Using gene expression databases for classical trait QTL candidate gene discovery in the BXD recombinant inbred genetic reference population: Mouse forebrain weight

Lu, Lu; Wei, Lai; Peirce, Jeremy L.; Wang, Xusheng; Zhou, Jianhua; Homayouni, Ramin; Williams, Robert W.; Airey, David

doi:10.1186/1471-2164-9-444

Cited by 29 publications

(21 citation statements)

References 42 publications

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“…VMB iron and VMB DA transporter (DAT) density were positively correlated, consistent with the previous report that iron deficiency reduces the protein density of DAT in the rat VMB [15]. VMB iron and several anxiety and depression-related phenotypes were also correlated [29], in line with observations of increased anxiety and depression-related behaviors in iron-deficient rodents and humans [1, 22]. …”

Section: Resultssupporting

confidence: 88%

Systems genetic analysis of the effects of iron deficiency in mouse brain

Jellen

Unger

et al. 2012

Neurogenetics

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Iron regulation in the brain is both necessary and highly complex. Too little or too much iron can compromise neurological function, yet we still do not know all of the regulatory processes. In our research, we seek to identify genes and gene networks underlying individual differences in brain iron regulation. To this end, we fed mice from 20+ inbred strains a diet low in iron from weaning to 4 months of age. At sacrifice, we measured iron content in the ventral midbrain (VMB). The VMB contains the substantia nigra, a region particularly vulnerable to iron imbalance. The results showed high, inter-strain variability in dietary iron reduction, from almost no loss to more than 40 % vs. control. When we performed quantitative trait loci (QTL) analysis, we observed a significant area on chromosome 2. Within this QTL, we selected glial high-affinity glutamate transporter 1 (Glt1) as the leading candidate. Expression of this gene is both correlated with VMB iron and is also cis-modulated by local sequence variants that segregate in the BXD family. VMB expression differences of Glt1 in six strains covary with differential susceptibility to VMB iron loss.

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Section: Resultssupporting

confidence: 88%

Systems genetic analysis of the effects of iron deficiency in mouse brain

Jellen

Unger

et al. 2012

Neurogenetics

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“…Furthermore, it combines experimental data and bioinformatics approaches of different experiments to facilitate the identification of candidate genes [61]. Initially, we selected the genes, which are physically located in the target QTL interval with the highest test statistic.…”

Section: Methodsmentioning

confidence: 99%

ATR-FTIR spectroscopy reveals genomic loci regulating the tissue response in high fat diet fed BXD recombinant inbred mouse strains

et al. 2013

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BackgroundObesity-associated organ-specific pathological states can be ensued from the dysregulation of the functions of the adipose tissues, liver and muscle. However, the influence of genetic differences underlying gross-compositional differences in these tissues is largely unknown. In the present study, the analytical method of ATR-FTIR spectroscopy has been combined with a genetic approach to identify genetic differences responsible for phenotypic alterations in adipose, liver and muscle tissues.ResultsMice from 29 BXD recombinant inbred mouse strains were put on high fat diet and gross-compositional changes in adipose, liver and muscle tissues were measured by ATR-FTIR spectroscopy. The analysis of genotype-phenotype correlations revealed significant quantitative trait loci (QTL) on chromosome 12 for the content of fat and collagen, collagen integrity, and the lipid to protein ratio in adipose tissue and on chromosome 17 for lipid to protein ratio in liver. Using gene expression and sequence information, we suggest Rsad2 (viperin) and Colec11 (collectin-11) on chromosome 12 as potential quantitative trait candidate genes. Rsad2 may act as a modulator of lipid droplet contents and lipid biosynthesis; Colec11 might play a role in apoptopic cell clearance and maintenance of adipose tissue. An increased level of Rsad2 transcripts in adipose tissue of DBA/2J compared to C57BL/6J mice suggests a cis-acting genetic variant leading to differential gene activation.ConclusionThe results demonstrate that the analytical method of ATR-FTIR spectroscopy effectively contributed to decompose the macromolecular composition of tissues that accumulate fat and to link this information with genetic determinants. The candidate genes in the QTL regions may contribute to obesity-related diseases in humans, in particular if the results can be verified in a bigger BXD cohort.

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“…Interestingly, the genetic and functional diversity of mouse strains can also be useful in identifying the molecular underpinnings of complex traits, as well as in defining a broader molecular and physiological impact of medications. Essential to this strategy is the presence of genetic or functional variation between strains that can be exploited to identify heritable influences (Holmes et al, 2002; Lu et al, 2008). We identified coding variation in SERT between C57BL/6J (Gly39 and Lys152=GK haplotype) and DBA/2J (Glu39 and Arg152=ER haplotype) and, using heterologous expression studies, demonstrated that this sequence variation imparted significant differences in 5-HT transport capacity (Carneiro et al, 2009) (Fig.…”

Section: Strain-based Genetic Variation In Mouse Sert and Its Use In mentioning

confidence: 99%

“…The dense genotyping of the BXD lines, along with the full sequencing of the parental genomes, provides the researcher with a powerful paradigm to map quantitative trait loci (QTLs) supporting functional variation (Lu et al, 2008; Gaglani et al, 2009). Additionally, correlations can also be identified between biochemical or functional traits due to their co-segregation across BXD lines, and then their common genetic underpinnings can be pursued (Koutnikova et al, 2009; Tapocik et al, 2009).…”

Section: Strain-based Genetic Variation In Mouse Sert and Its Use In mentioning

confidence: 99%

Natural and engineered coding variation in antidepressant-sensitive serotonin transporters

Blakely

2011

Neuroscience

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The presynaptic serotonin (5-HT) transporter (SERT) is a key regulator of 5-HT signaling and is a major target for antidepressant medications and psychostimulants. In recent years, studies of natural and engineered genetic variation in SERT have provided new opportunities to understand structural dimensions of drug interactions and regulation of the transporter, to explore 5-HT contributions to antidepressant action, and to assess the impact of SERT-mediated 5-HT contributions to neuropsychiatric disorders. Here we review three examples from our recent studies where genetic changes in SERT, identified or engineered, have led to new models, findings, and theories that cast light on new dimensions of 5-HT action in the CNS and periphery. First, we review our work to identify specific residues through which SERT recognizes antagonists, and the conversion of this knowledge to the creation of mice lacking high-affinity antidepressant and cocaine sensitivity. Second, we discuss our studies of functional coding variation in SERT that exists in commonly used strains of inbred mice, and how this variation is beginning to reveal novel 5-HT-associated phenotypes. Third, we review our identification and functional characterization of multiple, hyperactive SERT coding variants in subjects with autism. Each of these activities has driven the development of new model systems that can be further exploited to understand the contribution of 5-HT signaling to risk for neuropsychiatric disorders and their treatment.

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Using gene expression databases for classical trait QTL candidate gene discovery in the BXD recombinant inbred genetic reference population: Mouse forebrain weight

Cited by 29 publications

References 42 publications

Systems genetic analysis of the effects of iron deficiency in mouse brain

Systems genetic analysis of the effects of iron deficiency in mouse brain

ATR-FTIR spectroscopy reveals genomic loci regulating the tissue response in high fat diet fed BXD recombinant inbred mouse strains

Natural and engineered coding variation in antidepressant-sensitive serotonin transporters

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