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Genetic dissection of the ity3 locus identifies a role for ncf2 co-expression modules and suggests selp as a candidate gene underlying the ity3.2 locus.

Khan RT, Chevenon M, Yuki KE, Malo D - Front Immunol (2014)

Bottom Line: Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries.In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus.Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, McGill University , Montreal, QC , Canada ; Complex Traits Group, McGill University , Montreal, QC , Canada.

ABSTRACT
Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries. We model typhoid fever using mice infected with Salmonella typhimurium, which results in a systemic disease, whereby the outcome of infection is variable in different inbred strains of mice. This model recapitulates several clinical aspects of the human disease and allows the study of the host response to Salmonella typhimurium infection in vivo. Previous work in our laboratory has identified three loci (Ity, Ity2, and Ity3) in the wild-derived MOLF/Ei mice influencing survival after infection with Salmonella typhimurium. Fine mapping of the Ity3 locus indicated that two sub-loci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus. Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2. Furthermore, based on differential expression and complementation analysis using Selp (selectin-P) knock-out mice, Selp was identified as a strong candidate gene for the Ity3.2 sub-locus.

No MeSH data available.


Related in: MedlinePlus

Genes that are under the control of the Ity3.1 locus. Sample box plots of the gene lists provided in Table S2 in Supplementary Material are shown. (A) Represents genes, which do not show any changes in expression during infection and show a similar expression pattern in Ity3 and Ity3.RecG. (B,C) Represents a sample box plot of gene expression, which show a similar regulation pattern in Ity3 and Ity3.RecG. (D–G) Also illustrate genes within Tables S2D,G in Supplementary Material, which show similar expression patterns in Ity3 and Ity3.RecG, but different from Ity and Ity3.RecN. These genes are likely under the control of the Ity3.1 locus. Csrp1 (cysteine and glycine-rich protein 1), Chi3l1 (chitinase-like 1), (Plekhm3) Pleckstrin homology domain containing, family M, member 3), Sdsl (serine dehydratase-like), Cd59a (CD59a antigen), Lpxn (leupaxin), Asprv1 (aspartic peptidase, retroviral-like 1).
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Figure 3: Genes that are under the control of the Ity3.1 locus. Sample box plots of the gene lists provided in Table S2 in Supplementary Material are shown. (A) Represents genes, which do not show any changes in expression during infection and show a similar expression pattern in Ity3 and Ity3.RecG. (B,C) Represents a sample box plot of gene expression, which show a similar regulation pattern in Ity3 and Ity3.RecG. (D–G) Also illustrate genes within Tables S2D,G in Supplementary Material, which show similar expression patterns in Ity3 and Ity3.RecG, but different from Ity and Ity3.RecN. These genes are likely under the control of the Ity3.1 locus. Csrp1 (cysteine and glycine-rich protein 1), Chi3l1 (chitinase-like 1), (Plekhm3) Pleckstrin homology domain containing, family M, member 3), Sdsl (serine dehydratase-like), Cd59a (CD59a antigen), Lpxn (leupaxin), Asprv1 (aspartic peptidase, retroviral-like 1).

Mentions: We have previously reported that Ncf2 is a strong candidate for the Ity3.1 locus (13). To further characterize the downstream impact of Ity3.1 and Ncf2 on gene expression, we analyzed the data by evaluating variation in gene expression between Ity3, Ity3.RecG, or Ity3.RecN, and the control strain Ity at day 0 and day 3 post-infection (Figure 1B). Interestingly, 12 genes located within the introgressed Ity3 region had lower expression levels in Ity3 and Ity3.RecG, compared to both Ity and Ity3.RecN. Figure 3A shows the box plot expression pattern of one of these genes and the list is provided in Table S2A in Supplementary Material. None of these genes were differentially regulated during infection in any of the sub-congenic strains. For some of these genes, the low levels of expression detected in mouse strains Ity3 and Ity3.RecG appear to be a consequence of poor hybridization of MOLF/Ei cDNA to microarray probes as a result of high genomic variability between the MOLF/Ei and C57BL/6J strains (Figure S2 in Supplementary Material). The wild-derived inbred MOLF/Ei had been separated from the classical inbred trains by over 1 million year of evolution, and as a result they have accumulated significant sequence variability, to the order of 1 SNP every 100 bp (26, 27).


Genetic dissection of the ity3 locus identifies a role for ncf2 co-expression modules and suggests selp as a candidate gene underlying the ity3.2 locus.

Khan RT, Chevenon M, Yuki KE, Malo D - Front Immunol (2014)

Genes that are under the control of the Ity3.1 locus. Sample box plots of the gene lists provided in Table S2 in Supplementary Material are shown. (A) Represents genes, which do not show any changes in expression during infection and show a similar expression pattern in Ity3 and Ity3.RecG. (B,C) Represents a sample box plot of gene expression, which show a similar regulation pattern in Ity3 and Ity3.RecG. (D–G) Also illustrate genes within Tables S2D,G in Supplementary Material, which show similar expression patterns in Ity3 and Ity3.RecG, but different from Ity and Ity3.RecN. These genes are likely under the control of the Ity3.1 locus. Csrp1 (cysteine and glycine-rich protein 1), Chi3l1 (chitinase-like 1), (Plekhm3) Pleckstrin homology domain containing, family M, member 3), Sdsl (serine dehydratase-like), Cd59a (CD59a antigen), Lpxn (leupaxin), Asprv1 (aspartic peptidase, retroviral-like 1).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4129629&req=5

Figure 3: Genes that are under the control of the Ity3.1 locus. Sample box plots of the gene lists provided in Table S2 in Supplementary Material are shown. (A) Represents genes, which do not show any changes in expression during infection and show a similar expression pattern in Ity3 and Ity3.RecG. (B,C) Represents a sample box plot of gene expression, which show a similar regulation pattern in Ity3 and Ity3.RecG. (D–G) Also illustrate genes within Tables S2D,G in Supplementary Material, which show similar expression patterns in Ity3 and Ity3.RecG, but different from Ity and Ity3.RecN. These genes are likely under the control of the Ity3.1 locus. Csrp1 (cysteine and glycine-rich protein 1), Chi3l1 (chitinase-like 1), (Plekhm3) Pleckstrin homology domain containing, family M, member 3), Sdsl (serine dehydratase-like), Cd59a (CD59a antigen), Lpxn (leupaxin), Asprv1 (aspartic peptidase, retroviral-like 1).
Mentions: We have previously reported that Ncf2 is a strong candidate for the Ity3.1 locus (13). To further characterize the downstream impact of Ity3.1 and Ncf2 on gene expression, we analyzed the data by evaluating variation in gene expression between Ity3, Ity3.RecG, or Ity3.RecN, and the control strain Ity at day 0 and day 3 post-infection (Figure 1B). Interestingly, 12 genes located within the introgressed Ity3 region had lower expression levels in Ity3 and Ity3.RecG, compared to both Ity and Ity3.RecN. Figure 3A shows the box plot expression pattern of one of these genes and the list is provided in Table S2A in Supplementary Material. None of these genes were differentially regulated during infection in any of the sub-congenic strains. For some of these genes, the low levels of expression detected in mouse strains Ity3 and Ity3.RecG appear to be a consequence of poor hybridization of MOLF/Ei cDNA to microarray probes as a result of high genomic variability between the MOLF/Ei and C57BL/6J strains (Figure S2 in Supplementary Material). The wild-derived inbred MOLF/Ei had been separated from the classical inbred trains by over 1 million year of evolution, and as a result they have accumulated significant sequence variability, to the order of 1 SNP every 100 bp (26, 27).

Bottom Line: Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries.In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus.Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, McGill University , Montreal, QC , Canada ; Complex Traits Group, McGill University , Montreal, QC , Canada.

ABSTRACT
Typhoid fever and salmonellosis, which are caused by Salmonella typhi and typhimurium, respectively, are responsible for significant morbidity and mortality in both developed and developing countries. We model typhoid fever using mice infected with Salmonella typhimurium, which results in a systemic disease, whereby the outcome of infection is variable in different inbred strains of mice. This model recapitulates several clinical aspects of the human disease and allows the study of the host response to Salmonella typhimurium infection in vivo. Previous work in our laboratory has identified three loci (Ity, Ity2, and Ity3) in the wild-derived MOLF/Ei mice influencing survival after infection with Salmonella typhimurium. Fine mapping of the Ity3 locus indicated that two sub-loci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. In the current paper, we provided further evidence supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase) as the gene underlying the Ity3.1 sub-locus. Gene expression profiling indicated that the Ity3.1 sub-locus defined a global gene expression signature with networks articulated around Ncf2. Furthermore, based on differential expression and complementation analysis using Selp (selectin-P) knock-out mice, Selp was identified as a strong candidate gene for the Ity3.2 sub-locus.

No MeSH data available.


Related in: MedlinePlus