Study ERP001040 Download

TitleHigh_resolution_QTL_mapping_in_an_outbred_population_of_mice_using_low_coverage_next_generation_sequencing
AbstractGenome-wide association studies (GWAS) have been extensively used for mapping complex traits in humans but have so far proved difficult to implement in mice because populations with the requisite characteristics are lacking. We have recently shown that some of the large colonies of outbred mice maintained by commercial breeders may be suitable for GWAS. A combination of relatively low linkage disequilibrium (LD) and lack of rare alleles makes commercially available outbreds an attractive resource for mouse GWAS (Yalcin et al, PLoS Genet, 2010). In addition, we have found that almost all of the genetic variants present in these populations can be found in classical inbreds, which mean that the genome of each outbred mouse can be reconstructed as a mosaic of inbreds haplotypes. In the present study we have selected one of these populations (Crl:CFW(SW)-US_P08) and designed a high-throughput phenotyping pipeline to test 2000 mice for behavioural (anxiety, depression) and physiological (cardiac, respiratory) traits as well as collecting measures from numerous tissues (genomic instability, haematology, immunology, biochemistry). The phenotyping is well under way and will be completed by the end of December (2011). We have then designed and setup a completely novel approach for the genetic mapping using low-coverage Solexa sequencing: Barcoded libraries from 96 mice are pooled and sequenced generating 1-5% coverage which are mapped to the inbred strains sequences from the Mouse Genomes Project we have recently completed (Keane et al, Nature, 2011). Known SNPs are genotyped and are used to impute the underlying progenitors haplotype structure at each locus. Pilot experiments and simulations have shown that data generated from 1 lane of Hi-Seq on a pool of 96 DNA samples was sufficient to impute 10,000,000 SNPs with an error rate <0.5%. A subset of animals has also been genotyped with the Affymetrix Mouse Diversity Array (600K SNPs) to validate our genotype-by-sequence method. This project has 2 aims: First to perform QTL mapping in mice at a resolution never reached before and we are confident we can achieve that goal with the commercial population of mice we've chosen. In addition, we want to demonstrate that low-coverage sequencing represent an effective, un-biased and economically advantageous method for gene mapping in GWAS
Referencesno content
OrganismsHomo sapiens, Mus musculus
TypeWhole Genome Sequencing
DescriptionStudy description: Genome-wide association studies (GWAS) have been extensively used for mapping complex traits in humans but have so far proved difficult to implement in mice because populations with the requisite characteristics are lacking. We have recently shown that some of the large colonies of outbred mice maintained by commercial breeders may be suitable for GWAS. A combination of relatively low linkage disequilibrium (LD) and lack of rare alleles makes commercially available outbreds an attractive resource for mouse GWAS (Yalcin et al, PLoS Genet, 2010). In addition, we have found that almost all of the genetic variants present in these populations can be found in classical inbreds, which mean that the genome of each outbred mouse can be reconstructed as a mosaic of inbreds haplotypes. In the present study we have selected one of these populations (Crl:CFW(SW)-US_P08) and designed a high-throughput phenotyping pipeline to test 2000 mice for behavioural (anxiety, depression) and physiological (cardiac, respiratory) traits as well as collecting measures from numerous tissues (genomic instability, haematology, immunology, biochemistry). The phenotyping is well under way and will be completed by the end of December (2011). We have then designed and setup a completely novel approach for the genetic mapping using low-coverage Solexa sequencing: Barcoded libraries from 96 mice are pooled and sequenced generating 1-5% coverage which are mapped to the inbred strains sequences from the Mouse Genomes Project we have recently completed (Keane et al, Nature, 2011). Known SNPs are genotyped and are used to impute the underlying progenitors haplotype structure at each locus. Pilot experiments and simulations have shown that data generated from 1 lane of Hi-Seq on a pool of 96 DNA samples was sufficient to impute 10,000,000 SNPs with an error rate <0.5%. A subset of animals has also been genotyped with the Affymetrix Mouse Diversity Array (600K SNPs) to validate our genotype-by-sequence method. This project has 2 aims: First to perform QTL mapping in mice at a resolution never reached before and we are confident we can achieve that goal with the commercial population of mice we've chosen. In addition, we want to demonstrate that low-coverage sequencing represent an effective, un-biased and economically advantageous method for gene mapping in GWAS. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
SubmitterThe Sanger Center
Related objects
SubmissionsERA071297
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