Allelic Variation on Murine Chromosome 11 Modifies Host Inflammatory Responses and Resistance to Bacillus anthracis

Background: The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. Methods: We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test and imputed (with validation) CCR5del32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. Results: We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels. We found no evidence for association of CCL3L1 copy number or CCR5del32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.

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A comprehensive genetic map of murine chromosome 11 reveals extensive linkage conservation between mouse and human.

Genetics ◽

10.1093/genetics/122.1.153 ◽

1989 ◽

Vol 122 (1) ◽

pp. 153-161 ◽

Cited By ~ 3

Author(s):

A M Buchberg ◽

E Brownell ◽

S Nagata ◽

N A Jenkins ◽

N G Copeland

Keyword(s):

Human Chromosome ◽

Linkage Map ◽

Mouse Chromosome ◽

Chromosome 17 ◽

Human Chromosomes ◽

Chromosome 11 ◽

Murine Chromosome ◽

Human Chromosome 17 ◽

Mouse Chromosome 11 ◽

Linkage Conservation

Abstract Interspecific backcross animals from a cross between C57BL/6J and Mus spretus mice were used to generate a comprehensive linkage map of mouse chromosome 11. The relative map positions of genes previously assigned to mouse chromosome 11 by somatic cell hybrid or genetic backcross analysis were determined (Erbb, Rel, 11-3, Csfgm, Trp53-1, Evi-2, Erba, Erbb-2, Csfg, Myhs, Cola-1, Myla, Hox-2 and Pkca). We also analyzed genes that we suspected would map to chromosome 11 by virtue of their location in human chromosomes and the known linkage homologies that exist between murine chromosome 11 and human chromosomes (Mpo, Ngfr, Pdgfr and Fms). Two of the latter genes, Mpo and Ngfr, mapped to mouse chromosome 11. Both genes also mapped to human chromosome 17, extending the degree of linkage conservation observed between human chromosome 17 and mouse chromosome 11. Pdgfr and Fms, which are closely linked to II-3 and Csfgm in humans on chromosome 5, mapped to mouse chromosome 18 rather than mouse chromosome 11, thereby defining yet another conserved linkage group between human and mouse chromosomes. The mouse chromosome 11 linkage map generated in these studies substantially extends the framework for identifying homologous genes in the mouse that are involved in human disease, for elucidating the genes responsible for several mouse mutations, and for gaining insights into chromosome evolution and genome organization.

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Evaluation of spontaneous generation of allelic variation in soybean in response to sexual hybridization and stress

Canadian Journal of Plant Science ◽

10.4141/cjps-2014-324 ◽

2015 ◽

Vol 95 (2) ◽

pp. 405-415 ◽

Cited By ~ 3

Author(s):

Katherine Espinosa ◽

Jessica Boelter ◽

Susan Lolle ◽

Marianne Hopkins ◽

Susana Goggi ◽

...

Keyword(s):

De Novo ◽

Allelic Variation ◽

Accelerated Aging ◽

Physical Region ◽

Spontaneous Generation ◽

Chromosome 11 ◽

Sexual Hybridization ◽

Genetic Mechanisms ◽

Pure Lines ◽

Sexual Crosses

Espinosa, K., Boelter, J., Lolle, S., Hopkins, M., Goggi, S., Palmer, R. G. and Sandhu, D. 2015. Evaluation of spontaneous generation of allelic variation in soybean in response to sexual hybridization and stress. Can. J. Plant Sci. 95: 405–415. Intra-cultivar variation reported in pure lines of soybean has been hypothesized to result from genetic mechanisms contributing to de novo genetic variation. In this study we have detected allele switching by following segregation patterns of Aconitase-4 isozyme in sexual crosses and pure lines. In sexual crosses, one F2 plant showed a switch at the Aconitase-4 (Aco4) locus from the expected heterozygous genotype Aco4-ac to Aco4-ab. In the pure lines grown in a honeycomb planting design and treated with an accelerated aging test, multiple cases of allele switching were detected at the Aco4 locus. Both single and double switches were detected that were stable and heritable. These findings indicate that the generation of endogenous variation continues in pure lines as a result of intrinsic genetic mechanisms. With a long-term goal of understanding the genetic nature of the changes, we genetically mapped the Aco4 gene to a 3.3 cM region on Chromosome 11. The corresponding physical region is ∼293 kb with 39 predicted genes. Of these, Glyma.11g080600 is of particular interest, as it shows 93% and 88% identity to Medicago truncatula and Arabidopsis aconitase genes, respectively. Further characterization of the soybean Aco4 gene may shed light on genetic mechanisms responsible for allele switching.

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Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function

Wellcome Open Research ◽

10.12688/wellcomeopenres.13902.2 ◽

2018 ◽

Vol 3 ◽

pp. 13 ◽

Cited By ~ 2

Author(s):

Adeolu B. Adewoye ◽

Nick Shrine ◽

Linda Odenthal-Hesse ◽

Samantha Welsh ◽

Anders Malarstig ◽

...

Keyword(s):

Lung Function ◽

Copy Number ◽

Inflammatory Responses ◽

Allelic Variation ◽

Gene Dosage ◽

Association Studies ◽

Airflow Obstruction ◽

Ratio Test ◽

Gene Dosage Effect ◽

Ccr5 Antagonists

Background: The CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. Methods: We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test and imputed (with validation) CCR5d32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. Results: We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels. We found no evidence for association of CCL3L1 copy number or CCR5d32 genotype with lung function. Conclusions: These results suggest that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.

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Human CCL3L1 copy number variation, gene expression, and the role of the CCL3L1-CCR5 axis in lung function

10.1101/249508 ◽

2018 ◽

Author(s):

Adeolu B Adewoye ◽

Nick Shrine ◽

Linda Odenthal-Hesse ◽

Samantha Welsh ◽

Anders Malarstig ◽

...

Keyword(s):

Lung Function ◽

Copy Number ◽

Inflammatory Responses ◽

Allelic Variation ◽

Gene Dosage ◽

Association Studies ◽

Airflow Obstruction ◽

Ratio Test ◽

Gene Dosage Effect ◽

Ccr5 Antagonists

AbstractThe CCL3L1-CCR5 signaling axis is important in a number of inflammatory responses, including macrophage function, and T-cell-dependent immune responses. Small molecule CCR5 antagonists exist, including the approved antiretroviral drug maraviroc, and therapeutic monoclonal antibodies are in development. Repositioning of drugs and targets into new disease areas can accelerate the availability of new therapies and substantially reduce costs. As it has been shown that drug targets with genetic evidence supporting their involvement in the disease are more likely to be successful in clinical development, using genetic association studies to identify new target repurposing opportunities could be fruitful. Here we investigate the potential of perturbation of the CCL3L1-CCR5 axis as treatment for respiratory disease. Europeans typically carry between 0 and 5 copies of CCL3L1 and this multi-allelic variation is not detected by widely used genome-wide single nucleotide polymorphism studies. We directly measured the complex structural variation of CCL3L1 using the Paralogue Ratio Test (PRT) and imputed (with validation) CCR5del32 genotypes in 5,000 individuals from UK Biobank, selected from the extremes of the lung function distribution, and analysed DNA and RNAseq data for CCL3L1 from the 1000 Genomes Project. We confirmed the gene dosage effect of CCL3L1 copy number on CCL3L1 mRNA expression levels. We found no evidence for association of CCL3L1 copy number or CCR5del32 genotype with lung function suggesting that repositioning CCR5 antagonists is unlikely to be successful for the treatment of airflow obstruction.

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Integrative analysis reveals an indirect connection between COX-2/PTGS2 and extracellular matrix proteins in Ch11q-deleted neuroblastoma

10.22541/au.162212567.71149689/v1 ◽

2021 ◽

Author(s):

Thatyanne Gradowski Farias da Costa do Nascimento ◽

Nilton de França Júnior ◽

Lisiane de Castro Poncio ◽

Aline Simoneti Fonseca ◽

Bonald Figueiredo ◽

...

Keyword(s):

Extracellular Matrix ◽

Loss Of Heterozygosity ◽

Inflammatory Responses ◽

Matrix Proteins ◽

Matrix Remodeling ◽

Chromosome 11 ◽

Indirect Connection ◽

Network Interaction ◽

Cox 2 ◽

Related Proteins

The COX-2 protein, encoded by the PTGS2 gene, is related to tumor progression in adult and pediatric cancer. In neuroblastoma (NB), COX-2 was associated with loss of heterozygosity on the long arm of chromosome 11 (Ch11q loss of heterozygosity, LOH), defining a subset of aggressive disease. The present study aimed to investigate the protein expression of COX-2 in a set of 82 pre-chemotherapy (CT) and 20 post-CT NB specimens and its correlation with clinical and genomic data. A systems biology approach elucidated the network interaction of PTGS2 and other inflammation-related genes with those codified in the Ch11q deleted regions. The results indicated a significantly higher expression of COX-2 in post-CT samples. In addition, a significant positive correlation between the presence of aberrations in Ch11q and COX-2 levels and an indirect connection between the COX-2 gene and extracellular matrix remodeling (ECM)-related proteins were observed. Our findings suggest that deregulation of ECM proteolysis in Ch11q–deleted NB could elicit stromal alterations, triggering inflammatory responses via COX-2 overexpression, ultimately supporting NB progression.

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