Gene loci associated with insulin secretion in islets from nondiabetic mice

Keller, Mark P.; Rabaglia, Mary E.; Schueler, Kathryn L.; Stapleton, Donnie S.; Gatti, Daniel M.; Vincent, Matthew; Mitok, Kelly A.; Wang, Ziyue; Ishimura, Takanao; Simonett, Shane P.; Emfinger, Christopher H.; Das, Rahul; Beck, Tim; Kendziorski, Christina; Broman, Karl W.; Yandell, Brian S.; Churchill, Gary A.; Attie, Alan D.

doi:10.1172/jci129143

Cited by 71 publications

(85 citation statements)

References 67 publications

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“…Common forward genetics analyses include quantitative trait locus (QTL) mapping (linkage studies applied on related individuals) and genome-wide association study (GWAS) (association studies using a large number of related or unrelated individuals), which are widely used to map the genetic loci that correlate with a particular trait, ranging from phenotypes, metabolites, proteins, transcripts, to epigenetic markers [76,77]. In recent years, studies have been performed to study the genes involved in the various diseases and complex traits, including insulin secretion [88], diabetes [37], hepatic steatosis or fibrosis [43,44], blood pressure [89], and bone density [90].…”

Section: Trends Trends In In Genetics Geneticsmentioning

confidence: 99%

Mouse Systems Genetics as a Prelude to Precision Medicine

Auwerx

2020

Trends in Genetics

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Mouse models have been instrumental in understanding human disease biology and proposing possible new treatments. The precise control of the environment and genetic composition of mice allows more rigorous observations, but limits the generalizability and translatability of the results into human applications. In the era of precision medicine, strategies using mouse models have to be revisited to effectively emulate human populations. Systems genetics is one promising paradigm that may promote the transition to novel precision medicine strategies. Here, we review the state-of-the-art resources and discuss how mouse systems genetics helps to understand human diseases and to advance the development of precision medicine, with an emphasis on the existing resources and strategies. Promises and Problems with Precision Medicine Most complex traits and diseases, such as height, longevity, and diabetes, are heritable and influenced by various genetic factors [1], while being modulated by environmental stimuli. Due every individual's unique genetic makeup, response to drugs [2], nutrition [3], and lifestyle [4] vary considerably from person to person. This uniqueness of every human being underpins the purpose of precision medicine, which posits that disease prediction, diagnosis, and treatment for each individual is based on personal genomic variations and external environments [5]. Precision medicine is an innovative approach that takes the variability in genetics, environment, and lifestyle of each individual into account in disease prevention and treatment, and provides better prediction of effective treatments, while concurrently minimizing the possibility of drug side effects [6]. Therefore, precision medicine requires a good understanding of the genetic bases of variation in phenotypes and their interaction with the environment in health and disease. Highlights The mouse is the premier model organism for human biomedical research. So far, most of the research studies involving mouse models rely on a single or few genetic backgrounds and controlled external factors that limit the generalizability of the results. Systems genetics improves the translational potential of mouse studies in human. Systems genetics approaches in mouse panels could serve as the prototype and provide valuable insights for human precision medicine.

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Section: Trends Trends In In Genetics Geneticsmentioning

confidence: 99%

Mouse Systems Genetics as a Prelude to Precision Medicine

Auwerx

2020

Trends in Genetics

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“…To demonstrate information captured by LECIF for translation of biological findings between mouse and human in a phenotypic context, we analyzed mouse insulin secretion quantitative trait loci (QTL) and human diabetes GWAS variants 59 . Previously, it was shown that human regions syntenic to the mouse insulin secretion QTL were enriched for the human diabetes GWAS variants.…”

Section: Lecif Score Highlights Regions Within Mouse Quantitative Tramentioning

confidence: 99%

“…* and *** denote Bonferroni-corrected p-values for the LECIF score annotation's enrichment below 0.05 and 0.001, respectively. c. Distribution of mean LECIF score of non-overlapping 1-kb human genomic windows identified as lying within a mapped mouse insulin scretion QTL or containing a human diabetes GWAS variant or both 59 .…”

Section: Lecif Score Highlights Regions With Conserved Differential Mmentioning

confidence: 99%

Learning a genome-wide score of human-mouse conservation at the functional genomics level

Kwon¹,

Ernst²

2020

Preprint

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Identifying genomic regions with functional genomic properties that are conserved between human and mouse is an important challenge in the context of mouse model studies. To address this, we take a novel approach and learn a score of evidence of conservation at the functional genomics level by integrating large-scale information in a compendium of epigenomic, transcription factor binding, and transcriptomic data from human and mouse. The computational method we developed to do this, Learning Evidence of Conservation from Integrated Functional genomic annotations (LECIF), trains a neural network, which is then used to generate a genome-wide score in human and mouse. The resulting LECIF score highlights human and mouse regions with shared functional genomic properties and captures correspondence of biologically similar human and mouse annotations even though it was not explicitly given such information. LECIF will be a resource for mouse model studies.

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“…Zfp148 was recently implicated in glucose tolerance and insulin secretion from pancreatic islets in mice (Keller et al 2019). However, follow-up studies on insulin sensitivity here revealed no metabolic impact of ZFP30 loss, nor did we observe a significant difference in Pparg2 expression in the white adipose tissues of our mice.…”

Section: Discussionmentioning

confidence: 99%

Baseline and Innate Immune Response Characterization of aZfp30Knockout Mouse Strain

Laudermilk

Tovar

Homstad

et al. 2020

Preprint

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Airway neutrophilia is correlated with disease severity in a number of chronic and acute pulmonary diseases, and dysregulation of neutrophil chemotaxis can lead to host tissue damage. The gene Zfp30 was previously identified as a candidate regulator of neutrophil recruitment to the lungs and secretion of CXCL1, a potent neutrophil chemokine, in a genome-wide mapping study using the Collaborative Cross. ZFP30 is a putative transcriptional repressor with a KRAB domain capable of inducing heterochromatin formation. Using a CRISPR-mediated knockout mouse model, we investigated the role that Zfp30 plays in recruitment of neutrophils to the lung using models of allergic airway disease and acute lung injury. We found that the Zfp30 null allele did not affect CXCL1 secretion or neutrophil recruitment to the lungs in response to various innate immune stimuli. Intriguingly, despite the lack of neutrophil phenotype, we found there was a significant reduction in the proportion of live Zfp30 homozygous mutant mice produced from heterozygous matings. This deviation from the expected mendelian inheritance (i.e. transmission ratio distortion) implicates Zfp30 in fertility or embryonic development. Overall, our results indicate that Zfp30 is an essential gene but does not influence neutrophilic inflammation in this particular knockout model.

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Gene loci associated with insulin secretion in islets from nondiabetic mice

Cited by 71 publications

References 67 publications

Mouse Systems Genetics as a Prelude to Precision Medicine

Mouse Systems Genetics as a Prelude to Precision Medicine

Learning a genome-wide score of human-mouse conservation at the functional genomics level

Baseline and Innate Immune Response Characterization of aZfp30Knockout Mouse Strain

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