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Publications (249)
Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca ²⁺ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca ²⁺ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four...
Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred (DO) mice maintained on a Western-style diet. We identified 21 quanti...
Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four c...
We and others have previously shown that genetic association can be used to make causal connections between gene loci and small molecules measured by mass spectrometry in the bloodstream and in tissues. We identified a locus on mouse chromosome 7 where several phospholipids in liver showed strong genetic association to distinct gene loci. In this s...
Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four c...
Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four c...
We and others have previously shown that genetic association can be used to make causal connections between gene loci and small molecules measured by mass spectrometry in the bloodstream and in tissues. We identified a locus on mouse chromosome 7 where several phospholipids in liver showed strong genetic association to distinct gene loci. In this s...
The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modi...
Genetic susceptibility to type 2 diabetes is primarily due to β-cell dysfunction. However, a genetic study to directly interrogate β-cell function ex vivo has never been previously performed. We isolated 233,447 islets from 483 Diversity Outbred (DO) mice maintained on a Western-style diet, and measured insulin secretion in response to a variety of...
The high mapping resolution of multiparental populations, combined with technology to measure tens of thousands of phenotypes, presents a need for quantitative methods to enhance understanding of the genetic architecture of complex traits. When multiple traits map to a common genomic region, knowledge of the number of distinct loci provides importa...
The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modi...
The high mapping resolution of multiparental populations, combined with technology to measure tens of thousands of phenotypes, presents a need for quantitative methods to enhance understanding of the genetic architecture of complex traits. When multiple traits map to a common genomic region, knowledge of the number of distinct loci provides importa...
R/qtl2 is an interactive software environment for mapping quantitative trait loci (QTL) in experimental populations. The R/qtl2 software expands the scope of the widely-used R/qtl software package to include multiparental populations, better handles modern high-dimensional data....
R/qtl2 is an interactive software environment for mapping quantitat...
R/qtl2 is an interactive software environment for mapping quantitative trait loci (QTL) in experimental populations. The R/qtl2 software expands the scope of the widely-used R/qtl software package to include multi-parent populations derived from more than two founder strains, such as the Collaborative Cross and Diversity Outbred mice, heterogeneous...
The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet high in fat (45%-kcal) and sucrose (34%) and carried out genome-wide association mappin...
Carrot production suffers yield losses under weed pressure, and thus improved competitive ability is a breeding priority. However, continued improvement and in-depth genetic studies for these traits relies on knowledge of the underlying genetic architecture. This study estimated heritable and non-heritable components of carrot shoot growth from a d...
Crop establishment in carrot ( Daucus carota L.) is limited by slow seedling growth and delayed canopy closure, resulting in high management costs for weed control. Varieties with improved growth habit (i.e. larger canopy and increased shoot biomass) may help mitigate weed control, but the underlying genetics of these traits in carrot is unknown. T...
Genetic variation drives phenotypic diversity and influences the predisposition to metabolic disease. Here, we characterize the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a high-fat/high-sucrose diet. We found significant variation in diabetes-related phenotypes and gut microbiota composition among the di...
Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the ex...
Regional association plots for NFAT and fasting insulin in human GWAS.
Association (-log10 P-value) to fasting insulin levels for SNPs near NFATC1 (A) and NFATC2 (B). Plots were generated using LocusZoom [13] and data provided in [14]. Color scale shows correlation (r2) between the SNP with the strongest association within the plotted region (lead...
T2D GWAS islet eQTLs and plasma insulin QTL that are conditional on Nfatc2.
Heat maps show the linkage for plasma insulin and the islet eQTLs for Nfatc2 and 54 transcripts for genes identified in human GWAS that are associated with Type 2 Diabetes (T2D). Linkage data was obtained from an F2 intercross between diabetes resistant (B6) and diabetes-su...
Genotype dependence of T2D GWAS trans-eQTLs on Chr 2.
Expression of GWAS gene candidates in islets of 491 F2 mice. For each gene, mice are grouped according to genotype at the peak locus of the respective eQTL; homozygous B6 (B6:B6), heterozygous (B6:BTBR), or homozygous BTBR (BTBR:BTBR). The expression of 26 GWAS gene candidates increased (A) in r...
Genotype dependence of expression of Nfatc2 in pancreatic islets.
Expression of Nfatc2 in pancreatic islets of 491 F2 mice. Mice are grouped according to their genotype at ~168.4 Mb on Chr 2 (rs3024096), the marker position closest to the maximum LOD (~70) of the cis-eQTL for Nfatc2. At this position, mice were homozygous B6 (B6:B6, N = 127), heter...
Sequence comparison of mouse and human Nfatc1 and Nfatc2.
Amino acid sequence for mouse and human, proteins for equivalent isoforms of Nfatc2 (A) and Nfatc1 (B) were aligned using Clustal Omega. For Nfatc2, we used isoforms A (NP_035029.2) and C (NP_775114.1) for mouse and human, respectively. For Nfatc1, we used isoforms 1 (NP_058071.2) and I (NP_...
Expression of the NFAT gene family in mouse islets transduced with adenoviruses.
Normalized RNA-sequencing values for the NFAT gene family in mouse islets 48 hr after transduction with adenoviruses containing GFP, ca-Nfatc1 or ca-Nfatc2 (A). Average expression values (± S.E.M., N = 5) are shown for each gene/virus combination. Western blot analysis...
Comparison of GWAS genes that were regulated by NFAT in mouse and human islets.
Heat maps illustrate the change in the expression of T2D-associated GWAS gene candidates in mouse (left) and human (right) islets replotted from Fig 6 as the average Z-score for each transcript; N = 5 for mouse and N = 3 for human.
(TIF)
The overexpression of ca-Nfatc2 promotes cell cycle progression and not DNA damage repair pathways in mouse islets.
Immunocytochemistry of mouse islets for (A) Ki67, (B) pHH3 (S10) and (C) 53BP1 following Ad-LacZ (control) and Ad-ca-Nfatc2 transduction (72 hr). To identify β-cells, islets were stained for insulin. All islets were exposed to BrdU (1...
Additional cell cycle regulatory genes that were differentially regulated by ca-Nfatc1 in mouse and human islets.
The regulation of expression for cell cycle genes is illustrated in mouse (A) and human (B) islets following overexpression of either ca-Nfatc1 or ca-Nfatc2. The data is plotted as the log2 fold-change in expression relative to that mea...
Gene candidates linked to T2D risk loci from human GWAS, and their mouse homologues.
Separate tabs list: Tab 1, ~300 entries in the GWAS catalog for genomic loci associated with the disease/trait “Type 2 diabetes”; Tab 2, distinct genomic loci and their associated P-values; and Tab 3, candidate human genes reported for the loci, with accompanying m...
Summary scores for islet transcription factor cis-eQTLs on chromosome 2 for conditional dependence on T2D GWAS gene candidates.
Table summarizing conditional dependence of T2D GWAS gene candidates on islet Chr 2 cis-eQTLs for genes annotated as playing a role in "transcription" or "DNA binding" (https://david.ncifcrf.gov/). For each cis-eQTL, the s...
Isoform-specific expression of the NFAT gene family in mouse islets.
Islets from B6 mice were used for deep RNA-sequencing to determine isoform-specific expression of all genes. The table shows the expression level and relative proportion of each isoform for the NFAT gene family. Expression values for all genes is available at GEO submission GSE736...
Islet eQTLs for T2D GWAS candidates in mouse islets.
Excel sheet lists the 205 eQTLs for GWAS candidates genes that were identified genome-wide in islets from ~500 B6:BTBR-F2 obese mice. Genomic positions for the genes and their eQTLs are shown. Cis is defined as an eQTL that occurred within 2.5 cM (~5 Mbp) of the genomic position of the correspond...
Donor information for human islet preparations.
For several islet preparations, multiple studies were conducted, which are listed in the final column labeled “Experiments”. Values that are missing are not known.
(PDF)
Quantitative real time PCR primers used for gene expression measurements in human islets.
(XLSX)
Normalized expression values for all genes from RNA-sequencing of mouse islets following overexpression of GFP, ca-Nfatc1 or ca-Nfatc2.
Excel spreadsheet contains normalized expression values for all genes (Tab 1) identified in mouse islets 48 hr after overexpression of GFP, ca-Nfatc1 or ca-Nfatc2 (N = 5 ea.). Posterior probabilities (PP) for diffe...
The genetic factors underlying changes in ear morphology, and particularly the inheritance of kernel row number (KRN), have been broadly investigated in diverse mapping populations in maize (Zea mays L.). In this study, we mapped a region on the long arm of chromosome 1 containing a QTL for KRN. This work was performed using a set of recombinant ch...
Expression Data of the Genes located within the 1.5 LOD Confidence Interval of KRN1.4.
(DOCX)
Histogram of the Least Squared Means of Kernel Row Number.
(DOCX)
Genetic stock lines used for phenotyping.
(DOCX)
Since the advent of theoretical population biology, there have been a number of attempts to simulate the dynamics of biological systems using any number of individual-based modeling techniques. In some cases such techniques have been successful, while in other applications the same techniques fail. We present some of the properties that an individu...
Studies of the genetic loci that contribute to variation in gene expression
frequently identify loci with broad effect on gene expression: expression
quantitative trait locus (eQTL) hotspots. We describe a set of exploratory
graphical methods as well as a formal likelihood-based test for assessing
whether a given hotspot is due to one or multiple p...
We surveyed gene expression in six tissues in an F2 intercross between mouse strains C57BL/6J (abbreviated B6) and BTBR T(+) tf /J (abbreviated BTBR) made genetically obese with the Leptin(ob) mutation. We identified a number of expression quantitative trait loci (eQTL) affecting the expression of numerous genes distal to the locus, called trans-eQ...
Background/objectives:
Both genetic and dietary factors contribute to the metabolic syndrome (MetS) in humans and animal models. Characterizing their individual roles as well as relationships among these factors is critical for understanding MetS pathogenesis and developing effective therapies. By studying phenotypic responsiveness to high-risk ve...
We surveyed gene expression in six tissues in an F2 intercross between mouse strains C57BL/6J (abbreviated B6) and BTBR T+ tf /J (abbreviated BTBR) made genetically obese with the Leptin(ob) mutation. We identified a number of expression quantitative trait loci (eQTL) affecting the expression of numerous genes distal to the locus, called trans-eQTL...
A Bayesian network has often been modeled to infer a gene regulatory network from expression data. Genotypes along with gene expression can further reveal the regulatory relations and genetic ar-chitectures. Biological knowledge can also be incorporated to im-prove the reconstruction of a gene network. In this work, we propose a Bayesian framework...
The Rgcs1 quantitative trait locus, on mouse chromosome 5, influences susceptibility of retinal ganglion cells to acute damage of the optic nerve. Normally resistant mice (DBA/2J) congenic for the susceptible allele from BALB/cByJ mice exhibit susceptibility to ganglion cells, not only in acute optic nerve crush, but also to chronic inherited glauc...
In a mouse intercross with more than 500 animals and genome-wide gene expression data on six tissues, we identified a high proportion (18%) of sample mix-ups in the genotype data. Local expression quantitative trait loci (eQTL; genetic loci influencing gene expression) with extremely large effect were used to form a classifier to predict an individ...
Current efforts in systems genetics have focused on the development of statistical approaches that aim to disentangle causal relationships among molecular phenotypes in segregating populations. Reverse engineering of transcriptional networks plays a key role in the understanding of gene regulation. However, transcriptional regulation is only one po...
The expression of App gene in B6 ob mice is lower than in BTBR ob mice at 10th week. Y-axis value (mlratio) is log10(ratio) where the ratio is between the expression intensity of a particular sample versus the pooled intensity of all samples.
(TIF)
Conditioning on islet App expression, the plasma insulin QTL is no longer significant on chromosome 2 and 19. This supports that the regulation of genetic factors on chromosome 2 and 19 on insulin is mediated by App.
(TIF)
The cross eQTL group protein-protein interaction network in islets. This is the same as Figure 5, but a zoomable version.
(PDF)
Cross-group protein interaction list in pancreatic islet tissue as plotted in Figure 5.
(TXT)
Ranks of genes with TIE scores in adipose tissue.
(XLSX)
The interaction between chromosome 2 and 19 with respect to insulin level. The marker was selected based on insulin QTL mapping where the LOD score was maximized. Using linear regression modeling, the locus on chromosomes 2 and 19 explains 10.6% and 8.4% of the variation of plasma insulin, respectively; a model considering both loci jointly explain...
Blood triglyceride, an indicator of insulin resist, is not under strong genetic control in this F2 cross as indicated by its QTL map (green curve).
(TIF)
The correlation between insulin and App gene expression in five tissues. We observe a strong anti-correlation only in pancreatic islet tissue.
(TIF)
Genes located at insulin QTL loci. (a) Genes located on chromosome 2 insulin QTL region. (b) Genes located on chromosome 19 insulin QTL region.
(XLSX)
Content of insulin is not significantly different in either wild type and APP KO mice at age of both 10th (A) and 17th (B) week.
(TIF)
Causal and reactive genes function enrichment based on DAVID tool.
(XLSX)
The gene expression of App in F2 cross distribution in different groups based on chr2 and chr19 genotypes.
(TIF)
Gene enrichment of the TIE hits in islet network.
(XLSX)
Ranks of genes with TIE scores in pancreatic islet.
(XLSX)
Supplementary Methods: Generation of B6×BTBR cross F2 Mice and genotyping and gene expression data. Data analysis on eQTL mapping. Construct protein network and prioritize genes.
(DOCX)
Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made gen...
Mitochondria are dynamic organelles that play a central role in a diverse array of metabolic processes. Elucidating mitochondrial adaptations to changing metabolic demands and the pathogenic alterations that underlie metabolic disorders represent principal challenges in cell biology. Here, we performed multiplexed quantitative mass spectrometry-bas...
Quantitative trait loci (QTL) hotspots (genomic locations affecting many traits) are a common feature in genetical genomics studies and are biologically interesting since they may harbor critical regulators. Therefore, statistical procedures to assess the significance of hotspots are of key importance. One approach, randomly allocating observed QTL...
Nonalchoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction and is associated with metabolic diseases, including obesity, insulin resistance, and type 2 diabetes. We mapped a quantitative trait locus (QTL) for NAFLD to chromosome 17 in a cross between C57BL/6 (B6) and BTBR mouse strains made genetically obese with the Le...
1. Introduction.- 1.1 Smoothing Methods: a Nonparametric/Parametric Compromise.- 1.2 Uses of Smoothing Methods.- 1.3 Outline of the Chapters.- Background material.- Computational issues.- Exercises.- 2. Simple Univariate Density Estimation.- 2.1 The Histogram.- 2.2 The Frequency Polygon.- 2.3 Varying the Bin Width.- 2.4 The Effectiveness of Simple...
Transmission ratio distortion (TRD) is the departure from the expected genotypic frequencies under Mendelian inheritance. This departure can be due to multiple physiological mechanisms during gametogenesis, fertilization, fetal and embryonic development, and early neonatal life. Although a few TRD loci have been reported in mouse, inheritance patte...
Mitochondria are organelles that have their own DNA; serve as the powerhouses of eukaryotic cells; play important roles in stress responses, programmed cell death, and ageing; and in the vast majority of eukaryotes, are maternally transmitted. Strict maternal transmission of mitochondria makes it difficult to select for better-performing mitochondr...
R/qtlbim (www.qtlbim.org) provides a powerful suite of tools for model selection of the genetic architecture for traits influenced by multiple quantitative trait loci (QTL). The Markov chain Monte Carlo (MCMC) sampling approach draws samples from the more probable genetic architectures. Subsequent visualization and summary provides posterior estima...
SNPs and DIPs in QTL Region. Single nucleotide polymorphisms and deletion/insertion polymorphisms (DIPs) in the 36–38.5 Mb region underlying the chromosome 16 QTL were determined by Next Generation sequencing. Using the CLC Genomics 4.0.3 software, for each strain (B6, BTBR, B6.16BT36–38, B6.16BT24–37, and B6.16BT24–38), an algorithm generated a li...
Tomosyn-2 SNPs. Listed are those SNPs/DIPs that were located upstream and downstream of the tomosyn-2 gene. We identified 1 non-synonymous coding SNP and 8 intronic SNPs in tomosyn-2. Three of the intronic SNPs found are not listed in the MGI database but are listed in UCSC Genome Browser (rs4173887, rs4173899 and rs46721065). We were unable to con...
Gap data. Within our 36–38.5 Mb region on chromosome 16 there were 30531 bp of gap sequence (representing ∼ 1.2% of the region) where there was not sufficient sequence for both B6 and BTBR. This will be an overestimate of actual gaps, due to the fact that the sequence from other strains compared to either B6 or BTBR could still be used to determine...
Strain distribution of S912L SNP. Non-synonymous coding SNPs identified within Stxbp5l from mouse strains sequenced at the Sanger Institute. Reference sequence corresponds to C57BL/6NJ. -, indicates no change. Data obtained from http://www.sanger.ac.uk/cgi-bin/modelorgs/mousegenomes/snps.pl.
(DOCX)
SNP map for chromosome 16. Listed are the microsatellite markers, SNPs and DIPs used to identify the chromosome 16 B6/BTBR boundaries of our congenic mouse strains. Only those with a B6 or BT call were tested at each marker, SNP or DIP. The rest of the region was inferred from flanking markers.
(XLS)
We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lep(ob/ob) and C57BL/6 (B6) Lep(ob/ob) mouse strains. Introgression of BTBR Chr 16 into B6 mice resulted in a consomic mouse with reduced fasting plasma insulin and elevated glucose levels. We derived a panel of sub-congeni...
