Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing

Nicod, Jérôme; Davies, R. W.; Cai, Na; Hassett, Carl; Goodstadt, Leo; Cosgrove, Cormac; Yee, Benjamin K.; Lionikaite, Vikte; McIntyre, Rebecca E; Remme, Carol Ann; Lodder, Elisabeth M.; Gregory, Jennifer S.; Hough, Tertius; Joynson, Russell; Phelps, Hayley; Nell, Barbara; Rowe, Clare; Wood, Joe; Walling, Alison; Bopp, Nasrin; Bhomra, Amarjit; Hernandez-Pliego, Polinka; Crinon, Jacques; Aspden, Richard M.; Talbot, Nick P.; Robbins, Peter A.; Harrison, Mark E.; Fray, Martin; Launay, Jean‐Marie; Pinto, Yigal M.; Blizard, David A.; Bezzina, Connie R.; Adams, David J.; Franken, Paul; Weaver, Tom; Wells, Sara; Brown, Steve; Potter, Paul K.; Klenerman, Paul; Lionikas, Arimantas; Mott, Richard; Flint, Jonathan

doi:10.1038/ng.3595

Cited by 136 publications

(197 citation statements)

References 58 publications

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“…In general, heritability estimates were 119 larger for physiological traits than for behavioral traits (Fig.3B, Supplemental Table S2), which is 120 consistent with findings in other rodent GWAS (Parker et al 2016;Nicod et al 2016;Rat Genome 121 Sequencing and Mapping Consortium et al 2013). Mean heritability was 0.355 (se=0.045) for 122 physiological traits and 0.168 (se=0.038) for behavioral traits (conditioned place preference, locomotor 123 sensitization, and habituation to startle were not found to have a genetic component and were excluded 124 from the mean).…”

supporting

confidence: 75%

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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confidence: 75%

Genome wide association analysis in a mouse advanced intercross line

Gonzales

Seo

Hernandez-Cordero

et al. 2017

Preprint

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“…Genetic variability combined with environmental factors is the underlying cause of individual differences. In a recent study, we found that an allelic variant of the Met gene conferring an increase in mouse soleus weight had a decreasing effect on the fast-twitch EDL and gastrocnemius muscles (Nicod et al, 2016). Hence, it is reasonable to hypothesize that the adaptive response might also differ between the muscles.…”

Section: Discussionmentioning

confidence: 97%

Baseline Muscle Mass Is a Poor Predictor of Functional Overload-Induced Gain in the Mouse Model

2016

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Genetic background contributes substantially to individual variability in muscle mass. Muscle hypertrophy in response to resistance training can also vary extensively. However, it is less clear if muscle mass at baseline is predictive of the hypertrophic response. The aim of this study was to examine the effect of genetic background on variability in muscle mass at baseline and in the adaptive response of the mouse fast- and slow-twitch muscles to overload. Males of eight laboratory mouse strains: C57BL/6J (B6, n = 17), BALB/cByJ (n = 7), DBA/2J (D2, n = 12), B6.A-(rs3676616-D10Utsw1)/Kjn (B6.A, n = 9), C57BL/6J-Chr10A/J/NaJ (B6.A10, n = 8), BEH+/+ (n = 11), BEH (n = 12), and DUHi (n = 12), were studied. Compensatory growth of soleus and plantaris muscles was triggered by a 4-week overload induced by synergist unilateral ablation. Muscle weight in the control leg (baseline) varied from 5.2 ± 07 mg soleus and 11.4 ± 1.3 mg plantaris in D2 mice to 18.0 ± 1.7 mg soleus in DUHi and 43.7 ± 2.6 mg plantaris in BEH (p < 0.001 for both muscles). In addition, soleus in the B6.A10 strain was ~40% larger (p < 0.001) compared to the B6. Functional overload increased muscle weight, however, the extent of gain was strain-dependent for both soleus (p < 0.01) and plantaris (p < 0.02) even after accounting for the baseline differences. For the soleus muscle, the BEH strain emerged as the least responsive, with a 1.3-fold increase, compared to a 1.7-fold gain in the most responsive D2 strain, and there was no difference in the gain between the B6.A10 and B6 strains. The BEH strain appeared the least responsive in the gain of plantaris as well, 1.3-fold, compared to ~1.5-fold gain in the remaining strains. We conclude that variation in muscle mass at baseline is not a reliable predictor of that in the overload-induced gain. This suggests that a different set of genes influence variability in muscle mass acquired in the process of normal development, growth, and maintenance, and in the process of adaptive growth of the muscle challenged by overload.

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“…Integration of these two novel genome sequences with the growing catalog of known M. musculus genetic variation will provide a valuable resource to researchers using mouse models to study a wide variety of biological processes, including karyotype evolution (Chmátal et al 2014), speciation (Payseur and Place 2007), protein evolution (Karn et al 2008; Stempel et al 2016), gene duplications (Laukaitis et al 2008; Morgan et al 2016b), X-chromosome inactivation (Calaway et al 2013), and disease-associated quantitative traits (Cervino et al 2005; Perez et al 2013; Nicod et al 2016). …”

Section: Resultsmentioning

confidence: 99%

Whole Genome Sequence of Two Wild-Derived Mus musculus domesticus Inbred Strains, LEWES/EiJ and ZALENDE/EiJ, with Different Diploid Numbers

Morgan

Didion

Doran

et al. 2016

G3 Genes|Genomes|Genetics

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Wild-derived mouse inbred strains are becoming increasingly popular for complex traits analysis, evolutionary studies, and systems genetics. Here, we report the whole-genome sequencing of two wild-derived mouse inbred strains, LEWES/EiJ and ZALENDE/EiJ, of Mus musculus domesticus origin. These two inbred strains were selected based on their geographic origin, karyotype, and use in ongoing research. We generated 14× and 18× coverage sequence, respectively, and discovered over 1.1 million novel variants, most of which are private to one of these strains. This report expands the number of wild-derived inbred genomes in the Mus genus from six to eight. The sequence variation can be accessed via an online query tool; variant calls (VCF format) and alignments (BAM format) are available for download from a dedicated ftp site. Finally, the sequencing data have also been stored in a lossless, compressed, and indexed format using the multi-string Burrows-Wheeler transform. All data can be used without restriction.

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Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing

Cited by 136 publications

References 58 publications

Genome wide association analysis in a mouse advanced intercross line

Genome wide association analysis in a mouse advanced intercross line

Baseline Muscle Mass Is a Poor Predictor of Functional Overload-Induced Gain in the Mouse Model

Whole Genome Sequence of Two Wild-Derived Mus musculus domesticus Inbred Strains, LEWES/EiJ and ZALENDE/EiJ, with Different Diploid Numbers

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