Next-Generation Computational Genetic Analysis: Multiple Complement Alleles Control Survival after Candida albicans Infection

ABSTRACTCandida albicansis a fungal pathogen that causes severe disseminated infections that can be lethal in immunocompromised patients. Genetic factors are known to alter the initial susceptibility to and severity ofC. albicansinfection. We developed a next-generation computational genetic mapping program with advanced features to identify genetic factors affecting survival in a murine genetic model of hematogenousC. albicansinfection. This computational tool was used to analyze the median survival data after inbred mouse strains were infected withC. albicans, which provides a useful experimental model for identification of host susceptibility factors. The computational analysis indicated that genetic variation within early classical complement pathway components (C1q,C1r, andC1s) could affect survival. Consistent with the computational results, serum C1 binding to this pathogen was strongly affected byC1rsalleles, as was survival of chromosome substitution strains. These results led to a combinatorial, conditional genetic model, involving an interaction betweenC5andC1r/salleles, which accurately predicted survival after infection. Beyond applicability to infectious disease, this information could increase our understanding of the genetic factors affecting susceptibility to autoimmune and neurodegenerative diseases.

Download Full-text

High Throughput Computational Mouse Genetic Analysis

10.1101/2020.09.01.278465 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ahmed Arslan ◽

Yuan Guan ◽

Xinyu Chen ◽

Robin Donaldson ◽

Wan Zhu ◽

...

Keyword(s):

Genetic Factors ◽

Inbred Mouse ◽

Inbred Strains ◽

Mouse Strains ◽

Inbred Mouse Strains ◽

Mitochondrial Targeting ◽

Phenotypic Data ◽

Factors Affecting ◽

Wide Range ◽

Allelic Differences

AbstractBackgroundGenetic factors affecting multiple biomedical traits in mice have been identified when GWAS data, which measured responses in panels of inbred mouse strains, was analyzed using haplotype-based computational genetic mapping (HBCGM). Although this method was previously used to analyze one dataset at a time; but now, a vast amount of mouse phenotypic data is now publicly available, which could enable many more genetic discoveries.ResultsHBCGM and a whole genome SNP map covering 43 inbred strains was used to analyze 8300 publicly available datasets of biomedical responses (1.52M individual datapoints) measured in panels of inbred mouse strains. As proof of concept, causative genetic factors affecting susceptibility for eye, metabolic and infectious diseases were identified when structured automated methods were used to analyze the output. One analysis identified a novel genetic effector mechanism; allelic differences within the mitochondrial targeting sequence affected the subcellular localization of a protein. We also found allelic differences within the mitochondrial targeting sequences of many murine and human proteins, and these could affect a wide range of biomedical phenotypes.ImplicationsThese initial results indicate that genetic factors affecting biomedical responses could be identified through analysis of very large datasets, and they provide an early indication of how this type of ‘augmented intelligence’ can facilitate genetic discovery.

Download Full-text

Transmission-Ratio Distortion Through F1 Females at Chromosome 11 Loci Linked to Om in the Mouse DDK Syndrome

Genetics ◽

10.1093/genetics/142.4.1299 ◽

1996 ◽

Vol 142 (4) ◽

pp. 1299-1304

Author(s):

F Pardo-Manuel de Villena ◽

C Slamka ◽

M Fonseca ◽

A K Naumova ◽

J Paquette ◽

...

Keyword(s):

Genetic Model ◽

Inbred Mouse ◽

Transmission Ratio Distortion ◽

Transmission Ratio ◽

F1 Hybrids ◽

Mouse Strains ◽

Inbred Mouse Strains ◽

Chromosome 11 ◽

Ratio Distortion

Abstract We determined the genotypes of >200 offspring that are survivors of matings between female reciprocal F1 hybrids (between the DDK and C57BL/6J inbred mouse strains) and C57BL/6J males at markers linked to the Ovum mutant (Om) locus on chromosome 11. In contrast to the expectations of our previous genetic model to explain the “DDK syndrome,” the genotypes of these offspring do not reflect preferential survival of individuals that receive C57BL/6J alleles from the F1 females in the region of chromosome 11 to which the Om locus has been mapped. In fact, we observe significant transmission-ratio distortion in favor of DDK alleles in this region. These results are also in contrast to the expectations of Wakasugi's genetic model for the inheritance of Om, in which he proposed equal transmission of DDK and non-DDK alleles from F1 females. We propose that the results of these experiments may be explained by reduced expression of the maternal DDK Om allele or expression of the maternal DDK Om allele in only a portion of the ova of F1 females

Download Full-text

Mouse Susceptibility to Anthrax Lethal Toxin Is Influenced by Genetic Factors in Addition to Those Controlling Macrophage Sensitivity

Infection and Immunity ◽

10.1128/iai.72.8.4439-4447.2004 ◽

2004 ◽

Vol 72 (8) ◽

pp. 4439-4447 ◽

Cited By ~ 75

Author(s):

Mahtab Moayeri ◽

Nathaniel W. Martinez ◽

Jason Wiggins ◽

Howard A. Young ◽

Stephen H. Leppla

Keyword(s):

Genetic Factors ◽

Inbred Mouse ◽

Inbred Strains ◽

Lethal Toxin ◽

Cytokine Response ◽

Mouse Strains ◽

Anthrax Lethal Toxin ◽

Toll Like Receptor 4 ◽

Oxide Synthase

ABSTRACT Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages (Mφ) derived from certain inbred strains. We used nine inbred strains and two inducible nitric oxide synthase (iNOS) knockout C57BL/6J strains polymorphic for the LT Mφ sensitivity Kif1C locus to analyze the role of Mφ sensitivity (to lysis) in LT-mediated cytokine responses and lethality. LT-mediated induction of cytokines KC, MCP-1/JE, MIP-2, eotaxin, and interleukin-1β occurred only in mice having LT-sensitive Mφ. However, while iNOS knockout C57BL/6J mice having LT-sensitive Mφ were much more susceptible to LT than the knockout mice with LT-resistant Mφ, a comparison of susceptibilities to LT in the larger set of inbred mouse strains showed a lack of correlation between Mφ sensitivity and animal susceptibility to toxin. For example, C3H/HeJ mice, harboring LT-sensitive Mφ and having the associated LT-mediated cytokine response, were more resistant than mice with LT-resistant Mφ and no cytokine burst. Toll-like receptor 4 (Tlr4)-deficient, lipopolysaccharide-nonresponsive mice were not more resistant to LT. We also found that CAST/Ei mice are uniquely sensitive to LT and may provide an economical bioassay for toxin-directed therapeutics. The data indicate that while the cytokine response to LT in mice requires Mφ lysis and while Mφ sensitivity in the C57BL/6J background is sufficient for BALB/cJ-like mortality of that strain, the contribution of Mφ sensitivity and cytokine response to animal susceptibility to LT differs among other inbred strains. Thus, LT-mediated lethality in mice is influenced by genetic factors in addition to those controlling Mφ lysis and cytokine response and is independent of Tlr4 function.

Download Full-text

Dysregulated Inflammatory Response to Candida albicans in a C5-Deficient Mouse Strain

Infection and Immunity ◽

10.1128/iai.72.10.5868-5876.2004 ◽

2004 ◽

Vol 72 (10) ◽

pp. 5868-5876 ◽

Cited By ~ 58

Author(s):

Alaka Mullick ◽

Miria Elias ◽

Serge Picard ◽

Lucie Bourget ◽

Orce Jovcevski ◽

...

Keyword(s):

Candida Albicans ◽

Inflammatory Response ◽

Mouse Strain ◽

Host Response ◽

Inbred Mouse ◽

Differential Susceptibility ◽

Mouse Strains ◽

Causative Role ◽

Loss Of Function ◽

Necrosis Factor Alpha

ABSTRACT Experimental infection of inbred mouse strains with Candida albicans provides a good model system to identify host genetic determinants that regulate onset of, response to, and ultimate outcome of disseminated candidiasis. The A/J mouse strain is exquisitely sensitive to infection with C. albicans, while the C57BL/6J strain is relatively resistant, as measured by survival following intravenous injection of Candida blastospores. This differential susceptibility is caused by an A/J-specific loss-of-function mutation in the C5 component of the complement pathway. C5 plays several critical roles in host response to infection, including target lysis and phagocyte recruitment. Therefore, to determine which of its functions were required for host resistance to candidiasis, a detailed comparative analysis of pathophysiology and host response to acute C. albicans infection was conducted in A/J and C57BL/6J mice. C5-sufficient C57BL/6J mice were found to succumb late in infection due to severe kidney pathology, typified by fungal replication and robust neutrophil-based inflammatory response associated with extensive tissue damage. In contrast, A/J mice were moribund within 24 h postinfection but displayed little if any kidney damage despite an inability to mobilize granulocytes and a high fungal load in the kidney. Rather, C5 deficiency in A/J mice was associated with higher levels of circulating cytokines tumor necrosis factor alpha, interleukin-6, monocyte chemotactic protein 1 (MCP-1), MCP-5, and eotaxin in response to C. albicans. Transfer of the C5-defective allele from A/J onto a C57BL/6J genetic background in recombinant congenic strain BcA17 recapitulated the phenotypic aspects of the susceptibility of A/J mice to C. albicans, confirming the causative role of C5 deficiency in the dysregulated cytokine response.

Download Full-text

Epigenetic and genetic factors affect transgene methylation imprinting

Development ◽

10.1242/dev.107.1.165 ◽

1989 ◽

Vol 107 (1) ◽

pp. 165-168 ◽

Cited By ~ 3

Author(s):

C. Sapienza ◽

J. Paquette ◽

T.H. Tran ◽

A. Peterson

Keyword(s):

Dna Methylation ◽

Genetic Factors ◽

Inbred Mouse ◽

Mouse Strains ◽

Inbred Mouse Strains ◽

Maternal Genome ◽

Two Factors ◽

In Trans ◽

In Cis ◽

Transgene Locus

In some lines of transgenic mice, the methylation of MspI sites within or adjacent to the transgene locus is affected by the sex of the parent from which the transgene is inherited. These differences are consistent with a role for DNA methylation in genome imprinting. In a previous report, we noted that in one such line, all offspring of females exhibited hypermethylation of the transgene while only some offspring of males carried a hypomethylated transgene. In this report, we provide evidence that this phenomenon is controlled by at least two factors, one of which acts in cis and is dependent on the transgene locus, and one of which acts in trans and is supplied by the maternal genome. We also provide evidence that there are genetic differences between inbred mouse strains in the trans-acting factor.

Download Full-text

Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice

Clinical and Vaccine Immunology ◽

10.1128/cvi.00611-15 ◽

2016 ◽

Vol 23 (3) ◽

pp. 213-218 ◽

Cited By ~ 11

Author(s):

Mahtab Moayeri ◽

Jacqueline M. Tremblay ◽

Michelle Debatis ◽

Igor P. Dmitriev ◽

Elena A. Kashentseva ◽

...

Keyword(s):

Protective Antigen ◽

Inbred Mouse ◽

Lethal Factor ◽

Lethal Dose ◽

Serum Levels ◽

Mouse Strains ◽

Common Component ◽

Content Type ◽

Neutralizing Agent

ABSTRACTBacillus anthracis, the causative agent of anthrax, secretes three polypeptides, which form the bipartite lethal and edema toxins (LT and ET, respectively). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain-only antibodies (VHHs) and demonstrated theirin vivoefficacy. In this work, gene therapy with an adenoviral (Ad) vector (Ad/VNA2-PA) (VNA, VHH-based neutralizing agents) promoting the expression of a bispecific VHH-based neutralizing agent (VNA2-PA), consisting of two linked VHHs targeting different PA-neutralizing epitopes, was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 μg/ml, with some as high as 10 mg/ml. The levels were 10- to 100-fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels of >0.1 μg/ml survived LT challenge, and 9 of 10 C57BL/6J mice with serum levels of >1 μg/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors.

Download Full-text

Susceptibility of Inbred Mice to Rickettsia parkeri

Infection and Immunity ◽

10.1128/iai.00109-12 ◽

2012 ◽

Vol 80 (5) ◽

pp. 1846-1852 ◽

Cited By ~ 22

Author(s):

Britton J. Grasperge ◽

Kathryn E. Reif ◽

Timothy D. Morgan ◽

Piyanate Sunyakumthorn ◽

Joseph Bynog ◽

...

Keyword(s):

Inbred Mice ◽

Spotted Fever ◽

Inbred Mouse ◽

Transmission Model ◽

Mouse Strains ◽

Spotted Fever Group ◽

Limited Information ◽

Rickettsia Parkeri ◽

Content Type ◽

Boutonneuse Fever

ABSTRACTRickettsia parkeri, a member of the spotted fever groupRickettsia, is the causative agent of American boutonneuse fever in humans. Despite the increased recognition of human cases, limited information is available regarding the infection of invertebrate and vertebrate hosts for this emerging tick-borne disease. Toward the development of a viable transmission model and to further characterize the pathology associated withR. parkeriinfection, inbred mouse strains (A/J, BALB/c, C3H/HeJ, and C3H/HeN) were intravenously and intradermally inoculated with 105low-passage-numberR. parkeri(Portsmouth strain), and infection, gross pathology, and histopathology were scored. Additionally, a quantitative real-time PCR (qPCR) was performed to estimate rickettsial load in heart, lung, spleen, and liver tissues of infected mice at 19 days postinoculation. Of the A/J, BALB/c, and C3H/HeN mice, none displayed universal pathology consistent with sustained infection. Compared to age-matched control mice, the intravenously inoculated C3H/HeJ mice exhibited marked facial edema and marked splenomegaly upon gross examination, while the intradermally inoculated mice developed characteristic eschar-like lesions. The C3H/HeJ mice also exhibited the greatest concentrations of rickettsial DNA from heart, lung, liver, and spleen samples when examined by qPCR. The similarity of the pathology of human disease and sustained infection suggests that the C3H/HeJ strain of mice is a promising candidate for subsequent experiments to examine the tick transmission, dissemination, and pathology ofR. parkeririckettsiosis.

Download Full-text

A QUANTITATIVE ANALYSIS OF THE GENETICS OF RESTING BLOOD LACTIC ACID LEVELS IN MICE

Genetics ◽

10.1093/genetics/75.1.191 ◽

1973 ◽

Vol 75 (1) ◽

pp. 191-198

Author(s):

Patricia L Hatchell ◽

James W MacInnes

Keyword(s):

Lactic Acid ◽

Genetic Factors ◽

Inbred Mouse ◽

Inbred Strains ◽

Mouse Strains ◽

Environment Interaction ◽

Genotype X Environment ◽

Generation Means ◽

Nonallelic Interactions ◽

Lactate Levels

ABSTRACT Resting blood lactate levels were measured in inbred mouse strains, their F1, and several of their segregating generations to determine whether the level of lactic acid is influenced by genetic factors. The inbred strains in each of the two sets used differed significantly from one another for this character. Only one strain showed a significant sex difference. The data could not be fully analyzed because of the failure to fulfill Mather's first criterion for an adequate scale. Nonallelic interactions, in particular, additive x dominance and dominance x dominance, were found to influence the generation means. Genotype x environment interaction was detected and eliminated by log transformation. Negative heterosis was exhibited by all but one noninbred generation.—The data suggest that genes influencing the character are dispersed between the parental lines and that interactions are predominantly of the duplicate kind. A buffering system by which lactate levels are kept at a minimum is proposed.

Download Full-text

Analysis of Structural Variation Among Inbred Mouse Strains Identifies Genetic Factors for Autism-Related Traits

10.1101/2021.02.18.431863 ◽

2021 ◽

Author(s):

Ahmed Arslan ◽

Zhuoqing Fang ◽

Meiyue Wang ◽

Zhuanfen Cheng ◽

Boyoung Yoo ◽

...

Keyword(s):

Genetic Factors ◽

Sequence Data ◽

Inbred Mouse ◽

Inbred Strains ◽

Autism Spectrum ◽

Mouse Strains ◽

Inbred Mouse Strains ◽

Genetic Traits ◽

Long Read ◽

Short Read Sequence

AbstractThe genomes of six inbred strains were analyzed using long read (LR) sequencing. The results revealed that structural variants (SV) were very abundant within the genome of inbred mouse strains (4.8 per gene), which indicates that they could impact genetic traits. Analysis of the relationship between SNP and SV alleles across 53 inbred strains indicated that we have a very limited ability to infer whether SV are present using short read sequence data, even when nearby SNP alleles are known. The benefit of having a more complete map of the pattern of genetic variation was demonstrated by identifying at least three genetic factors that could underlie the unique neuroanatomic and behavioral features of BTBR mice that resemble human Autism Spectrum Disorder (ASD). Similar to the genetic findings in human ASD cohorts, the identified BTBR-unique alleles are very rare, and they cause high impact changes in genes that play a role in neurodevelopment and brain function.

Download Full-text