Mouse genomic variation and its effect on phenotypes and gene regulation

Keane, Thomas M.; Goodstadt, Leo; Danecek, Petr; White, Michael A.; Wong, Kim; Yalcin, Binnaz; Heger, Andreas; Agam, Avigail; Slater, Guy; Goodson, Martin; Furlotte, Nick; Eskin, Eleazar; Nellåker, Christoffer; Whitley, Helen; Cleak, James; Janowitz, Deborah; Hernandez-Pliego, Polinka; Edwards, Andrew; Belgard, T. Grant; Oliver, Peter L.; McIntyre, Rebecca E; Bhomra, Amarjit; Nicod, Jérôme; Gan, Xiangchao; Wei, Yuan; Weyden, Louise van der; Steward, Charles A.; Bala, Sendu; Stalker, Jim; Mott, Richard; Durbin, Richard; Jackson, Ian J.; Czechanski, Anne; Guerra-Assunção, José Afonso; Donahue, Leah Rae; Reinholdt, Laura G.; Payseur, Bret A.; Ponting, Chris P.; Birney, Ewan; Flint, Jonathan; Adams, David J.

doi:10.1038/nature10413

Cited by 1,426 publications

(1,840 citation statements)

References 46 publications

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“…The maintenance of these mice on an F1, rather than single inbred genetic background, may certainly contribute to higher levels of phenotypic variation (Keane et al, 2011). In addition, Chd7 gt/+ embryos may be more susceptible to unknown, stochastic effects on developmental gene expression.…”

Section: Discussionmentioning

confidence: 99%

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Whittaker

Kasah

Donovan

et al. 2017

American J of Med Genetics Pt C

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Mutations in the gene encoding the ATP dependent chromatin‐remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital‐urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio‐temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay.

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Section: Discussionmentioning

confidence: 99%

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Whittaker

Kasah

Donovan

et al. 2017

American J of Med Genetics Pt C

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“…For the additional data source used by Tshrink+, the four striatum RNA-Seq samples [25] in Table 1 were chosen as they gave the second highest value but were not generated from the same lab as the analysis dataset (as the microarray data were).…”

Section: Resultsmentioning

confidence: 99%

Improved moderation for gene-wise variance estimation in RNA-Seq via the exploitation of external information

et al. 2013

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BackgroundThe cost of RNA-Seq has been decreasing over the last few years. Despite this, experiments with four or less biological replicates are still quite common. Estimating the variances of gene expression estimates becomes both a challenging and interesting problem in these situations of low replication. However, with the wealth of microarray and other publicly available gene expression data readily accessible on public repositories, these sources of information can be leveraged to make improvements in variance estimation.ResultsWe have proposed a novel approach called Tshrink+ for inferring differential gene expression through improved modelling of the gene-wise variances. Existing methods share information between genes of similar average expression by shrinking, or moderating, the gene-wise variances to a fitted common variance. We have been able to achieve improved estimation of the common variance by using gene-wise sample variances from external experiments, as well as gene length.ConclusionsUsing biological data we show that utilising additional external information can improve the modelling of the common variance and hence the calling of differentially expressed genes. These sources of additional information include gene length and gene-wise sample variances from other RNA-Seq and microarray datasets, of both related and seemingly unrelated tissue types. The results of this are promising, with our differential expression test, Tshrink+, performing favourably when compared to existing methods such as DESeq and edgeR when considering both gene ranking and sensitivity. These improved variance models could easily be implemented in both DESeq and edgeR and highlight the need for a database that offers a profile of gene variances over a range of tissue types and organisms.

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“…Compared to C57BL/6J mice as reference strain, the genome of NZO mice contains over four million single nucleotide polymorphisms (SNPs) of which approximately 200,000 are specific to NZO when compared to other mouse strains (Keane et al 2011). Using outcross populations of NZO mice, several variants have been identified in genes that are associated with different adipogenic and diabetogenic traits such as food intake, fat accumulation, and insulin levels (Joost and Schurmann 2014) in genes such as Pctp (Pan et al 2006a, b), Tbc1d1 (Chadt et al 2008), Zfp69 Ifi202b (Vogel et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

et al. 2015

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Induction of skeletal muscle (SM) mitochondrial stress by expression of uncoupling protein 1 (UCP1) in mice results in a healthy metabolic phenotype associated with increased secretion of FGF21 from SM. Here, we investigated whether SM mitochondrial uncoupling can compensate obesity and insulin resistance in the NZO mouse, a polygenic diabesity model. Male NZO mice were crossed with heterozygous UCP1 transgenic (tg) mice (mixed C57BL/6/CBA background) and further backcrossed to obtain F1 and N2 offspring with 50 and 75 % NZO background, respectively. Male F1 and N2 progeny were fed a high-fat diet ad libitum for 20 weeks from weaning. Blood glucose was reduced, and diabetes (severe hyperglycemia [300 mg/dl) was fully prevented in both F1-and N2-tg progeny compared to a diabetes prevalence of 15 % in F1 and 42 % in N2 wild type. In contrast, relative body fat content and plasma insulin were decreased, and glucose tolerance was improved, in F1-tg only. Both F1 and N2-tg showed decreased lean body mass. Accordingly, induction of SM stress response including FGF21 expression and secretion was similar in both F1 and N2-tg mice. In white adipose tissue, expression of FGF21 target genes was enhanced in F1 and N2-tg mice, whereas lipid metabolism genes were induced in F1-tg only. There was no evidence for induction of browning in either UCP1 backcross. We conclude that SM mitochondrial uncoupling induces FGF21 expression and prevents diabetes in mice with a 50-75 % NZO background independent of its effects on adipose tissue.

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Mouse genomic variation and its effect on phenotypes and gene regulation

Cited by 1,426 publications

References 46 publications

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

Improved moderation for gene-wise variance estimation in RNA-Seq via the exploitation of external information

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

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