The Mouse Universal Genotyping Array: From Substrains to Subspecies

Morgan, Andrew P.; Fu, Chen; Kao, Chia Yu; Welsh, Catherine E.; Didion, John P.; Yadgary, Liran; Hyacinth, Leeanna; Ferris, Martin T.; Bell, Timothy A.; Miller, Darla R.; Giusti‐Rodríguez, Paola; Nonneman, Randal J.; Cook, Kevin D.; Whitmire, Jason K.; Gralinski, Lisa E.; Keller, Mark P.; Attie, Alan D.; Churchill, Gary A.; Petkov, Petko M.; Sullivan, Patrick F.; Brennan, Jennifer; McMillan, Leonard; Villena, Fernando Pardo Manuel de

doi:10.1534/g3.115.022087

Cited by 232 publications

(257 citation statements)

References 51 publications

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“…Because our sample contained 405 opposite-sex siblings, we were able to identify and resolve sample mix-ups by comparing genetic kinship 406 estimates to kinship estimated from the LG x SM pedigree (described in the Supplemental Methods). In 407 addition, we re-genotyped 24 mice on the GigaMUGA (Morgan et al 2015) to evaluate GBS variant calls 408 (Supplemental Table S5 lists concordance rates at various stages of our pipeline; see Supplemental 409…”

Section: ) (See Supplemental Methods and 398mentioning

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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Section: ) (See Supplemental Methods and 398mentioning

confidence: 99%

“…1A). Even before 284 imputation, GBS yielded nearly 50% more informative SNPs compared to the best available SNP 285 genotyping chip (Morgan et al 2015) at about half the cost (Supplemental Fig.S1). 286 .…”

Section: S1) 194mentioning

confidence: 99%

Genome wide association analysis in a mouse advanced intercross line

Gonzales

Seo

Hernandez-Cordero

et al. 2017

Preprint

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“…These samples were genotyped on one of the MUGA, MegaMUGA, or GigaMUGA (Neogen, Lincoln, NE) array platforms (Morgan et al 2016a). Genotype data from DO mice are being archived at http://do.jax.org, and will also be accessible from the Mouse Phenome Database (http://mpd.jax.org).…”

Section: Methodsmentioning

confidence: 99%

Diversity Outbred Mice at 21: Maintaining Allelic Variation in the Face of Selection

Chesler

Gatti

Morgan

et al. 2016

G3 Genes|Genomes|Genetics

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Multi-parent populations (MPPs) capture and maintain the genetic diversity from multiple inbred founder strains to provide a resource for high-resolution genetic mapping through the accumulation of recombination events over many generations. Breeding designs that maintain a large effective population size with randomized assignment of breeders at each generation can minimize the impact of selection, inbreeding, and genetic drift on allele frequencies. Small deviations from expected allele frequencies will have little effect on the power and precision of genetic analysis, but a major distortion could result in reduced power and loss of important functional alleles. We detected strong transmission ratio distortion in the Diversity Outbred (DO) mouse population on chromosome 2, caused by meiotic drive favoring transmission of the WSB/EiJ allele at the R2d2 locus. The distorted region harbors thousands of polymorphisms derived from the seven non-WSB founder strains and many of these would be lost if the sweep was allowed to continue. To ensure the utility of the DO population to study genetic variation on chromosome 2, we performed an artificial selection against WSB/EiJ alleles at the R2d2 locus. Here, we report that we have purged the WSB/EiJ allele from the drive locus while preserving WSB/EiJ alleles in the flanking regions. We observed minimal disruption to allele frequencies across the rest of the autosomal genome. However, there was a shift in haplotype frequencies of the mitochondrial genome and an increase in the rate of an unusual sex chromosome aneuploidy. The DO population has been restored to genome-wide utility for genetic analysis, but our experience underscores that vigilant monitoring of similar genetic resource populations is needed to ensure their long-term utility.

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“…Novel alleles presented here have already been used to increase the utility of SNP arrays for genotyping of wild mice (Morgan et al 2016a). We provide tools to browse the variants, the underlying read alignments, and the raw reads (see Data Availability in Materials and Methods ).…”

Section: Resultsmentioning

confidence: 99%

“…R2d2 was first identified in WSB/EiJ, a M. m. domesticus strain derived from mice trapped in Centreville, MD. SNP genotyping data (Yang et al 2011; Didion et al 2012; Morgan et al 2016a) indicated that ZALENDE/EiJ harbors the high-copy ( i.e. , distortion-associated) R2d2 allele, while LEWES/EiJ—derived from mice trapped only ∼100 km away from Centreville—has the low-copy ( i.e.…”

mentioning

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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The Mouse Universal Genotyping Array: From Substrains to Subspecies

Cited by 232 publications

References 51 publications

Genome wide association analysis in a mouse advanced intercross line

Genome wide association analysis in a mouse advanced intercross line

Diversity Outbred Mice at 21: Maintaining Allelic Variation in the Face of Selection

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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