An experimental assessment of in silico haplotype association mapping in laboratory mice

Burgess-Herbert, Sarah L.; Tsaih, Shirng‐Wern; Stylianou, Ioannis M.; Walsh, Kenneth A.; Cox, Allison; Paigen, Beverly

doi:10.1186/1471-2156-10-81

Cited by 19 publications

(16 citation statements)

References 33 publications

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“…However, a major obstacle of identifying QTL genes is the difficulty of resolving large chromosomal regions (10-20 cM) into sufficiently small intervals to make positional cloning practical. With advances in genome sequencing, dense SNP maps have proven successful in the refinement of previous QTL regions and the identification of new genetic determinants of complex traits (21).…”

Section: Discussionmentioning

confidence: 99%

“…Constant acquisition of genome-wide information on numerous species, including more than 40 mouse strains (18)(19)(20)(21), makes the mouse a useful model to facilitate rapid evaluation of the genetic basis of human physiology and pathophysiology (22,23). Complementing conventional single gene mapping approaches, genome-wide mapping has mainly used quantitative trait locus (QTL) analysis in mice, which has been a valued tool to identify candidate genes responsible for complex traits un-…”

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confidence: 99%

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Haplotype Association Mapping of Acute Lung Injury in Mice Implicates Activin A Receptor, Type 1

Leikauf

Concel²,

Liu³

et al. 2011

Am J Respir Crit Care Med

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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 6 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 realtime polymerase chain reaction. Microarray revealed several enriched pathways including transforming growth factor-b 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 39untranslated 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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Haplotype Association Mapping of Acute Lung Injury in Mice Implicates Activin A Receptor, Type 1

Leikauf

Concel²,

Liu³

et al. 2011

Am J Respir Crit Care Med

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“…Four have been described in part previously: NZxSM and KSxSM, 3 Bx129S1, 11 and BxCB. 12 Phenotyping EDTA (ethylenediaminetetraacetic acid)-anticoagulated whole blood was obtained from cross progeny (8 weeks of age) via the retro-orbital sinus as described, 13 with the exception of BxWSB progeny, where 20 L of EDTA-anticoagulated whole blood were obtained via the retro-orbital sinus and mixed with 180 L of 5% bovine serum albumin in phosphate-buffered saline before analysis using an Advia120 Multispecies Hematology Analyzer (Bayer Diagnostics).…”

Section: Crossesmentioning

confidence: 99%

Sequence variation at multiple loci influences red cell hemoglobin concentration

Peters

Shavit²,

Lambert

et al. 2010

Blood

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A substantial genetic contribution underlies variation in baseline peripheral blood counts. We performed quantitative trait locus/loci analyses to identify chromosome regions harboring genes influencing red cell hemoglobin concentration using the cell hemoglobin concentration mean (CHCM), a directly measured parameter analogous to the mean cell hemoglobin concentration. Fourteen significant loci (gene symbols Chcmq1-Chcmq14) were detected. Seven of these influenced CHCM in a sex-specific fashion, and 2 showed significant interactive effects (epistasis). For quantitative trait locus/ loci detected in multiple crosses, confidence intervals were narrowed using statistical and bioinformatic approaches. Two strong candidate genes emerged and were further analyzed: adult ␤-globin (Hbb) for

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“…However, several concerns regarding the utility of this method have been expressed, including the number of strains needed to achieve statistical power, adequate control of false discovery rate (12,16), population structure (44), and genome organization in inbred mice (15). Since then, a number of improved in silico mapping methods have been applied taking into account some of these concerns (11, 34 -36, 40, 51, 64), but despite this, a few studies have reported a high number of false positives and have suggested that QTL discovery by in silico mapping should be verified by linkage studies (8,39). Furthermore, several studies have pointed out that the value of in silico analysis increases in combination with other available information, such as known QTL mapped by classical approaches, or comparative genomic or gene expression data, in both mapping novel QTL as well as in narrowing down known QTL (7,10,11,64).…”

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confidence: 99%

In silico QTL mapping of basal liver iron levels in inbred mouse strains

McLachlan

Lee

Steele

et al. 2011

Physiological Genomics

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Both iron deficiency and iron excess are detrimental in many organisms, and previous studies in both mice and humans suggest that genetic variation may influence iron status in mammals. However, these genetic factors are not well defined. To address this issue, we measured basal liver iron levels in 18 inbred strains of mice of both sexes on a defined iron diet and found ∼4-fold variation in liver iron in males (lowest 153 μg/g, highest 661 μg/g) and ∼3-fold variation in females (lowest 222 μg/g, highest 658 μg/g). We carried out a genome-wide association mapping to identify haplotypes underlying differences in liver iron and three other related traits (copper and zinc liver levels, and plasma diferric transferrin levels) in a subset of 14 inbred strains for which genotype information was available. We identified two putative quantitative trait loci (QTL) that contain genes with a known role in iron metabolism: Eif2ak1 and Igf2r. We also identified four putative QTL that reside in previously identified iron-related QTL and 22 novel putative QTL. The most promising putative QTL include a 0.22 Mb region on Chromosome 7 and a 0.32 Mb region on Chromosome 11 that both contain only one candidate gene, Adam12 and Gria1, respectively. Identified putative QTL are good candidates for further refinement and subsequent functional studies.

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An experimental assessment of in silico haplotype association mapping in laboratory mice

Cited by 19 publications

References 33 publications

Haplotype Association Mapping of Acute Lung Injury in Mice Implicates Activin A Receptor, Type 1

Haplotype Association Mapping of Acute Lung Injury in Mice Implicates Activin A Receptor, Type 1

Sequence variation at multiple loci influences red cell hemoglobin concentration

In silico QTL mapping of basal liver iron levels in inbred mouse strains

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