The JAX Synteny Browser for mouse-human comparative genomics

Kolishovski, Georgi; Lamoureux, Anna; Hale, Paul; Richardson, Joel E.; Recla, Jill M; Adesanya, Omoluyi; Simons, Al; Kunde-Ramamoorthy, Govindarajan; Bult, Carol J.

doi:10.1007/s00335-019-09821-4

Cited by 20 publications

(17 citation statements)

References 35 publications

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“…Further, the regional impacts of the translocation may be more or less homologous depending on how widely these impacts reach. For example, Atf1 is on mouse chromosome 15, where only a small region immediately surrounding the locus is syntenic to the host chromosome of ATF1 on human chromosome 12 (29). The breadth of these syntenic regions will determine whether enhancer elements and other regionally important sequences are shared sufficiently to make the model of these larger shifts in mouse chromosomal segments a true mimic of the human translocation.…”

Section: Discussionmentioning

confidence: 99%

The clear cell sarcoma functional genomic landscape

Panza¹,

Ozenberger²,

Straessler³

et al. 2021

Journal of Clinical Investigation

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Clear Cell Sarcoma (CCS) is a deadly malignancy affecting adolescents and young adults. It is characterized by reciprocal translocations resulting in the expression of the chimeric EWSR1-ATF1 or EWSR1-CREB1 fusion proteins, driving sarcomagenesis. Besides these characteristics, CCS has remained genomically uncharacterized. Copy number analysis of human CCSs showed frequent amplifications of the MITF locus and chromosomes 7 and 8. Few alterations were shared with Ewing sarcoma or desmoplastic small round cell tumors, other EWSR1-rearranged tumors. Exome sequencing in mouse tumors generated by expressing EWSR1-ATF1 from the Rosa26 locus demonstrated no other repeated pathogenic variants.Additionally, we generated a new CCS mouse by Cre-loxP-induced chromosomal translocation between Ewsr1 and Atf1, resulting in copy number loss of chromosome 6 and chromosome 15 instability, including amplification of a portion syntenic with human chromosome 8, surrounding Myc. Additional experiments in the Rosa26 conditional model demonstrated that Mitf or Myc can contribute to sarcomagenesis. Copy number observations in human tumors and genetic experiments in mice render, for the first time, a functional landscape of the CCS genome. These data advance efforts to understand the biology of CCS with innovative models, in which we can eventually validate preclinical therapies, necessary to move toward longer and better survival of the young victims of this disease.

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Section: Discussionmentioning

confidence: 99%

The clear cell sarcoma functional genomic landscape

Panza¹,

Ozenberger²,

Straessler³

et al. 2021

Journal of Clinical Investigation

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“…We compiled links between 2380 genes and 6506 HPOs. Next, we exploited mouse gene–phenotype relationships in the MGI database, which houses gene–phenotype relationship data obtained from mouse gene knockout experiments used for phenotyping ( 22 ). We downloaded and compiled ‘MGI GenePheno rpt’ and ‘MPK_ENSEMBL.rpt’ files from the MGI database.…”

Section: Methodsmentioning

confidence: 99%

Evolutionary rewiring of regulatory networks contributes to phenotypic differences between human and mouse orthologous genes

Kim

Kim³

et al. 2022

Nucleic Acids Research

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Mouse models have been engineered to reveal the biological mechanisms of human diseases based on an assumption. The assumption is that orthologous genes underlie conserved phenotypes across species. However, genetically modified mouse orthologs of human genes do not often recapitulate human disease phenotypes which might be due to the molecular evolution of phenotypic differences across species from the time of the last common ancestor. Here, we systematically investigated the evolutionary divergence of regulatory relationships between transcription factors (TFs) and target genes in functional modules, and found that the rewiring of gene regulatory networks (GRNs) contributes to the phenotypic discrepancies that occur between humans and mice. We confirmed that the rewired regulatory networks of orthologous genes contain a higher proportion of species-specific regulatory elements. Additionally, we verified that the divergence of target gene expression levels, which was triggered by network rewiring, could lead to phenotypic differences. Taken together, a careful consideration of evolutionary divergence in regulatory networks could be a novel strategy to understand the failure or success of mouse models to mimic human diseases. To help interpret mouse phenotypes in human disease studies, we provide quantitative comparisons of gene expression profiles on our website (http://sbi.postech.ac.kr/w/RN).

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“…b) Map of human chromosomes syntenic with mouse chromosome 7. The Synteny Browser was used to define relationships between mouse and human chromosomes [ 54 ]. The outer ring represents mouse chromsomes, the inner ring represents human chromsomes and the connections show syntenic regions to mouse chromosome 7.…”

Section: Figurementioning

confidence: 99%

Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome

et al. 2021

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Breast cancer is the most common tumor among women with inherited variants in the TP53 tumor suppressor, but onset varies widely suggesting interactions with genetic or environmental factors. Rodent models haploinsufficent for Trp53 also develop a wide variety of malignancies associated with Li-Fraumeni Syndrome, but BALB/c mice are uniquely susceptible to mammary tumors and is genetically linked to the Suprmam1 locus on chromosome 7. To define mechanisms that interact with deficiencies in p53 to alter susceptibility to mammary tumors, we fine-mapped the Suprmam1 locus in females from an N2 backcross of BALB/cMed and C57BL/6J mice. A major modifier was localized within a 10 cM interval on chromosome 7. The effect of the locus on DNA damage responses was examined in the parental strains and mice that are congenic for C57BL/6J alleles on the BALB/cMed background (SM1- Trp53 +/− ). The mammary epithelium of C57BL/6J- Trp53 +/− females exhibited little radiation-induced apoptosis compared to BALB/cMed- Trp53 +/− and SM1- Trp53 +/− females indicating that the Suprmam1 B6/B6 alleles could not rescue repair of radiation-induced DNA double-strand breaks mostly relying on non-homologous end joining. In contrast, the Suprmam1 B6/B6 alleles in SM1- Trp53 +/− mice were sufficient to confer the C57BL/6J- Trp53 +/− phenotypes in homology-directed repair and replication fork progression. The Suprmam1 B6/B6 alleles in SM1- Trp53 +/− mice appear to act in trans to regulate a panel of DNA repair and replication genes which lie outside the locus. Significance: Genetic variation in replication-associated DNA repair can modify consequences of heterozygous mutations in Trp53 and contribute to susceptibility to mammary tumors in mouse models of Li-Fraumeni syndrome.

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The JAX Synteny Browser for mouse-human comparative genomics

Cited by 20 publications

References 35 publications

The clear cell sarcoma functional genomic landscape

The clear cell sarcoma functional genomic landscape

Evolutionary rewiring of regulatory networks contributes to phenotypic differences between human and mouse orthologous genes

Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome

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