A Locus on Chromosome 15 Contributes to Acute Ozone-induced Lung Injury in Collaborative Cross Mice

Tovar, Adelaide; Smith, Gregory J.; Nalesnik, Morgan; Thomas, J. M.; McFadden, Kathryn M.; Harkema, Jack R.; Kelada, Samir N. P.

doi:10.1165/rcmb.2021-0326oc

Cited by 8 publications

(7 citation statements)

References 55 publications

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“…As recombinant populations, the CC and DO can be used to map quantitative trait loci (QTLs) and have thus been used to genetically dissect a wide range of phenotypes. Traits that have been studied in the CC include behavioral traits ( Philip et al 2011 ), hematology traits ( Kelada et al 2012 ), airway damage ( Tovar et al 2022 ) and allergies ( Kelada et al 2014 ), susceptibility to influenza ( Ferris et al 2013 ) and SARS-CoV ( Gralinski et al 2015 ; Schäfer et al 2022 ), homeostatic immune regulation ( Hampton et al 2022 ), and drug response ( Mosedale et al 2017 , 2019 , 2021 ); in the DO, serum cholesterol ( Svenson et al 2012 ), insulin secretion ( Keller et al 2019 ), glutathione metabolism ( Gould et al 2021 ), response to benzene exposure ( French et al 2015 ), bone and skeletal traits ( Al-Barghouthi et al 2021 ), and working ( Ouellette et al 2020 ) and short-term ( Hsiao et al 2020 ) memory.…”

Section: Introductionmentioning

confidence: 99%

Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population

Keele

2023

G3: Genes, Genomes, Genetics

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Multiparental populations (MPPs) encompass greater genetic diversity than traditional experimental crosses of two inbred strains, enabling broader surveys of genetic variation underlying complex traits. Two such mouse MPPs are the Collaborative Cross (CC) inbred panel and the Diversity Outbred (DO) population, which are descended from the same eight inbred strains. Additionally, the F1 intercrosses of CC strains (CC-RIX) have been used and enable study designs with replicate outbred mice. Genetic analyses commonly used by researchers to investigate complex traits in these populations include characterizing how heritable a trait is, i.e., its heritability, and mapping its underlying genetic loci, i.e., its quantitative trait loci (QTLs). Here we evaluate the relative merits of these populations for these tasks through simulation, as well as provide recommendations for performing the quantitative genetic analyses. We find that sample populations that include replicate animals, as possible with the CC and CC-RIX, provide more efficient and precise estimates of heritability. We report QTL mapping power curves for the CC, CC-RIX, and DO across a range of QTL effect sizes and polygenic backgrounds for samples of 174 and 500 mice. The utility of replicate animals in the CC and CC-RIX for mapping QTLs rapidly decreased as traits became more polygenic. Only large sample populations of 500 DO mice were well-powered to detect smaller effect loci (7.5-10%) for highly complex traits (80% polygenic background). All results were generated with our R package musppr, which we developed to simulate data from these MPPs and evaluate genetic analyses from user-provided genotypes.

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Section: Introductionmentioning

confidence: 99%

Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population

Keele

2023

G3: Genes, Genomes, Genetics

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“…2011), hematology traits (Kelada et al . 2012), airway damage (Tovar et al . 2022) and allergies (Kelada et al .…”

Section: Introductionmentioning

confidence: 99%

“…As recombinant populations, the CC and DO are valuable resources for mapping quantitative trait loci (QTLs) and have been used to genetically dissect a wide range of phenotypes. Traits that have been studied in the CC include behavioral traits (Philip et al 2011), hematology traits ( Kelada et al 2012), airway damage (Tovar et al 2022) and allergies ( Kelada et al 2014), susceptibility to influenza (Ferris et al 2013) and SARS-CoV (Gralinski et al 2015; Schäfer et al 2022), homeostatic immune regulation (Hampton et al 2021), and drug response ( Mosedale et al 2017, 2019, 2021); in the DO, serum cholesterol (Svenson et al 2012), insulin secretion (Keller et al 2019), glutathione metabolism (Gould et al 2021), response to benzene exposure (French et al 2015), bone and skeletal traits (Al-Barghouthi et al 2021), and working (Ouellette et al 2020) and short-term (Hsiao et al 2020) memory.…”

Section: Introductionmentioning

confidence: 99%

“…As recombinant populations, the CC and DO are valuable resources for mapping quantitative trait loci 27 (QTLs) and have been used to genetically dissect a wide range 28 of phenotypes. Traits that have been studied in the CC include 29 behavioral traits (Philip et al 2011), hematology traits (Kelada et al 30 2012), airway damage (Tovar et al 2022) and allergies (Kelada et al The number of realized fully-inbred CC strains was lower than planned (The Complex Trait Consortium 2004), with approxi-41 mately 70 strains rather than 1,000 realized due to extinctions caused by allelic incompatibilities (Shorter et al 2017). This re-43 duction in the number of available unique genomes reduces the genetic mapping power possible with the CC; however, the inbred 45 nature of the CC enables the use of replicates within and across 46 experiments.…”

Section: Introductionmentioning

confidence: 99%

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Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population

Keele

2022

Preprint

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Multiparental populations (MPPs) encompass more genetic diversity than traditional experimental crosses, enabling a wide array of experimental designs for deep genetic dissections of complex traits. For mouse models, two related MPPs have emerged: the Collaborative Cross (CC) inbred panel and the Diversity Outbred (DO) population. Additionally, the F1 intercrosses of the CC (CC-RIX) allow for studies of replicable outbred mice. Researchers often seek to characterize and genetically dissect traits through heritability estimation and mapping regulatory genetic loci. Here we evaluate the relative merits of these populations for these tasks through simulation, as well as provide recommendations for performing the quantative analyses. We find that sample populations that include replicate animals, as possible with the CC and CC-RIX, provide more efficient and precise estimates of heritability. CC-RIX populations with replicates enable heritability to be decomposed into additive and non-additive components. All populations of approximately 200 animals were well-powered to detect large effect loci that explain ≥ 40% of the phenotypic variation, but only large sample populations of 500 DO mice were well-powered to detect smaller effect loci (≤10%) for highly polygenic traits. All results were produced with our R package musppr, which we developed to simulate data and evaluate genetic analyses from user-provided genotypes from these MPPs.

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“…Notably, the size of the chromosome involved in the aneuploidy is not associated with the level of severity in phenotype, rather the phenotypic severity is mostly associated with the number of protein coding regions (Epstein, 1985;O'Connor, 2008). Of the four models of trisomy considered in this project, Trisomy 15 produced the most severe phenotype because of the high number of protein coding regions in Chromosome 15 (Epstein, 1985;Tovar et al, 2022). The human and mouse genomes share high levels of synteny.…”

Section: Robertsonian Translocations In Micementioning

confidence: 99%

Synthesis and Validation of Fluorescence in situ Hybridisation Probes (FISH) for Genotyping Mouse Models of Embryonic Lethal Aneuploidies

Derecourt¹

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Approximately 50% of all embryos produced in fertility clinics have an abnormal number of chromosomes (i.e., aneuploid)(Vera-Rodriguez et al., 2015). Of these, 25% have aneuploidies that are embryonic lethal (O’Connor, 2008) and result in spontaneous abortions in the first trimester(Chen et al., 2017). My research contributes to wider research programme that aimsto develop a non-invasive method for detecting aneuploidies in preimplantation humanembryos. For the overarching research program, several models of embryonic lethal aneuploidies must be developed and validated. One way to produce embryonic lethal aneuploidies is through mouse breeding programmes that make use of Robertsonian translocations. Robertsonian translocations (RobT) are one of the most common forms of chromosomal rearrangements in humans and can cause whole chromosome duplications/deletions(Zhuang et al., 2014). A balanced carrier of these RobT is viable but produces normal gametes, carrier gametes, as well as gametes that will result in aneuploid (trisomy or monosomy) embryos(Beyer & Willats, 2017). As these RobT mouse models are being developed in our laboratory, an accurate method for identifying the trisomic and monosomic (i.e., aneuploid) embryos produced is critical. This project aims to synthesise and validate fluorescence in situ hybridisation (FISH) point probes for mouse chromosomes 4, 10, 11, and 15 using a cost-effective, PCR-based method (Bienko et al., 2013). Herein, I present data from experiments that were conducted to validate FISH probes for mouse chromosome 4, 10, 11, and 15. I also describe a series of experiments to optimise metaphase spread preparation from two different sample types, mouse lymphocytes and cleavage stage embryos. From this study, four FISH probes (specific for chromosome 4, 10, 11, & 15) were synthesised. Based on existing metrics, these were determined to be sufficiently labelled and at a high enough concentration to be evaluated as FISH probes. However, when FISH was performed using each of these probes, no specific signal due to hybridisation was observed. This is despite attempts to identify and address the cause of this lack of binding. Despite this, a positive, pan-centromeric control was successfully validated using the optimised FISH protocol. Also, metaphase spread protocols for two different tissue types were also devised to produce a reliable sample source for FISH validation. Overall, this project has shown that these PCR based point probes are not appropriate for the genotyping of RobT induced aneuploidies and other forms of genotyping should be considered.

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A Locus on Chromosome 15 Contributes to Acute Ozone-induced Lung Injury in Collaborative Cross Mice

Cited by 8 publications

References 55 publications

Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population

Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population

Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population

Synthesis and Validation of Fluorescence in situ Hybridisation Probes (FISH) for Genotyping Mouse Models of Embryonic Lethal Aneuploidies

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