Project description:The extent to which differences in germ line DNA copy number contribute to natural phenotypic variation is unknown. We analyzed the copy number content of the mouse genome to a sub-10 kb resolution. We identified over 1,300 copy number variant regions (CNVRs), most of which are < 10 kb in length, are found in more than one strain, and, in total, span 3.2% (85 Mb) of the genome. To assess the potential functional impact of copy number variation, we mapped expression profiles of purified hematopoietic stem and progenitor cells, adipose tissue and hypothalamus to CNVRs in cis. Of the more than 600 significant associations between CNVRs and expression profiles, most map to CNVRs outside of the transcribed regions of genes. In hematopoietic stem/progenitor cells, up to 28% of strain-dependent expression variation is associated with copy number variation, supporting the role of germ line CNVs as major contributors to natural phenotypic variation in the laboratory mouse.
Project description:The extent to which differences in germ line DNA copy number contribute to natural phenotypic variation is unknown. We analyzed the copy number content of the mouse genome to a sub-10 kb resolution. We identified over 1,300 copy number variant regions (CNVRs), most of which are < 10 kb in length, are found in more than one strain, and, in total, span 3.2% (85 Mb) of the genome. To assess the potential functional impact of copy number variation, we mapped expression profiles of purified hematopoietic stem and progenitor cells, adipose tissue and hypothalamus to CNVRs in cis. Of the more than 600 significant associations between CNVRs and expression profiles, most map to CNVRs outside of the transcribed regions of genes. In hematopoietic stem/progenitor cells, up to 28% of strain-dependent expression variation is associated with copy number variation, supporting the role of germ line CNVs as major contributors to natural phenotypic variation in the laboratory mouse. To map the CNV content of the mouse genome, we selected 17 Tier 1-3 Mouse Phenome Project strains and three additional strains of biomedical interest, representing all major inbred lineages. We performed comparative genomic hybridization using a long-oligonucleotide array containing 2,149,887 probes evenly spaced across the reference genome with a median inter-probe spacing of 1,015 bases. Labeling, hybridization, washing and array imaging were performed as previously described (PMID:16075461). We performed segmentation using wuHMM, a Hidden Markov Model algorithm that utilizes sequence-level information and can detect CNVs less than 5 kb in length (fewer than five probes) at a low false positive rate (PMID:18334530). To estimate the overall impact of CNV on gene expression in vivo, we performed expression profiling of hematopoietic stem/progenitors cells using the Illumina Mouse Beadchip-6v1 platform. See manuscript for further details.
Project description:This is a mathematical model describing the hematopoietic lineages with leukemia lineages, as controlled by end-product negative feedback inhibition. Variables include hematopoietic stem cells, progenitor cells, terminally differentiated HSCs, leukemia stem cells, and terminally differentiated leukemia stem cells.
Project description:A transcriptome study in mouse hematopoietic stem cells was performed using a sensitive SAGE method, in an attempt to detect medium and low abundant transcripts expressed in these cells. Among a total of 31,380 unique transcript, 17,326 (55%) known genes were detected, 14,054 (45%) low-copy transcripts that have no matches to currently known genes. 3,899 (23%) were alternatively spliced transcripts of the known genes and 3,754 (22%) represent anti-sense transcripts from known genes.