirical evidence for how these different genetic architectures shape the transition from quantitative variation in sex expression to distinct male and female phenotypes. To explore these processes, we leveraged the recent transition of Amaranthus tuberculatus to dioecy within a predominantly monoecious genus, along with a sex-phenotyped population genomic dataset, and six newly generated chromosome-level haplotype phased assemblies. We identify a ~3 Mb region strongly associated with sex through complementary SNP genotype and sequence-depth-based analyses. Comparative genomics of these proto-sex chromosomes within the species and across the Amaranthus genus demonstrates remarkable variability in their structure and genic content, including numerous polymorphic inversions. No such inversion underlies the extended linkage we observe associated with sex determination. Instead, we identify a complex presence/absence polymorphism reflecting substantial Y-haplotype variation-structured by ancestry, geography, and habitat-but only partially explaining phenotyped sex. Just over 10% of sexed individuals show phenotype-genotype mismatch in the sex-linked region, and along with observation of leakiness in the phenotypic expression of sex, suggest additional modifiers of sex and dynamic gene content within and between the proto-X and Y. Together, this work reveals a complex genetic architecture of sex determination in A. tuberculatus characterized by the maintenance of substantial haplotype diversity, and variation in the expression of sex.

Haplotypes↗

PubMed2024

Genetic and Microbial Analysis of Invasiveness for Escherichia coli Strains Associated With Inflammatory Bowel Disease.

BACKGROUND & AIMS: The adherent-invasive Escherichia coli (AIEC) pathotype is implicated in inflammatory bowel disease (IBD) pathogenesis. AIEC strains are currently defined by phenotypic measurement of their pathogenicity, including invasion of epithelial cells. This broad definition, combined with the genetic diversity of AIEC across patients with IBD, has complicated the identification of virulence determinants. We sought to quantify the invasion phenotype of clinical isolates from patients with IBD and identify the genetic basis for their invasion into epithelial cells. METHODS: A pangenome with core and accessory genes (genotype) was assembled using whole genome sequencing of 168 E coli samples isolated from 13 patients with IBD. A modified assay for invasion of epithelial cells (phenotype) was established with consideration of antibiotic resistance phenotypes. Isolate genotype was correlated to invasiveness phenotype to identify genetic factors that cosegregate with invasion. RESULTS: Pangenome-wide comparisons of E coli clinical isolates identified accessory genes that can cosegregate with invasion phenotype. These correlations found the acquisition of antibiotic resistance genes in clinical isolates compromised the traditional gentamicin protection assays used to quantify invasion. Therefore, an alternate assay, based on amikacin resistance, identified genes cosegregating with invasion. These genes encode an arylsulfatase, a glycoside hydrolase, and genetic islands carrying propanediol utilization and sulfoquinovose metabolism pathways. CONCLUSIONS: This study highlights the importance of incorporating antibiotic resistance screening for invasion assays used in AIEC identification. Accurately screened invasion phenotypes identified accessory genome elements among E coli IBD isolates that correlate with their ability to invade epithelial cells. These results help explain why single genetic markers for the AIEC phylotype are challenging to identify.

Humans↗

PubMed1979

Developmental changes of sepiapterin synthase activity associated with a variegated purple gene in Drosophila melanogaster.

A variegated position effect on the autonomous gene, purple, has been studid enzymologically in Drosophila melanogaster. Sepiapterin synthase, the enzyme system associated with pr+, was examined for activity in different developmental stages of the fly. The results indicate that T(y:22)prc5, cn/prc4 cn flies (flies in which pr+ has been translocated and which exhibit variegation) have a reduced amount of enzyme activity as compared with both Oregon-R and pr1 flies. This reduction in activity was not found in larval stages, which suggests that the inactivation process probably occurs in late larval or early pupal stages. The phenotype of the variegated adult has white eyes with red-colored spots and patches where drosopterins occur. The phenotype of the fly carrying the translocation is modified by the presence of additional Y chromosomes. This extends the observation from other systems that extra heterochromatin acts to suppress the variegated position effect. The advantages of studying the variegation by measuring enzyme activity, as well as the phenotypic expression, are several; for example, the developmental time at which variegation occurs may be estimated even though drosopterin synthesis is not occurring.

Animals↗

PubMed2026

Complex genotype-phenotype relationships in neurodevelopmental disorders.

With the advent of sequencing technologies in recent years, hundreds of high-confidence risk genes have been implicated in neurodevelopmental disorders (NDDs). However, individuals carrying pathogenic variants in the same gene frequently exhibit diverse clinical presentations, including varied symptoms and diagnoses. We propose that this heterogeneity arises from different interacting factors that modulate the phenotypic outcomes of pathogenic variants, including variant-level features, modifying variation across the genome, prenatal and early-life environmental exposures, and developmental noise. Resolving these factors requires integrative approaches that combine population-scale genetics and functional genomics with environmental monitoring and quantitative assessments of stochastic developmental variation. Advancing our understanding of these factors is critical to elucidating the etiology of NDDs and improving diagnostic and personalized therapeutic strategies.

Humans↗

PubMed2026

Domestication as gene-culture coevolution.

Human preferences can shape the genetic evolution of other species via conservation practices, public health actions, and domestication. While the dynamics of domestication have been explored in depth through empirical and theoretical analyses, few studies have analyzed models for the coevolution of human cultural preferences with the genetics of a domesticate population. Humans shape the fitness landscape of domesticate populations both intentionally and unconsciously, by selecting for desirable traits and modifying environments; in turn, changes in domesticate phenotypes can affect the cultural preferences in the domesticator population. We present a model for the dynamics of domestication which includes interactions between genetic evolution, cultural transmission, and selective pressures. The model includes forms of selection due to culturally transmitted domesticator preferences that can affect the dynamics of domesticate genetic variants, which then affect the dynamics of domesticators. Equilibria with simultaneous genetic and cultural polymorphisms may exist, and may occur under apparent heterozygote disadvantage in the domesticate. Stable quasiperiodic cycles in both domesticates and domesticators are also possible.

Humans↗

PubMed1979

Biochemical and genetic characterization of three hamster cell mutants resistant to diphtheria toxin.

We describe here three different hamster cell mutants which are resistant to diphtheria toxin and which provide models for investigating some of the functions required by the toxin inactivates elongation factor 2 (EF-2). Cell-free extracts from mutants Dtx(r)-3 was codominant. The evidence suggests that the codominant phenotype is the result of a mutation in a gene coding for EF-2. The recessive phenotype might arise by alteration of an enzyme which modifies the structure of EF-2 so that it becomes a substrate for reaction with the toxin. Another mutant, Dtx(r)-2, contained EF-2 that was sensitive to the toxin and this phenotype was recessive. Pseudomonas aeruginosa exotoxin is known to inactivate EF-2 as does diphtheria toxin and we tested the mutants for cross-resistance to pseudomonas exotoxin. Dtx(r)-1 and Dtx(r)-3 were cross-resistant while Dtx(r)-2 was not. It is known that diphtheria toxin does not penetrate to the cytoplasm of mouse cells and that these cell have a naturally occurring phenotype of diphtheria toxin resistance. We fused each of the mutants with mouse 3T3 cells and measured the resistance. We fused each of the mutants with mouse 3T3 cells and measured the resistance of the hybrid cells to diphtheria toxin. Intraspecies hybrids containing the genome of mutants Dtx(r)-1 and Dtx(r)-3 had some resistance while those formed with Dtx(r)-2 were as sensitive as hybrids derived from fusions between wild-type hamster cells and mouse 3T3 cells.

Animals↗

PubMed2024

cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.

Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al., Genetics 215, 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2, as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH. We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43.

Animals↗

PubMed1977

The evolution of dominance: Haldane v Fisher revisited.

Fisher's model for the evolution of dominance indicates that the accumulation of dominance modifiers will be accelerated by (1) an increased frequency of the mutant heterozygote, (2) increased selection for the phenotype of the normal homozygote. The model has been criticised by Haldane on the grounds that point (1) is not fulfilled, that is dominance appears to be more common in populations with a low frequency of mutant heterozygotes (populations of inbreeders). In support of Fisher's model it is argued that intense selection for the wild type phenotype is more common in inbreeders than outbreeders. This situation should promote the accumulation of dominance modifiers (point (2) above).

Biological Evolution↗

PubMed1978

Use of a programmable calculator in processing and interpreting serum cholinesterase phenotypes.

Cholinesterase phenotyping is done at 25 degrees C with use of benzoylcholine as substrate and dibucaine, fluoride, chloride, and succinyldicholine as inhibitors. We wrote a diagnostic program in modified BASIC language for the processing and interpretation of these cholinesterase phenotypes. We used the HP 9830A calculator. The diagnostic aspect of the program uses 646 words, a further 86 words being used to run this program. The traditional and the programmed reporting procedures were duplicated for 296 consecutive patients, with no case of disagreement between the two reporting methods as to the appropriate phenotype. The programmed system requested nine repeat analyses more than did the traditional method. Seven of these were due to the tight limits set in the program for the fluoride inhibitor numbers. These tight limits were set to ensure that there was as limited an overlap as possible between the phenotypes E1uE1u and E1uE1f. The remaining two repeats were due to the restrictions placed on the succinyldicholine inhibitor numbers that would be acceptable before a patient was designated as having the relatively rare phenotype, E1aE1f.

Cholinesterases↗

PubMed2026

Natural variation in the PmbHLH162 promoter regulates anthocyanin biosynthesis and accumulation in Prunus mume.

Anthocyanin accumulation is a vital agronomic and ornamental trait, as it not only contributes to adaptation to environmental stress but also enhances ornamental value. In this study, a genome-wide association study (GWAS) was conducted using 328 accessions of mei (Prunus mume) to identify single-nucleotide polymorphisms (SNPs) associated with red pigmentation in petals, filaments, and xylem. Based on these significant SNPs, we defined 2 haplotypes (bHLH162hap1 and bHLH162hap2) and identified PmbHLH162, a bHLH transcription factor gene responsible for anthocyanin biosynthesis regulation. Transient silencing of PmbHLH162 in mei petals via Agrobacterium-mediated transformation resulted in significant color fading, whereas its overexpression dramatically elevated anthocyanin levels. Haplotype analysis showed that 2 promoter variants in bHLH162hap2 (Chr03_2669885 A/C and Chr03_2670272 A/G) alter the binding affinity of transcription factors PmWRKY18 and PmWRKY70. Stronger binding to the G/C alleles gave rise to higher PmbHLH162 expression in bHLH162hap2, thereby promoted red pigmentation in multiple tissues. By contrast, accessions carrying bHLH162hap1 displayed light/colorless phenotype without accumulation of red pigment. Furthermore, PmbHLH162 interacted respectively with PmMYC2, PmTT8, and PmEGL1 to form heterodimers, and markedly enhanced PmMYC2-mediated transcriptional activation of the anthocyanin biosynthetic structural genes PmCHS and PmANS. Geographic haplotype analysis revealed that bHLH162hap2 was predominantly enriched in high-latitude northern populations but was declining markedly at lower latitudes. Collectively, our study reveals the genetic and molecular basis underlying anthocyanin accumulation in mei and identifies a PmbHLH162-PmMYC2 regulatory module in which PmbHLH162 enhances PmMYC2-mediated activation of key anthocyanin biosynthetic genes. The additional interactions of PmbHLH162 with the MBW-associated bHLH factors PmTT8 and PmEGL1 further suggest potential crosstalk between this module and the canonical anthocyanin regulatory network.

Anthocyanins↗

PubMed1976

Mutant of herpes simplex virus type 1 conditionally able to transform thymidine kinaseless L cells to a tk+ phenotype.

After nitrous acid mutagenesis of herpes simplex virus type 1 (HSV-1), a mutant, 1093, was isolated which, during productive infection, induced very low levels of thymidine kinase (tk). The mutant virus was found, after UV irradiation, to be unable to transform L cells lacking tk (Ltk-) to a tk+ phenotype as chararcterized by growth of the cells in a modified HAT-selective medium containing 1.6 X 10(-5) M thymidine. Cells transformed by wild-type virus grew vigorously under the same conditions. The mutant was able to transform Ltk- cells if the medium contained 10(-3) M thymidine. These transformed cells maintained their conditional character and would not grow in low concentrations of thymidine in selective medium. Therefore, this mutant is conditional on the thymidine concentration in the selection medium in its ability to transform Ltk- cells to a tk+ phenotype. The conditionally transformed cells could be supertransformed with wild-type UV-irradiated HSV-1 to a phenotype which would grow in low-thymidine selective medium. The frequency of supertransformation closely approximated the frequency of transformation of Ltk- cells by wild-type virus. Supertransformation at high frequency could not be effected by mutant 1093 or the tk- mutant B2006. These results indicate that the presence of HSV-1 genetic information in HSV-1-transformed cells does not preclude the acquisition by these cells of at least one additional HSV-1 gene, that for tk.

Cell Transformation, Neoplastic↗

PubMed1977

[Role of the Lewis (Le-le) and secretor (Se-se) systems in the rejection of kidney grafts].

ABH and Lewis antigens are secreted in distal convoluted and collector tubes of the kidney. The renal ABH secretion is genetically controlled by the Se-se system, while the Lewis specificities are controlled by the Le-le system. The secretory status of the recipient does not modify the probability of graft survival, while the Lewis phenotype seems to play a major role in rejection. The probability of graft survival at 2 years in le-le homozygous recipients (29%) is much lower than that of Le recipients (58%) p less than 0.01.

ABO Blood-Group System↗

PubMed2025

Abiotic conditions can modify the penetrance of transgene-based lethality systems for insect population control.

Modern genetic biocontrol techniques for insect pest management, when compared to chemical insecticide spraying, offer high species specificity and reduced environmental impact, and some of these methods require the environmental release of genetically modified (GM) insects. Because organisms exposed to different environments often show variability in phenotype and gene expression, it is likely that GM insects will also experience environmentally mediated variation, potentially compromising pest control efficiency. This study examines the impact of temperature and nutrition on the early embryonic Tet-off conditional lethality system in Drosophila melanogaster. By independently manipulating parental and offspring environments, we assessed how exposure to variable environments influenced the probability of larval hatching and the transcript abundance of the transgenic system. Our findings revealed that: (i) transgene performance distinctly responds to temperature and nutrition; (ii) thermal stress has a greater impact when embryos, rather than parents, are exposed; and (iii) extreme nutritional conditions can markedly reduce the penetrance of transgenic lethality. Although changes in transgene transcript abundance were observed across environments, these changes did not fully explain the phenotypic variation, suggesting that factors downstream of transcription probably drive variation in transgenic lethality.

Animals↗

PubMed2026

Molecular characterization and antimicrobial resistance profiles of Shigella flexneri isolates from pediatric clinical cases in Ahvaz, Iran.

Shigella is a highly invasive pathogen that causes dysentery and is associated with significant morbidity and mortality in children under five years of age. This agent is a major public health problem in developing countries. Multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA) is a reliable, cost-effective typing method with high discriminatory power and reproducible results. The rise of drug resistance in Shigella strains is a growing global health threat. Despite the significance of Shigella in Iran, there is limited knowledge about genetic diversity and drug resistance profiles of local strains. Therefore, the purpose of this study was to characterize the genetic diversity and drug resistance profiles of Shigella strains isolated in Ahvaz, Iran. A total of 49 Shigella flexneri isolates were recovered from 500 stool samples of pediatric patients. Routine biochemical tests were used to identify all isolates. Antimicrobial susceptibility testing was performed, and resistance genes were detected by polymerase chain reaction (PCR). Extended-spectrum β-lactamases (ESBL), carbapenemase, and Metallo-β-lactamase (MBL) production were detected phenotypically using combination disk assays and confirmed by the CLSI-recommended modified Carbapenem inactivation method (mCIM) and EDTA-modified carbapenem inactivation method (eCIM). MLVA based on seven VNTR loci was performed to characterize the genetic diversity of the isolates. All 49 isolates were resistant to ceftazidime, trimethoprim/sulfamethoxazole, ampicillin, and ceftriaxone (100% each). High resistance rates were also observed for imipenem 36/49 (73.5%), meropenem 36/49 (73.5%), azithromycin 21/49 (42.9%), and ciprofloxacin 16/49 (32.7%). Furthermore, phenotypic testing revealed ESBL production in 46/49 (93.9%) isolates and carbapenemase activity in 36/49 (73.5%), of which 22/49 (44.9%) were MBL. PCR analysis identified blaCTX-M 38/49 (77.6%) and blaSHV 35/49 (71.4%) as the most prevalent ESBL genes, whereas blaNDM 14/49 (28.6%), and blaOXA-48 14/49 (28.6%) were the most common carbapenemase genes. MLVA typing divided the isolates into 22 different MLVA types, including 10 clusters and 12 singletons, and locus ms21 showed the highest discriminatory power. The isolates exhibited high genetic diversity with a non-clonal distribution of resistance, which indicates dissemination through horizontal gene transfer. Our results demonstrated that mCIM/eCIM and MLVA are viable methods for investigating Shigella species as they are cost-effective, provide quick results, and allow for easy sharing of numerical data between laboratories.

Humans↗

PubMed2026

Single-cell vector copy number analysis of phenotypically defined long-term hematopoietic stem cells for gene therapy safety assessment.

Hematopoietic stem cell (HSC)-based gene therapy has emerged as a transformative approach for the treatment of genetic diseases; however, accurate evaluation of vector copy number (VCN) remains critical for ensuring safety. Conventional bulk VCN assays, including quantitative PCR (qPCR) and droplet digital PCR (ddPCR), do not resolve clonal heterogeneity and cannot identify rare high-VCN cells that may contribute disproportionately to insertional mutagenesis risk. Here, we developed an accessible single-cell VCN profiling method by combining fluorescence-activated cell sorting (FACS) of phenotypically defined long-term HSCs (Lineage- CD34+ CD38- CD90+ CD45RA- cells) with whole-genome amplification followed by conventional qPCR. This approach enabled resolution of VCN distributions at single-cell level using standard laboratory techniques. Notably, single-cell analysis revealed a high VCN tail that bulk VCN analysis could not resolve. Furthermore, in a humanized mouse transplantation model, single-cell VCN profiling demonstrated that overall VCN distributions could be analyzed after engraftment, although inter-donor and inter-mouse variability was observed. Collectively, this method provides a rapid, cost-effective, and phenotypically resolved strategy for assessing VCN heterogeneity in gene-modified HSCs. Single-cell VCN profiling offers complementary insights beyond conventional bulk assays and may enhance preclinical safety evaluation of gene and cell therapy products.

lentiviral vector↗

PubMed1979

Microenvironmental influences on the in vivo behavior of neoplastic lymphocytes.

A transplantable hamster lymphocytic neoplasma of probable monoclonal derivation, induced by the oncogenic DNA simian virus 40, has been adapted to grow in the allogeneic host either as leukemia (characterized by dissemination and poor prognosis) or as lymphoma (characterized by localization and favorable prognosis) [Diamandopoulos, G. Th. (1978) Proc. Natl. Acad. Sci. USA 75, 2011-2015]. In the present experiments the circumstances under which neoplastic lymphocytes that are transplanted in allogeneic animals retain, lose, or regain the capacity for dissemination or localization are assessed. Results indicate that the in vivo behavior of neoplastic lymphocytes is not a stable, irreversible characteristic that is transmitted to the cell progeny. On the contrary, it can be altered by the origin/tissue microenvironment in which the cells proliferate. It is suggested that, whereas neoplastic cell mutation followed by host selection could be responsible for changes in cell behavior, a more likely explanation is that the proliferating neoplastic lymphocytes acquire reversible nonmutational phenotypic characteristics during their interaction with the host microenvironment, which modify their behavior and, as a result, the prognosis of the neoplastic process.

Animals↗

PubMed1977

Growth of murine sarcoma virus-transformed rat kidney cells in nude mice: absence of induction of host endogenous viruses.

Clonal isolates of the normal rat kidney cell line (NRK) transformed by a defective murine sarcoma virus (Kirsten strain) were injected into nude mice of BALB/c background to determine whether the growth of these cells as tumors was accompanied by the induction of host endogenous type C viruses. All the virus-transformed clones produced rapidly growing tumors in nude mice, but neither the induction of mouse endogenous viruses nor the rescue and spread of the transforming sarcoma virus were observed during the growth of tumors. The degree of expression of the tumor virus structural proteins in the transformed cells did not determine the cellular phenotype with regard to tumorigenicity in nude mice, nor did it modify the cellular growth properties in vitro. Consistent with earlier observations with simian virus 40-transformed mouse and rat cells, the ability of sarcoma virus-transformed NRK cells to initiate tumor growth in nude mice appeared to be correlated with anchorage-independent growth in vitro.

Animals↗

PubMed2026

Expert consensus on the reporting and clinical follow up of individuals with incidentally discovered germline RET variants in the UK.

Incidentally discovered pathogenic germline genetic variants refer to the finding of a pathogenic variant in a gene that is unrelated to the reason for the initial test and is not actively sought. Our clinical understanding of the risk of developing a particular medical condition and the required clinical action for a specific pathogenic gene variant is predominantly based on knowledge and information acquired from cases ascertained through a 'phenotype-first approach' rather than in clinically unselected individuals. Therefore, a modified approach is required for incidentally discovered gene variants. Data from large UK and US population-based cohorts have demonstrated that RET variants classified as moderate-risk RET variants as per the American Thyroid Association (ATA) classification have a low penetrance for medullary thyroid cancer and other RET-related conditions (e.g. phaeochromocytoma) and are not associated with excess mortality when identified incidentally in clinically unselected adult individuals. Here, we provide guidance based on multidisciplinary expert consensus opinion for the reporting and subsequent clinical surveillance and management of patients with incidentally discovered RET gene variants in the UK.

Humans↗