High-Throughput Mouse Knockouts Provide a Functional Analysis of the Genome

Friddle, Carl; Abuin, Alejandro; Ramírez‐Solís, Ramiro; Richter, Lizabeth J.; Buxton, Eric C.; Edwards, Joel; Finch, Robert A.; Gupta, Anand P.; Hansen, Gwenn M.; Holt, Kathleen H.; Hu, Yi; Huang, Wenhu; Jaing, Crystal; Key, Billie; Kipp, Peter; Kohlhauff, Buckley; Q., Z.; Markesich, Diane C.; Newhouse, Matthew M.; Perry, T.; Platt, Kenneth A.; Potter, David; Qian, Ny; Shaw, Joseph R.; Schrick, Jeff; Shi, Zheng Zheng; Sparks, Mary J.; Tran, David; Wann, Elisabeth R.; Walke, Wade; Wallace, James D.; Xu, Nanfei; Zhu, Qingfu; Person, Christophe; Sands, Arthur; Zambrowicz, Brian

doi:10.1101/sqb.2003.68.311

Cited by 14 publications

(10 citation statements)

References 22 publications

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“…Constitutive Csmd1 knock-out (KO) mice were obtained from Taconic Farms (TF0137) and were originally created by Lexicon pharmaceuticals [24]. They were generated by knocking a Neomycin cassette into exon 1 using embryonic stem (ES) cells derived from 129SvEvBrd mice.…”

Section: Methodsmentioning

confidence: 99%

Assessment of Behaviors Modeling Aspects of Schizophrenia in Csmd1 Mutant Mice

et al. 2012

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Schizophrenia is a debilitating psychotic disorder that affects up to 1.5% of the population worldwide. Two recent studies in humans identified genome-wide significant associations between schizophrenia and single-nucleotide polymorphisms (SNPs) in an intron of CSMD1. The effect of deleting CSMD1 on mouse behavior is unknown. The present study utilized mice with a mutant Csmd1 allele in which the first exon had been ablated (KO mice). All Csmd1 transcripts that included the first exon were absent in the brains of KO mice, but there was persistent expression of at least one other transcript that does not include the first exon. Wild type (WT), heterozygous (HET), and KO mice were assessed using several well-established behavioral paradigms that model aspects of schizophrenia. Csmd1 KO mice did not differ from wild-type littermates for sensorimotor gating (measured as prepulse inhibition), social interaction, anhedonia (measured by sucrose preference), or sensitivity to the locomotor stimulant effects of the dopaminergic agent d-amphetamine. These data demonstrate that loss of Csmd1 transcripts that include the first exon does not alter multiple well-established behaviors that model aspects of schizophrenia. The SNP most strongly associated with schizophrenia in humans is between exons 3 and 4; therefore, ablation of exon 1 appeared to be a logical animal model. Nevertheless, future studies should consider alternative mouse models including gain-of-function mutations, and loss-of-function mutations that target alternative transcripts of Csmd1.

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Section: Methodsmentioning

confidence: 99%

Assessment of Behaviors Modeling Aspects of Schizophrenia in Csmd1 Mutant Mice

et al. 2012

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“…Csmd1 mutants were created by Lexicon Genetics by inserting a Neomycin cassette into the first exon of 507 Csmd1 using embryonic stem cells derived from 129S5 mice (Friddle et al 2003) as described by Distler 508 et al (2012). The mice we used were the result of a C57BL/6 x 129S5 intercross designated B6;129S5-509…”

Section: Csmd1 Mutant Mice 506mentioning

confidence: 99%

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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“…KO strategies (described below) involved both gene trapping, 7 using the OmniBank® I embryonic stem (ES) cell library, and homologous recombination technologies. Lexicon generated a second ES cell library (OmniBank ® II) for the TIGM gene trap repository 8 and since 2009, over 100 studies have used this resource to examine gene disruptions in mice (http://www.tigm.org/publications/).…”

Section: Introductionmentioning

confidence: 99%

High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes

et al. 2014

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Screening gene function in vivo is a powerful approach to discover novel drug targets. We present high-throughput screening (HTS) data for 3 762 distinct global gene knockout (KO) mouse lines with viable adult homozygous mice generated using either gene-trap or homologous recombination technologies. Bone mass was determined from DEXA scans of male and female mice at 14 weeks of age and by microCT analyses of bones from male mice at 16 weeks of age. Wild-type (WT) cagemates/littermates were examined for each gene KO. Lethality was observed in an additional 850 KO lines. Since primary HTS are susceptible to false positive findings, additional cohorts of mice from KO lines with intriguing HTS bone data were examined. Aging, ovariectomy, histomorphometry and bone strength studies were performed and possible non-skeletal phenotypes were explored. Together, these screens identified multiple genes affecting bone mass: 23 previously reported genes (Calcr, Cebpb, Crtap, Dcstamp, Dkk1, Duoxa2, Enpp1, Fgf23, Kiss1/Kiss1r, Kl (Klotho), Lrp5, Mstn, Neo1, Npr2, Ostm1, Postn, Sfrp4, Slc30a5, Slc39a13, Sost, Sumf1, Src, Wnt10b), five novel genes extensively characterized (Cldn18, Fam20c, Lrrk1, Sgpl1, Wnt16), five novel genes with preliminary characterization (Agpat2, Rassf5, Slc10a7, Slc26a7, Slc30a10) and three novel undisclosed genes coding for potential osteoporosis drug targets.

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High-Throughput Mouse Knockouts Provide a Functional Analysis of the Genome

Cited by 14 publications

References 22 publications

Assessment of Behaviors Modeling Aspects of Schizophrenia in Csmd1 Mutant Mice

Assessment of Behaviors Modeling Aspects of Schizophrenia in Csmd1 Mutant Mice

Genome wide association analysis in a mouse advanced intercross line

High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes

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