Using whole-genome sequences of the LG/J and SM/J inbred mouse strains to prioritize quantitative trait genes and nucleotides

Nikolskiy, Igor; Conrad, Donald F.; Chun, Sung; Fay, Justin C.; Cheverud, James M.; Lawson, Heather A.

doi:10.1186/s12864-015-1592-3

Cited by 34 publications

(53 citation statements)

References 101 publications

(69 reference statements)

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“…There are 5 small deletion polymorphisms in the SM/J founder strain relative to the LG/J founder strain in the Hpx genic region (Supplementary Table 4). Four of these polymorphisms fall in intronic sequence while the 5 th , a 6bp deletion, falls in an exonic region (28). The expression pattern of Hpx is similar between the two strains, however it is possible that these polymorphisms contribute to the observed difference in expression magnitude (Figure 1c).…”

Section: Discussionmentioning

confidence: 99%

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

et al. 2017

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Background/Objectives Elevated triglycerides predict insulin resistance and vascular disease in obesity, but how the inert triglyceride molecule is related to development of metabolic disease is unknown. To pursue novel potential mediators of triglyceride-associated metabolic disease, we used a forward genetics approach involving inbred mice and translated our findings to human subjects. Subjects/Methods Hemopexin was identified as a differentially expressed gene within a quantitative trait locus associated with serum triglycerides in an F16 advanced intercross between the LG/J and SM/J strains of mice. Hpx expression was evaluated in both reproductive fatpads and livers of mice representing three strains, LG/J (n = 25), SM/J (n = 27) and C57Bl/6J (n = 19), on high- and low-fat diets. The effect of altered Hpx expression on adipogenesis was studied in 3T3-L1 cells. Circulating HPX protein along with HPX expression were characterized in subcutaneous white adipose tissue samples obtained from a cohort of metabolically abnormal (n = 18) and of metabolically normal (n = 24) obese human subjects. We further examined the relationship between HPX and triglycerides in human atherosclerotic plaques (n = 18). Results Hemopexin expression in mouse adipose tissue, but not liver, was regulated by dietary fat regardless of genetic background. Hemopexin increased in concert with adipogenesis in 3T3-L1 cells, and disruption of its expression impaired adipocyte differentiation. RNAseq data from the adipose tissue of obese humans showed differential expression of hemopexin based on metabolic disease status (p < 0.05), and circulating hemopexin levels were correlated with serum triglycerides in these subjects (r = 0.33; p = 0.03). Hemopexin was also found in an unbiased proteomic screen of human atherosclerotic plaques, and shown to display differential abundance based on extent of disease and triglyceride content (p < 0.05). Conclusions Our findings suggest that hemopexin is associated with triglycerides and provide a framework for understanding mechanisms underlying lipid metabolism and metabolic disease.

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Section: Discussionmentioning

confidence: 99%

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

et al. 2017

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“…We sequenced 24 uniquely 395 barcoded samples per lane of an Illumina HiSeq 2500 using single-end, 100 bp reads. We aligned 1,110 396 GBS libraries to the mm10 reference genome before using GATK (DePristo et al 2011) to realign reads 397 around known indels in LG and SM (Nikolskiy et al 2015…”

Section: Gbs Variant Calling and Imputation 391mentioning

confidence: 99%

“…446 RNA-sequencing and quality control 447 We extracted mRNA from HIP, PFC and STR as described in Parker et al (2016) Because mapping quality tends to be higher for reads that closely match the reference genome 455 (Degner et al 2009), read mapping in an AIL may be biased toward the reference strain (C57BL/6J) 456 (Wang and Clark 2014). We addressed this concern by aligning RNA-seq reads to custom genomes 457 created from LG and SM using whole-genome sequence data (Nikolskiy et al 2015). We used default 458 parameters in HISAT (Kim et al 2015) for alignment and GenomicAlignments (Lawrence et al 2013) for 459 assembly, assigning each read to a gene as defined by Ensembl (Mus_musculus.GRCm38.85) (Aken et 460 al.…”

Section: Loco-lmm 424mentioning

confidence: 99%

“…(A) SNP distribution and density of GWAS SNPs are plotted in 500 kb windows for each chromosome. As shown in Supplemental Fig.1, regions with low SNP density correspond to regions predicted to be nearly IBD in LG and SM (Nikolskiy et al 2015). (B) MAF distributions are shown for ~4.3 million imputed SNPs (gold; unfiltered) and for the 523,028 SNPs used for GWAS (orange; filtered).…”

Section: Introduction 19mentioning

confidence: 99%

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Genome wide association analysis in a mouse advanced intercross line

Gonzales

Seo

Hernandez-Cordero

et al. 2017

Preprint

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Genome wide association analyses (GWAS) in model organisms have numerous advantages compared 2 to human GWAS, including the ability to use populations with well-defined genetic diversity, the ability to 3 collect tissue for gene expression analysis and the ability to perform experimental manipulations. We 4 examined behavioral, physiological, and gene expression traits in 1,063 male and female mice from a 5 50-generation intercross between two inbred strains (LG/J and SM/J). We used genotyping by 6 sequencing in conjunction with whole genome sequence data from the two founder strains to obtain 7 genotypes at 4.3 million SNPs. As expected, all alleles were common (mean MAF=0.35) and linkage 8 disequilibrium degraded rapidly, providing excellent power and sub-megabase mapping precision. We 9 identified 126 genome-wide significant loci for 50 traits and integrated this information with 7,081 cis-10 eQTLs and 1,476 trans-eQTLs identified in hippocampus, striatum and prefrontal cortex. We replicated 11 several loci that were identified using an earlier generation of this intercross, including an association 12 between locomotor activity and a locus containing a single gene, Csmd1. We also showed that Csmd1 13 mutant mice recapitulated the locomotor phenotype. Our results demonstrate the utility of this population, 14 identify numerous novel associations, and provide examples of replication in an independent cohort, 15 which is customary in human genetics, and replication by experimental manipulation, which is a unique 16 advantage of model organisms.

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“…Several important features contribute to their utility, including a high quality reference genome with more than a decade’s worth of improved assembly and annotation (Church et al 2009; Waterston et al 2002), multiple complete genomes from distinct genetic strains (Keane et al 2011; Nikolskiy et al 2015; Srivastava et al 2017; Wang et al 2016; Waterston et al 2002; Wong et al 2012) and wild individuals (Harr et al 2016), and dense genotyping of commonly used laboratory strains (Laurie et al 2007; Lindblad-Toh et al 2000; Petkov et al 2004; Wade et al 2002; Yang et al 2007; Yang et al 2009; Yang et al 2011). Thousands of phenotypes have been gathered from hundreds of inbred mouse strains (Grubb et al 2004; Wang et al 2016; White et al 2013), many of which are commercially available through institutions like The Jackson Laboratory.…”

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing of wild-derived inbred strains of mice improves power to link phenotype and genotype

et al. 2017

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The house mouse is a powerful model to dissect the genetic basis of phenotypic variation, and serves as a model to study human diseases. Despite a wealth of discoveries, most classical laboratory strains have captured only a small fraction of genetic variation known to segregate in their wild progenitors, and existing strains are often related to each other. Inbred strains of mice independently derived from natural populations have the potential to increase power in genetic studies with the addition of novel genetic variation. Here, we perform exome-enrichment and high-throughput sequencing (~8X coverage) of 26 wild-derived strains known in the mouse research community as the “Montpellier strains”. We identified 1.46 million SNPs in our dataset, approximately 19% of which have not been detected from other inbred strains. This novel genetic variation is expected to contribute to phenotypic variation, as they include 18,496 nonsynonymous variants and 262 early stop codons. Simulations demonstrate that the higher density of genetic variation in the Montpellier strains provides increased power for quantitative genetic studies. Inasmuch as the power to connect genotype to phenotype depends on genetic variation, it is important to incorporate these additional genetic strains into future research programs.

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Using whole-genome sequences of the LG/J and SM/J inbred mouse strains to prioritize quantitative trait genes and nucleotides

Cited by 34 publications

References 101 publications

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans

Genome wide association analysis in a mouse advanced intercross line

Whole exome sequencing of wild-derived inbred strains of mice improves power to link phenotype and genotype

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