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1.  Genetic Control of Susceptibility to Infection with Candida albicans in Mice 
PLoS ONE  2011;6(4):e18957.
Candida albicans is an opportunistic pathogen that causes acute disseminated infections in immunocompromised hosts, representing an important cause of morbidity and mortality in these patients. To study the genetic control of susceptibility to disseminated C. albicans in mice, we phenotyped a group of 23 phylogenetically distant inbred strains for susceptibility to infection as measured by extent of fungal replication in the kidney 48 hours following infection. Susceptibility was strongly associated with the loss-of-function mutant complement component 5 (C5/Hc) allele, which is known to be inherited by approximately 40% of inbred strains. Our survey identified 2 discordant strains, AKR/J (C5-deficient, resistant) and SM/J (C5-sufficient, susceptible), suggesting that additional genetic effects may control response to systemic candidiasis in these strains. Haplotype association mapping in the 23 strains using high density SNP maps revealed several putative loci regulating the extent of C. albicans replication, amongst which the most significant were C5 (P value = 2.43×10−11) and a novel effect on distal chromosome 11 (P value = 7.63×10−9). Compared to other C5-deficient strains, infected AKR/J strain displays a reduced fungal burden in the brain, heart and kidney, and increased survival, concomitant with uniquely high levels of serum IFNγ. C5-independent genetic effects were further investigated by linkage analysis in an [A/JxAKR/J]F2 cross (n = 158) where the mutant Hc allele is fixed. These studies identified a chromosome 11 locus (Carg4, Candida albicans resistance gene 4; LOD = 4.59), and a chromosome 8 locus (Carg3; LOD = 3.95), both initially detected by haplotype association mapping. Alleles at both loci were inherited in a co-dominant manner. Our results verify the important effect of C5-deficiency in inbred mouse strains, and further identify two novel loci, Carg3 and Carg4, which regulate resistance to C. albicans infection in a C5-independent manner.
doi:10.1371/journal.pone.0018957
PMCID: PMC3080400  PMID: 21533108
2.  Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction 
BMC Genomics  2011;12:508.
Background
Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction.
Results
Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists.
Conclusions
These results appear to offer new insights into the genetic factors underlying drug addiction.
doi:10.1186/1471-2164-12-508
PMCID: PMC3215751  PMID: 21999673
3.  Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice 
The genetic basis for the underlying individual susceptibility to chlorine-induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling. Using ≥ 10% allelic frequency and ≥ 10% phenotype explained as threshold criteria, promoter SNPs that could eliminate putative transcriptional factor recognition sites in candidate genes were assessed by determining transcript levels through microarray and reverse real-time PCR during chlorine exposure. The mean survival time varied by approximately 5-fold among strains, and SNP associations were identified for 13 candidate genes on chromosomes 1, 4, 5, 9, and 15. Microarrays revealed several differentially enriched pathways, including protein transport (decreased more in the sensitive C57BLKS/J lung) and protein catabolic process (increased more in the resistant C57BL/10J lung). Lung metabolomic profiling revealed 95 of the 280 metabolites measured were altered by chlorine exposure, and included alanine, which decreased more in the C57BLKS/J than in the C57BL/10J strain, and glutamine, which increased more in the C57BL/10J than in the C57BLKS/J strain. Genetic associations from haplotype mapping were strengthened by an integrated assessment using transcriptomic and metabolomic profiling. The leading candidate genes associated with increased susceptibility to acute lung injury in mice included Klf4, Sema7a, Tns1, Aacs, and a gene that encodes an amino acid carrier, Slc38a4.
doi:10.1165/rcmb.2012-0026OC
PMCID: PMC3423464  PMID: 22447970
ARDS; countermeasures; glutamine; genetics; metabolomics
4.  Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density 
Bone  2012;50(5):1188-1195.
Trps1 has been proposed as a candidate gene for a mouse bone mineral density (BMD) QTL on Chromosome (Chr) 15, but it remained unclear if this gene was associated with BMD in humans. We used newly available data and advanced bioinformatics techniques to confirm that Trps1 is the most likely candidate gene for the mouse QTL. In short, by combining the raw genetic mapping data from two F2 generation crosses of inbred strains of mice, we narrowed the 95% confidence interval of this QTL down to the Chr 15 region spanning from 6 to 24 cM. This region contains 131 annotated genes. Using block haplotyping, all other genes except Trps1 were eliminated as candidates for this QTL. We then examined associations of 208 SNPs within 10kb of TRPS1 with BMD and hip geometry, using human genome-wide association study (GWAS) data from the GEFOS consortium. After correction for multiple testing, six TRPS1 SNPs were significantly associated with femoral neck BMD (P=0.0015–0.0019; adjusted P=0.038–0.048). We also found that three SNPs were highly associated with femoral neck width in women (rs10505257, P = 8.6x10−5, adjusted P=2.15x10−3; rs7002384, P = 5.5x10−4, adjusted P=01.38x10−2). In conclusion, we demonstrated that combining association studies in humans with murine models provides an efficient strategy to identify new candidate genes for bone phenotypes.
doi:10.1016/j.bone.2012.01.011
PMCID: PMC3322322  PMID: 22306695
Trichorhinophalangeal syndrome I; mouse models; human genetic association study; bone mineral density
5.  Deletion of T Cells Bearing the Vβ8.1 T-Cell Receptor following Mouse Mammary Tumor Virus 7 Integration Confers Resistance to Murine Cerebral Malaria  
Infection and Immunity  2002;70(7):3701-3706.
Plasmodium berghei ANKA induces a fatal neurological syndrome known as cerebral malaria (CM) in susceptible mice. Host genetic elements are among the key factors determining susceptibility or resistance to CM. Analysis of mice of the same H-2 haplotype revealed that mouse mammary tumor virus 7 (MTV-7) integration into chromosome 1 is one of the key factors associated with resistance to neurological disease during P. berghei ANKA infection. We investigated this phenomenon by infecting a series of recombinant inbred mice (CXD2), derived from BALB/c (susceptible to CM) and DBA/2 (resistant to CM) mice, with P. berghei ANKA. We observed differences in susceptibility to CM induced by this Plasmodium strain. Mice with the MTV-7 sequence in their genome were resistant to CM, whereas those without integration of this gene were susceptible. Thus, an integrated proviral open reading frame or similar genomic sequences may confer protection against neuropathogenesis during malaria, at least in mice.
doi:10.1128/IAI.70.7.3701-3706.2002
PMCID: PMC128078  PMID: 12065512
6.  Two Genes on A/J Chromosome 18 Are Associated with Susceptibility to Staphylococcus aureus Infection by Combined Microarray and QTL Analyses 
PLoS Pathogens  2010;6(9):e1001088.
Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N2 backcross mice (F1 [C18A]×C57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus–challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 β and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.
Author Summary
Staphylococcus aureus has a wide spectrum of human infection, ranging from asymptomatic nasal carriage to overwhelming sepsis and death. Mouse models offer an attractive strategy for investigating complex diseases such as S. aureus infections. A/J mice are highly susceptible to S. aureus infection compared with C57BL/6J mice. We showed that genes on chromosomes 8, 11, and 18 in A/J are responsible for susceptibility to S. aureus by using chromosome substitution strains (CSS). From the ∼4200 genes on these three chromosomes, we identified 191 which were differentially expressed between A/J and C57BL/6J when challenged with S. aureus. Next, we identified two significant QTLs on chromosome 18 that are associated with susceptibility to S. aureus infection in N2 backcross mice. Ten genes (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTLs and were differentially expressed between A/J and C57BL/6J. One gene on each QTL, Tnfaip8 and Seh1l, affected expression of cytokines in mouse macrophages exposed to S. aureus. These cytokine response patterns were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18, but not C57BL/6J. Tnfaip8 and Seh1l are strong candidates for genes influencing susceptibility to S. aureus of A/J mice.
doi:10.1371/journal.ppat.1001088
PMCID: PMC2932726  PMID: 20824097
7.  Genetic Factors Regulating Lung Vasculature and Immune Cell Functions Associate with Resistance to Pneumococcal Infection 
PLoS ONE  2014;9(3):e89831.
Streptococcus pneumoniae is an important human pathogen responsible for high mortality and morbidity worldwide. The susceptibility to pneumococcal infections is controlled by as yet unknown genetic factors. To elucidate these factors could help to develop new medical treatments and tools to identify those most at risk. In recent years genome wide association studies (GWAS) in mice and humans have proved successful in identification of causal genes involved in many complex diseases for example diabetes, systemic lupus or cholesterol metabolism. In this study a GWAS approach was used to map genetic loci associated with susceptibility to pneumococcal infection in 26 inbred mouse strains. As a result four candidate QTLs were identified on chromosomes 7, 13, 18 and 19. Interestingly, the QTL on chromosome 7 was located within S. pneumoniae resistance QTL (Spir1) identified previously in a linkage study of BALB/cOlaHsd and CBA/CaOlaHsd F2 intercrosses. We showed that only a limited number of genes encoded within the QTLs carried phenotype-associated polymorphisms (22 genes out of several hundred located within the QTLs). These candidate genes are known to regulate TGFβ signalling, smooth muscle and immune cells functions. Interestingly, our pulmonary histopathology and gene expression data demonstrated, lung vasculature plays an important role in resistance to pneumococcal infection. Therefore we concluded that the cumulative effect of these candidate genes on vasculature and immune cells functions as contributory factors in the observed differences in susceptibility to pneumococcal infection. We also propose that TGFβ-mediated regulation of fibroblast differentiation plays an important role in development of invasive pneumococcal disease. Gene expression data submitted to the NCBI Gene Expression Omnibus Accession No: GSE49533
SNP data submitted to NCBI dbSNP Short Genetic Variation http://www.ncbi.nlm.nih.gov/projects/SNP/snp_viewTable.cgi?handle=MUSPNEUMONIA.
doi:10.1371/journal.pone.0089831
PMCID: PMC3940657  PMID: 24594938
8.  Dusp3 and Psme3 Are Associated with Murine Susceptibility to Staphylococcus aureus Infection and Human Sepsis 
PLoS Pathogens  2014;10(6):e1004149.
Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus –infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.
Author Summary
Staphylococcus aureus causes life-threatening infections in humans. Host genetic determinants influence the outcome of S. aureus infection, yet are poorly understood. Susceptible A/J and resistant C57BL/6J mice provide a unique platform to study the genetic difference responsible for variable host response to S. aureus infection. We showed that chromosome 11 in A/J was responsible for susceptibility to S. aureus. We further identified a QTL locus on Chromosome 11 significantly associated with S. aureus susceptibility. Five genes in the QTL (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) were significantly differently expressed in a) susceptible vs. resistant mice, and b) humans with S. aureus blood stream infection vs. healthy human subjects. Three genes (Dusp3, Psme3, and Dcaf7) were down-regulated in susceptible A/J mice. siRNA-mediated knockdown of Dusp3 and Psme3 in bone marrow derived macrophage (BMDMs) significantly enhanced cytokine responses through NF-κB activity upon S. aureus challenge in a pattern that was also present in S. aureus-challenged BMDMs from susceptible CSS11 (chr. 11 from A/J but otherwise C57BL/6J) mice, but not resistant C57BL/6J mice. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.
doi:10.1371/journal.ppat.1004149
PMCID: PMC4047107  PMID: 24901344
9.  New outbred colony derived from Mus musculus castaneus to identify skin tumor susceptibility loci 
Molecular carcinogenesis  2010;49(7):653-661.
Susceptibility to tumor development varies among mice strains. Using inbred NIH and wild-derived outbred Mus spretus backcrosses, skin cancer-susceptibility loci were mapped [1][2], and Skts13 was identified as the Aurka gene using a conventional linkage in conjunction with haplotype analysis [3].
In the present study, we examined another wild-derived outbred Mus musculus castaneus (M.m.castaneus) in which 10.3% of the analyzed SNPs showed heterogeneity among the colony. All mice examined were completely resistant to the two-stage skin carcinogenesis protocol using 7.12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA), and this resistant phenotype was dominant when we crossed them with the highly susceptible strain FVB. By scanning F1 backcross progeny between M.m.castaneus and FVB, we found a highly significant linkage for tumor multiplicity on Chromosome 4, which was overlapped with the Skts-fp1 locus, found in the previous study using FVB and PWK cross [4]. The linkage was observed in all pedigrees from the five F1 founders, while the linkage for papilloma size on Chromosome 4 was mapped only in pedigrees from founders 1 and 2. By scanning the whole Chromosome 4 of the five F1 founders, founder1, 2-specific haplotype block was found between D4Mit293 (20.6 Mbp) and D4Mit171 (22.4 Mbp).
In this study we exploited the outbred nature of M.m.castaneus stock to identify a haplotype contributing to papilloma size on mouse chromosome 4. These data illustrate the strength of using outbred mice in identification of the genetic component of a mouse complex trait such as the skin cancer-susceptibility phenotype.
doi:10.1002/mc.20635
PMCID: PMC2892251  PMID: 20564342
Two stage skin carcinogenesis; Cancer susceptibility; Mus musculus castaneus; Outbred colony; Linkage disequilibrium mapping
10.  Confirmation of Linkage to and Localization of Familial Colon Cancer Risk Haplotype on Chromosome 9q22 
Cancer research  2010;70(13):5409-5418.
Colorectal cancer is the second leading cause of cancer mortality in adult Americans and is caused by both genetic and environmental risk factors. We have replicated our originally reported linkage signal at 9q22-31 by fine mapping an independent collection of colon cancer families. Then, using a custom array of single nucleotide polymorphisms (SNPs) densely spaced across the candidate region, we performed both single-SNP and moving-window association analyses to identify a colon neoplasia risk haplotype. We isolated the association effect to a five SNP haplotype centered around 98.15 megabases (Mb) on chromosome 9q. This haplotype is in strong linkage disequilibrium with the haplotype block containing HABP4 and may be a surrogate for the effect of this CD30 Ki-1 antigen. It is also in close proximity to the GALNT12, which has been recently shown to be altered in colon tumors. Finally, we used a predictive modeling algorithm to demonstrate the contribution of this risk haplotype and surrounding candidate genes in distinguishing between colon cancer cases and healthy controls. The ability to replicate this finding, the strength of the haplotype association (OR=3.68) and the accuracy of our prediction model (~60%) all strongly support the presence of a locus for familial colon cancer on chromosome 9q.
doi:10.1158/0008-5472.CAN-10-0188
PMCID: PMC2896448  PMID: 20551049
colon cancer; linkage analysis; association analysis; risk; family cancer syndrome
11.  Prioritizing genes responsible for host resistance to influenza using network approaches 
BMC Genomics  2013;14(1):816.
Background
The genetic make-up of humans and other mammals (such as mice) affects their resistance to influenza virus infection. Considering the complexity and moral issues associated with experiments on human subjects, we have only acquired partial knowledge regarding the underlying molecular mechanisms. Although influenza resistance in inbred mice has been mapped to several quantitative trait loci (QTLs), which have greatly narrowed down the search for host resistance genes, only few underlying genes have been identified.
Results
To prioritize a list of promising candidates for future functional investigation, we applied network-based approaches to leverage the information of known resistance genes and the expression profiles contrasting susceptible and resistant mouse strains. The significance of top-ranked genes was supported by different lines of evidence from independent genetic associations, QTL studies, RNA interference (RNAi) screenings, and gene expression analysis. Further data mining on the prioritized genes revealed the functions of two pathways mediated by tumor necrosis factor (TNF): apoptosis and TNF receptor-2 signaling pathways. We suggested that the delicate balance between TNF’s pro-survival and apoptotic effects may affect hosts’ conditions after influenza virus infection.
Conclusions
This study considerably cuts down the list of candidate genes responsible for host resistance to influenza and proposed novel pathways and mechanisms. Our study also demonstrated the efficacy of network-based methods in prioritizing genes for complex traits.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-14-816) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-14-816
PMCID: PMC4046670  PMID: 24261899
12.  Sequence divergence of Mus spretus and Mus musculus across a skin cancer susceptibility locus 
BMC Genomics  2008;9:626.
Background
Mus spretus diverged from Mus musculus over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing M. musculus and M. spretus for quantitative trait locus (QTL) mapping, relatively little genomic information on M. spretus exists, and most of the available sequence and polymorphic data is for one strain of M. spretus, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different M. spretus by M. musculus F1 backcrosses. One locus, skin tumor susceptibility 5 (Skts5) on chromosome 12, shows strong linkage in one cross.
Results
To identify potential candidate genes for Skts5, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred spretus, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional M. spretus strains and one additional M. musculus strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across M. spretus, we conducted phylogenetic analyses. The relatedness of the M. spretus strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice.
Conclusion
Our analyses suggest that, if Skts5 on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other M. spretus strains.
doi:10.1186/1471-2164-9-626
PMCID: PMC2628916  PMID: 19105829
13.  Evidence for exclusion of a mutation in NRAMP as the cause of familial disseminated atypical mycobacterial infection in a Maltese kindred. 
Journal of Medical Genetics  1995;32(11):904-906.
In mice, susceptibility to intracellular infections in inbred strains is controlled by a single locus, Lsh/Ity/Bcg, and the gene responsible has been cloned and designated Nramp (Natural resistance associated macrophage protein). We have identified a group of related children who appear to have a single gene defect, inherited recessively, which results in increased susceptibility to myocabacterial infection. The immunological defect observed in the affected children resembles that in mice homozygous for the Lsh/Ity/Bcg susceptible allele. To test the hypothesis that a mutation in NRAMP is responsible for the immunodeficiency observed in the affected children, we have typed eight markers in the region of human 2q34-q37 where NRAMP, the human homologue of Nramp, maps. We have shown discordance with the defect in one family and the chromosomes in the three affected children have different haplotypes making it unlikely that inheritance of an ancestral mutation in the NRAMP gene is the cause of increased mycobacterial susceptibility in this group of children.
PMCID: PMC1051747  PMID: 8592339
14.  Use of a Dense Single Nucleotide Polymorphism Map for In Silico Mapping in the Mouse 
PLoS Biology  2004;2(12):e393.
Rapid expansion of available data, both phenotypic and genotypic, for multiple strains of mice has enabled the development of new methods to interrogate the mouse genome for functional genetic perturbations. In silico mapping provides an expedient way to associate the natural diversity of phenotypic traits with ancestrally inherited polymorphisms for the purpose of dissecting genetic traits. In mouse, the current single nucleotide polymorphism (SNP) data have lacked the density across the genome and coverage of enough strains to properly achieve this goal. To remedy this, 470,407 allele calls were produced for 10,990 evenly spaced SNP loci across 48 inbred mouse strains. Use of the SNP set with statistical models that considered unique patterns within blocks of three SNPs as an inferred haplotype could successfully map known single gene traits and a cloned quantitative trait gene. Application of this method to high-density lipoprotein and gallstone phenotypes reproduced previously characterized quantitative trait loci (QTL). The inferred haplotype data also facilitates the refinement of QTL regions such that candidate genes can be more easily identified and characterized as shown for adenylate cyclase 7.
A large resource of genetic markers, typed in 48 strains of mice, combined with statistical techniques, allow "in silico" mapping of genetic regions involved in interesting traits in mice
doi:10.1371/journal.pbio.0020393
PMCID: PMC526179  PMID: 15534693
15.  Haplotype Association Mapping of Acute Lung Injury in Mice Implicates Activin A Receptor, Type 1 
Rationale: Because acute lung injury is a sporadic disease produced by heterogeneous precipitating factors, previous genetic analyses are mainly limited to candidate gene case-control studies.
Objectives: To develop a genome-wide strategy in which single nucleotide polymorphism associations are assessed for functional consequences to survival during acute lung injury in mice.
Methods: To identify genes associated with acute lung injury, 40 inbred strains were exposed to acrolein and haplotype association mapping, microarray, and DNA-protein binding were assessed.
Measurements and Main Results: The mean survival time varied among mouse strains with polar strains differing approximately 2.5-fold. Associations were identified on chromosomes 1, 2, 4, 11, and 12. Seven genes (Acvr1, Cacnb4, Ccdc148, Galnt13, Rfwd2, Rpap2, and Tgfbr3) had single nucleotide polymorphism (SNP) associations within the gene. Because SNP associations may encompass “blocks” of associated variants, functional assessment was performed in 91 genes within ± 1 Mbp of each SNP association. Using 10% or greater allelic frequency and 10% or greater phenotype explained as threshold criteria, 16 genes were assessed by microarray and reverse real-time polymerase chain reaction. Microarray revealed several enriched pathways including transforming growth factor-β signaling. Transcripts for Acvr1, Arhgap15, Cacybp, Rfwd2, and Tgfbr3 differed between the strains with exposure and contained SNPs that could eliminate putative transcriptional factor recognition sites. Ccdc148, Fancl, and Tnn had sequence differences that could produce an amino acid substitution. Mycn and Mgat4a had a promoter SNP or 3′untranslated region SNPs, respectively. Several genes were related and encoded receptors (ACVR1, TGFBR3), transcription factors (MYCN, possibly CCDC148), and ubiquitin-proteasome (RFWD2, FANCL, CACYBP) proteins that can modulate cell signaling. An Acvr1 SNP eliminated a putative ELK1 binding site and diminished DNA–protein binding.
Conclusions: Assessment of genetic associations can be strengthened using a genetic/genomic approach. This approach identified several candidate genes, including Acvr1, associated with increased susceptibility to acute lung injury in mice.
doi:10.1164/rccm.201006-0912OC
PMCID: PMC3137140  PMID: 21297076
acute respiratory distress syndrome; smoke inhalation; carboxyl stress; transforming growth factor-&beta signaling; ubiquitination
16.  Natural Genetic Variation of Integrin Alpha L (Itgal) Modulates Ischemic Brain Injury in Stroke 
PLoS Genetics  2013;9(10):e1003807.
During ischemic stroke, occlusion of the cerebrovasculature causes neuronal cell death (infarction), but naturally occurring genetic factors modulating infarction have been difficult to identify in human populations. In a surgically induced mouse model of ischemic stroke, we have previously mapped Civq1 to distal chromosome 7 as a quantitative trait locus determining infarct volume. In this study, genome-wide association mapping using 32 inbred mouse strains and an additional linkage scan for infarct volume confirmed that the size of the infarct is determined by ancestral alleles of the causative gene(s). The genetically isolated Civq1 locus in reciprocal recombinant congenic mice refined the critical interval and demonstrated that infarct size is determined by both vascular (collateral vessel anatomy) and non-vascular (neuroprotection) effects. Through the use of interval-specific SNP haplotype analysis, we further refined the Civq1 locus and identified integrin alpha L (Itgal) as one of the causative genes for Civq1. Itgal is the only gene that exhibits both strain-specific amino acid substitutions and expression differences. Coding SNPs, a 5-bp insertion in exon 30b, and increased mRNA and protein expression of a splice variant of the gene (Itgal-003, ENSMUST00000120857), all segregate with infarct volume. Mice lacking Itgal show increased neuronal cell death in both ex vivo brain slice and in vivo focal cerebral ischemia. Our data demonstrate that sequence variation in Itgal modulates ischemic brain injury, and that infarct volume is determined by both vascular and non-vascular mechanisms.
Author Summary
Stroke is the second leading cause of death and the most common cause of acquired adult disability worldwide. Ischemic stroke is caused by an interruption of blood flow in the cerebral arteries and results in neuronal damage (infarct) to the area of perfusion in the brain. Although significant progress has been made in the identification of genetic risk factors for stroke susceptibility, identification of genetic factors determining the severity of tissue damage has proven more challenging. By contrast, infarct volume varies widely among laboratory inbred mouse strains. Using a well-established mouse model of stroke and complex genetic analysis, we have exploited these differences and identified Itgal as one of the candidate genes. We further show that allelic variation in Itgal segregates with infarct volume among inbred mouse strains and deficiency of the gene increases ischemic neuronal cell death in stroke.
doi:10.1371/journal.pgen.1003807
PMCID: PMC3794904  PMID: 24130503
17.  A QTL on Chromosome 10 Modulates Cone Photoreceptor Number in the Mouse Retina 
This study combines classical QTL mapping with tissue-specific microarray analysis to identify novel genes potentially involved in the establishment of the cone photoreceptor population of the mouse retina.
Purpose.
This investigation examines the genetic sources of marked variation in cone photoreceptor number among inbred lines of mice, identifying candidate genes that may control the proliferation, differentiation, or survival of this neuronal population.
Methods.
Cone photoreceptor populations were counted in C57BL/6J (B6/J) and A/J strains, and 26 recombinant inbred (RI) strains derived from them. Eyes from RI strains were also collected for microarray analysis. Quantitative trait locus (QTL) analysis was carried out by simple and composite interval mapping and validated using a consomic line. Candidate genes were evaluated based on genetic variance between the parental strains and analysis of gene expression. Expression data, deposited in GeneNetwork (www.GeneNetwork.org), were used to generate a coexpression network of established cone photoreceptor genes as a reference standard.
Results.
B6/J has 70% more cone photoreceptors than A/J. A significant QTL was mapped to chromosome 10 (Chr 10) and confirmed using B6.A<10> mice. Of 19 positional candidate genes, one—the myeloblastosis oncogene (Myb)—stood out. Myb has a potentially damaging missense mutation, high retinal expression, and a known role in cell proliferation. The ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (Enpp1) was a second strong candidate, with an expression pattern that covaried with cone photoreceptors and that was differentially expressed between the parental strains. Enpp1 and several other candidate genes covaried with multiple genes within the cone photoreceptor gene network.
Conclusions.
The mouse retina shows marked variation in cone photoreceptor number, some of which must be controlled by polymorphisms in a gene or genes on Chr 10.
doi:10.1167/iovs.10-6693
PMCID: PMC3109025  PMID: 21330668
18.  Multiple Genes on Chromosome 7 Regulate Dopaminergic Amacrine Cell Number in the Mouse Retina 
Purpose
The size of neuronal populations is modulated by gene variants that influence cell production and survival, in turn influencing neuronal connectivity, function, and disease risk. The size of the dopaminergic amacrine (DA) cell population is a highly heritable trait exhibiting six-fold variation among inbred strains of mice, and is used here to identify genes that modulate the number of DA cells.
Methods
The entire population was counted in retinal wholemounts from 37 genetically defined lines of mice, including six standard inbred strains, 25 recombinant inbred strains (AXB/BXA), reciprocal F1 hybrids, a chromosome (Chr) 7 consomic line, and three additional genetically modified lines.
Results
We mapped much of this variation to a broad locus on Chr 7 (Dopaminergic amacrine cell number control, Chr 7). The Dacnc7 locus is flanked by two candidate genes known to modulate the number of other types of retinal neuron—the pro-apoptotic gene, Bax, and tyrosinase. The Tyr mutation was shown to modulate DA cell number modestly, although in the direction opposite that predicted. In contrast, Bax deficiency increased the population four-fold. Bax expression was significantly greater in the A/J strain relative to C57BL/6J, an effect that may be due to an SNP in a p53 consensus binding site known to modulate transcription. Finally, we note a strong candidate situated at the peak of the Dacnc7 locus, Lrrk1, a Parkinson’s disease gene exhibiting mis-sense mutations segregating within the AXB/BXA cross.
Conclusions
Multiple polymorphic genes on Chr. 7 modulate the size of the population of DA cells.
doi:10.1167/iovs.08-2556
PMCID: PMC2672967  PMID: 19168892
QTL; recombinant inbred strain; consomic strain; tyrosinase; Bax; Lrrk1; cell death
19.  Y chromosome of the inbred mouse KK/Ta strain is associated with reduced body size in Y-consomic strains 
BMC Research Notes  2013;6:64.
Background
We have established 17 Y chromosome consomic (Y-consomic) mouse strains in an inbred DH/Sgn strain. In this study, based on investigations in four different genetic backgrounds, we proved that the Y chromosome of the inbred mouse KK/Ta strain is associated with reduced body size.
Findings
In the DH-Chr Y-+/+ background, Y chromosome substitution significantly decreased the body weight in DH-Chr YKK-+/+ and DH-Chr YSJL-+/+ strains, and the DH-Chr YKK-+/+ strain was the lightest among the 17 Y-consomic strains. In the DH-Chr Y-Dh/+ background (Dh/+ mice have skeletal malformations and are usually lighter than +/+ mice), although Y chromosome substitution did not significantly alter the body weight, the DH-Chr YKK-Dh/+ strain was the lightest among the 17 Y-consomic-Dh/+ strains. In the (B6.Cg-Ay × DH-Chr Y) F1-+/+ background, Y chromosome substitution significantly decreased the body weight and length in the (B6.Cg-Ay × DH-Chr YKK) F1 hybrids. In the (B6.Cg-Ay × DH-Chr Y) F1-Ay/+ background (Ay causes obesity and promotes linear growth), Y chromosome substitution significantly decreased body weight and length in the (B6.Cg-Ay × DH-Chr YKK) F1-Ay/+ hybrids.
Conclusion
A body-size-reducing effect of the Y chromosome of the KK/Ta mouse strain was observed irrespective of genetic background. The effect was observed in the presence of Dh and Ay, the autosomal dominant mutations, both of which are known to have substantial effects on body size. These results suggest that there are Y-linked genes that control the body size in mice.
doi:10.1186/1756-0500-6-64
PMCID: PMC3598876  PMID: 23418893
Ay allele; Body length; Body weight; Body size; Consomic mice; Dh; Y chromosome
20.  Genetic dissection of testis weight in a mouse strain having an extremely large testis: major testis weight determinants are autosomal rather than Y-linked on the basis of comprehensive analyses in Y-chromosome consomic strains 
I investigated the potential contribution of Y-linked genes by analyzing 16 Y-consomic strains that had been established on a DH-strain background. The results provided evidence that only the Y chromosome from the C3H/HeJ strain was different from most other inbred strains. The CBA strain has the lightest testis and the DDD strain has the heaviest testis among mouse strains; however, Y-consomic analysis revealed that there were no significant differences in testis weight among DH, DH-Chr YDDD, and DH-Chr YCBA strains, suggesting that YDDD and YCBA themselves do not influence testis weight. QTL analysis in DDD × DH F2 mice identified significant testis weight QTLs on chromosomes 9, 14, and 17, and the DDD allele at all these loci was associated with an increase in testis weight. Contribution of Y chromosome itself to testis weight was thus rather modest, and therefore, major testis weight determinants are autosomal. However, it was uncertain whether there would be any effects by interactions between Y chromosomal and autosomal genes.
doi:10.2183/pjab/84.393
PMCID: PMC3721203  PMID: 18997451
mouse; QTL; testis weight; Y-consomic strain
21.  Molecular Correlates of Host Specialization in Staphylococcus aureus 
PLoS ONE  2007;2(10):e1120.
Background
The majority of Staphylococcus aureus isolates that are recovered from either serious infections in humans or from mastitis in cattle represent genetically distinct sets of clonal groups. Moreover, population genetic analyses have provided strong evidence of host specialization among S. aureus clonal groups associated with human and ruminant infection. However, the molecular basis of host specialization in S. aureus is not understood.
Methodology/Principal Findings
We sequenced the genome of strain ET3-1, a representative isolate of a common bovine mastitis-causing S. aureus clone. Strain ET3-1 encodes several genomic elements that have not been previously identified in S. aureus, including homologs of virulence factors from other Gram-positive pathogens. Relative to the other sequenced S. aureus associated with human infection, allelic variation in ET3-1 was high among virulence and surface-associated genes involved in host colonization, toxin production, iron metabolism, antibiotic resistance, and gene regulation. Interestingly, a number of well-characterized S. aureus virulence factors, including protein A and clumping factor A, exist as pseudogenes in ET3-1. Whole-genome DNA microarray hybridization revealed considerable similarity in the gene content of highly successful S. aureus clones associated with bovine mastitis, but not among those clones that are only infrequently recovered from bovine hosts.
Conclusions/Significance
Whole genome sequencing and comparative genomic analyses revealed a set of molecular genetic features that distinguish clones of highly successful bovine-associated S. aureus optimized for mastitis pathogenesis in cattle from those that infect human hosts or are only infrequently recovered from bovine sources. Further, the results suggest that modern bovine specialist clones diverged from a common ancestor resembling human-associated S. aureus clones through a combination of foreign DNA acquisition and gene decay.
doi:10.1371/journal.pone.0001120
PMCID: PMC2040198  PMID: 17971880
22.  Variation in Galr1 expression determines susceptibility to excitotoxin-induced cell death in mice 
Genes, brain, and behavior  2008;7(5):587-598.
Inbred strains of mice differ in their susceptibility to excitotoxin-induced cell death, but the genetic basis of individual variation in differential susceptibility is unknown. Previously, we identified a highly significant quantitative trait locus (QTL) on chromosome 18 that influenced susceptibility to kainic acid-induced cell death (Sicd1). Comparison of susceptibility to seizure-induced cell death between reciprocal congenic lines for Sicd1 and parental background mice indicates that genes influencing this trait were captured in both strains. Two positional gene candidates, Galr1 and Mbp, map to 55 cM, where the Sicd1 QTL had been previously mapped. Thus, this study was undertaken to determine if Galr1 and/or Mbp could be considered as candidate genes. Genomic sequence comparison of these two functional candidate genes from the C57BL/6J (resistant at Sicd1) and the FVB/NJ (susceptible at Sicd1) strains showed no single-nucleotide polymorphisms. However, expression studies confirmed that Galr1 shows significant differential expression in the congenic and parental inbred strains. Galr1 expression was downregulated in the hippocampus of C57BL/6J mice and FVB.B6-Sicd1 congenic mice when compared with FVB/NJ or B6.FVB-Sicd1 congenic mice. A survey of Galr1 expression among other inbred strains showed a significant effect such that ‘susceptible’ strains showed a reduction in Galr1 expression as compared with ‘resistant’ strains. In contrast, no differences in Mbp expression were observed. In summary, these results suggest that differential expression of Galr1 may contribute to the differences in susceptibility to seizure-induced cell death between cell death-resistant and cell death-susceptible strains.
doi:10.1111/j.1601-183X.2008.00395.x
PMCID: PMC2836321  PMID: 18363852
Candidate genes; cell death; congenic mice; C57BL/6J; FVB/NJ; hippocampus; quantitative trait locus; seizure
23.  Inflammatory priming predisposes mice to age-related retinal degeneration 
The Journal of Clinical Investigation  2012;122(8):2989-3001.
Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age-related disorders, but their complex etiology is poorly understood. Postmitotic neurons, such as photoreceptor cells in the retina and epithelial cells in the adjacent retinal pigmented epithelium, are especially susceptible to cellular senescence, which contributes to age-related retinal degeneration (ARD). The multigenic and complex etiology of ARD in humans is reflected by the relative paucity of effective compounds for its early prevention and treatment. To understand the genetic differences that drive ARD pathogenesis, we studied A/J mice, which develop ARD more pronounced than that in other inbred mouse models. Although our investigation of consomic strains failed to identify a chromosome associated with the observed retinal deterioration, pathway analysis of RNA-Seq data from young mice prior to retinal pathological changes revealed that increased vulnerability to ARD in A/J mice was due to initially high levels of inflammatory factors and low levels of homeostatic neuroprotective factors. The genetic signatures of an uncompensated preinflammatory state and ARD progression identified here aid in understanding the susceptible genetic loci that underlie pathogenic mechanisms of age-associated disorders, including several human blinding diseases.
doi:10.1172/JCI64427
PMCID: PMC3408755  PMID: 22797304
24.  Haplotype Analysis Improved Evidence for Candidate Genes for Intramuscular Fat Percentage from a Genome Wide Association Study of Cattle 
PLoS ONE  2011;6(12):e29601.
In genome wide association studies (GWAS), haplotype analyses of SNP data are neglected in favour of single point analysis of associations. In a recent GWAS, we found that none of the known candidate genes for intramuscular fat (IMF) had been identified. In this study, data from the GWAS for these candidate genes were re-analysed as haplotypes. First, we confirmed that the methodology would find evidence for association between haplotypes in candidate genes of the calpain-calpastatin complex and musculus longissimus lumborum peak force (LLPF), because these genes had been confirmed through single point analysis in the GWAS. Then, for intramuscular fat percent (IMF), we found significant partial haplotype substitution effects for the genes ADIPOQ and CXCR4, as well as suggestive associations to the genes CEBPA, FASN, and CAPN1. Haplotypes for these genes explained 80% more of the phenotypic variance compared to the best single SNP. For some genes the analyses suggested that there was more than one causative mutation in some genes, or confirmed that some causative mutations are limited to particular subgroups of a species. Fitting the SNPs and their interactions simultaneously explained a similar amount of the phenotypic variance compared to haplotype analyses. Haplotype analysis is a neglected part of the suite of tools used to analyse GWAS data, would be a useful method to extract more information from these data sets, and may contribute to reducing the missing heritability problem.
doi:10.1371/journal.pone.0029601
PMCID: PMC3247274  PMID: 22216329
25.  Identification of Quantitative Trait Loci for Susceptibility to Mouse Adenovirus Type 1†  
Journal of Virology  2005;79(17):11517-11522.
Adult SJL/J mice are highly susceptible to mouse adenovirus type 1 (MAV-1) infections, whereas other inbred strains, including BALB/cJ, are resistant (K. R. Spindler, L. Fang, M. L. Moore, C. C. Brown, G. N. Hirsch, and A. K. Kajon, J. Virol. 75:12039-12046, 2001). Using congenic mouse strains, we showed that the H-2s haplotype of SJL/J mice is not associated with susceptibility to MAV-1. Susceptibility of MAV-1-infected (BALB/cJ × SJL/J)F1 mice was intermediate between that of SJL/J mice and that of BALB/cJ mice, indicating that susceptibility is a genetically controlled quantitative trait. We mapped genetic loci involved in mouse susceptibility to MAV-1 by analysis of 192 backcross progeny in a genome scan with 65 simple sequence length polymorphic markers. A major quantitative trait locus (QTL) was detected on chromosome 15 (Chr 15) with a highly significant logarithm of odds score of 21. The locus on Chr 15 alone accounts for 40% of the total trait variance between susceptible and resistant strains. QTL modeling of the data indicated that there are a number of other QTLs with small effects that together with the major QTL on Chr 15 account for 54% of the trait variance. Identification of the major QTL is the first step in characterizing host genes involved in susceptibility to MAV-1.
doi:10.1128/JVI.79.17.11517-11522.2005
PMCID: PMC1193630  PMID: 16103204

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