High-Resolution Genetic Mapping of Complex Traits from a Combined Analysis of F2 and Advanced Intercross Mice

Parker, Clarissa C.; Carbonetto, Peter; Sokoloff, Greta; Park, Yeonhee J.; Abney, Mark; Palmer, Abraham A.

doi:10.1534/genetics.114.167056

Cited by 44 publications

(64 citation statements)

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“…In the 240 present study, we used 1,063 male and female mice from LG x SM G50-56 to identify 126 loci for a 241 variety of traits selected for their relevance to human psychiatric and metabolic diseases (Lawson and 242 Cheverud 2010;Swerdlow et al 2016;de Wit and Phillips 2012) (Fig.3; Supplemental Table S1; 243 Supplemental Fig.S2). Whereas our previous work established AILs as an effective tool for fine-244 mapping loci identified in F2 crosses (Gonzales and Palmer 2014;Carroll et al 2017;Parker et al 2014;245 Cheng et al 2010;Samocha et al 2010;Lionikas et al 2010), this study 246 demonstrates that AILs are also a powerful fine mapping population in their own right. We show that 247 several QTGs we identified are corroborated by extant human and mouse genetic data.…”

Section: S1) 194mentioning

confidence: 66%

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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Section: S1) 194mentioning

confidence: 66%

Genome wide association analysis in a mouse advanced intercross line

Gonzales

Seo

Hernandez-Cordero

et al. 2017

Preprint

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“…BXD RI mice have been used in quantitative trait locus (QTL) analyses and have been instrumental in identifying relevant chromosomal loci involved in ethanol and stress responses as well as potential candidate genes that underlie these QTLs (Mulligan et al, 2011, 2012, 2006; Belknap & Atkins, 2001; Buck, Metten, Belknap, & Crabbe, 1997; Cook et al, 2015; Hitzemann et al, 2004; Porcu et al, 2011; Wang et al, 2012; Weng, Symons, & Singh, 2009). Furthermore, BXD RI mice have been extensively evaluated for expression differences across a wide variety of brain regions and other organs (Boughter et al, 2012; Di Curzio & Goldowitz, 2011; Jellen et al, 2012; Lu et al, 2008, 2011; Mozhui, Lu, Armstrong, & Williams, 2012; Overall et al, 2009; Parker et al, 2014; Swaminathan, Lu, Williams, Lu, & Jablonski, 2013). The combination of all the data generated using BXD mice provides a powerful collection of resources that can be used to uncover genetic networks involved in complex phenotypes, making them an excellent model system.…”

Section: Introductionmentioning

confidence: 99%

Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice

Baker

Zhou

et al. 2017

Alcohol

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Alcohol abuse is a complex disorder, which is confounded by other factors, including stress. In the present study, we examined gene expression in the hippocampus of BXD recombinant inbred mice after exposure to ethanol (NOE), stress (RSS), and the combination of both (RSE). Mice were given an intra-peritoneal (i.p.) injection of 1.8 g/kg ethanol or saline, and subsets of both groups were exposed to acute restraint stress for 15 min or controls. Gene expression in the hippocampus was examined using microarray analysis. Genes that were significantly (p < 0.05, q < 0.1) differentially expressed were further evaluated. Bioinformatic analyses were predominantly performed using tools available at GeneNetwork. org, and included gene ontology, presence of cis-regulation or polymorphisms, phenotype correlations, and principal component analyses. Comparisons of differential gene expression between groups showed little overlap. Gene Ontology demonstrated distinct biological processes in each group with the combined exposure (RSE) being unique from either the ethanol (NOE) or stress (RSS) group, suggesting that the interaction between these variables is mediated through diverse molecular pathways. This supports the hypothesis that exposure to stress alters ethanol-induced gene expression changes and that exposure to alcohol alters stress-induced gene expression changes. Behavior was profiled in all groups following treatment, and many of the differentially expressed genes are correlated with behavioral variation within experimental groups. Interestingly, in each group several genes were correlated with the same phenotype, suggesting that these genes are the potential origins of significant genetic networks. The distinct sets of differentially expressed genes within each group provide the basis for identifying molecular networks that may aid in understanding the complex interactions between stress and ethanol, and potentially provide relevant therapeutic targets. Using Ptp4a1, a candidate gene underlying the quantitative trait locus for several of these phenotypes, and network analyses, we show that a large group of differentially expressed genes in the NOE group are highly interrelated, some of which have previously been linked to alcohol addiction or alcohol-related phenotypes.

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“…); genetic markers can yield more precise estimates of genome sharing than the pedigree (Parker et al. ; Speed and Balding ). See below for more details on calculation of marker‐based relatedness estimates.…”

Section: Methodsmentioning

confidence: 99%

Replication and discovery of musculoskeletal QTLs in LG/J and SM/J advanced intercross lines

et al. 2018

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The genetics underlying variation in health-related musculoskeletal phenotypes can be investigated in a mouse model. Quantitative trait loci (QTLs) affecting musculoskeletal traits in the LG/J and SM/J strain lineage remain to be refined and corroborated. The aim of this study was to map muscle and bone traits in males (n = 506) of the 50th filial generation of advanced intercross lines (LG/SM AIL) derived from the two strains. Genetic contribution to variation in all musculoskeletal traits was confirmed; the SNP heritability of muscle mass ranged between 0.46 and 0.56; and the SNP heritability of tibia length was 0.40. We used two analytical software, GEMMA and QTLRel, to map the underlying QTLs. GEMMA required substantially less computation and recovered all the QTLs identified by QTLRel. Seven significant QTLs were identified for muscle weight (Chr 1, 7, 11, 12, 13, 15, and 16), and two for tibia length, (Chr 1 and 13). Each QTL explained 4-5% of phenotypic variation. One muscle and both bone loci replicated previous findings; the remaining six were novel. Positional candidates for the replicated QTLs were prioritized based on in silico analyses and gene expression in muscle tissue. In summary, we replicated existing QTLs and identified novel QTLs affecting muscle weight, and replicated bone length QTLs in LG/SM AIL males. Heritability estimates substantially exceed the cumulative effect of the QTLs, hence a richer genetic architecture contributing to muscle and bone variability could be uncovered with a larger sample size.

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High-Resolution Genetic Mapping of Complex Traits from a Combined Analysis of F2 and Advanced Intercross Mice

Cited by 44 publications

References 78 publications

Genome wide association analysis in a mouse advanced intercross line

Genome wide association analysis in a mouse advanced intercross line

Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice

Replication and discovery of musculoskeletal QTLs in LG/J and SM/J advanced intercross lines

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