Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity

Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes were evaluated by mining GWAS datasets. eQTL analysis identified 1,971 and 2,078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2, were identified in both tissues. 62.1% of top cis-eSNPs were within ±50kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes, (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu) and identified genetically-regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Distribution of Inhaled m-Xylene in Rat Brain and its Effect on GABA A Receptor Binding

Abstract: Distribution of Inhaled m-Xylene in Rat Brain and its Effect on GABA A Receptor Binding: Takehiko ITO, et al. Faculty of Education, Okayama University-Organic solvents generally depress the central nervous system (CNS), similarly to volatile anesthetics. The precise mechanism of their action on the CNS, however, is not fully understood, and remains to be clarified. This study is focused on how inhaled m-xylene distributes in the brain, and whether region specific change in GABA A receptor binding takes place due to the exposure. To conduct this study, we first developed a simple exposure system suitable for inhalation experiments with small animals. Using this system, six-week-old male Sprague-Dawley rats were exposed to m-xylene vapor (2000 ppm) 4 h/d, for 5 consecutive days. At the end of the exposure, m-xylene levels in four different regions of the brain were measured by head-space gas chromatography. Also 14 µm-thick frozen sections of the brain were made, and [ 35 S] t-butylbicyclophosphorothionate (TBPS) binding autoradiography was performed. Uneven distribution of m-xylene in the brain was observed. The concentration in the cerebellum (976 ± 93.4 µg/g tissue) was the highest, while that in the cerebral cortex (467 ± 43.6 µg/g tissue) was the lowest. Received June 29, 2001; Accepted Oct 13, 2001 Correspondence to: Takehiko Ito, Faculty of Education, Okayama University, 3-1-1 Tsushima-naka, Okayama City, 700-8530, Japan Despite the usefulness of organic solvents in industries, uncontrolled use of solvents may be hazardous to workers because of their acute and chronic toxicity 1) . Pharmacologically, organic solvents are generally central nervous system (CNS) depressants, and similar to volatile anesthetics. Because of their lipophilicity, they distribute in lipid-rich organs such as the brain, which is one of the main targets of the action of organic solvents. The neurotoxicity of organic solvents including xylene has been well documented In the present study we developed an exposure system suitable for inhalation experiments on small animals. With this system we exposed rats acutely to m-xylene, and examined the region specific distribution of inhaled m-xylene in the brain, as well as the distribution in other organs and tissues. In this way we have attempted to show whether m-xylene is evenly distributed in the brain or not. Because the functions of the brain are localized in discrete areas, the distribution of inhaled m-xylene in the brain was of particular interest. Several lines of evidenc

Investigating stable oxygen and carbon isotopic variability in speleothem records over the last millennium using multiple isotope-enabled climate models

The incorporation of water isotopologues into the hydrology of general circulation models (GCMs) facilitates the comparison between modeled and measured proxy data in paleoclimate archives. However, the variability and drivers of measured and modeled water isotopologues, as well as the diversity of their representation in different models, are not well constrained. Improving our understanding of this variability in past and present climates will help to better constrain future climate change projections and decrease their range of uncertainty. Speleothems are a precisely datable terrestrial paleoclimate archives and provide well-preserved (semi-)continuous multivariate isotope time series in the lower latitudes and mid-latitudes and are therefore well suited to assess climate and isotope variability on decadal and longer timescales. However, the relationships of speleothem oxygen and carbon isotopes to climate variables are influenced by site-specific parameters, and their comparison to GCMs is not always straightforward. Here we compare speleothem oxygen and carbon isotopic signatures from the Speleothem Isotopes Synthesis and Analysis database version 2 (SISALv2) to the output of five different water-isotope-enabled GCMs (ECHAM5-wiso, GISS-E2-R, iCESM, iHadCM3, and isoGSM) over the last millennium (850-1850 CE). We systematically evaluate differences and commonalities between the standardized model simulation outputs. The goal is to distinguish climatic drivers of variability for modeled isotopes and compare them to those of measured isotopes. We find strong regional differences in the oxygen isotope signatures between models that can partly be attributed to differences in modeled surface temperature. At low latitudes, precipitation amount is the dominant driver for stable water isotope variability; however, at cave locations the agreement between modeled temperature variability is higher than for precipitation variability. While modeled isotopic signatures at cave locations exhibited extreme events coinciding with changes in volcanic and solar forcing, such fingerprints are not apparent in the speleothem isotopes. This may be attributed to the lower temporal resolution of speleothem records compared to the events that are to be detected. Using spectral analysis, we can show that all models underestimate decadal and longer variability compared to speleothems (albeit to varying extents). We found that no model excels in all analyzed comparisons, although some perform better than the others in either mean or variability. Therefore, we advise a multi-model approach whenever comparing proxy data to modeled data. Considering karst and cave internal processes, e.g., through isotope-enabled karst models, may alter the variability in speleothem isotopes and play an important role in determining the most appropriate model. By exploring new ways of analyzing the relationship between the oxygen and carbon isotopes, their variability, and co-variability across timescales, we provide methods that may serve as a baseline for future studies with different models using, e.g., different isotopes, different climate archives, or different time periods

Investigating stable oxygen and carbon isotopic variability in speleothem records over the last millennium using multiple isotope-enabled climate models

The incorporation of water isotopologues into the hydrology of general circulation models (GCMs) facilitates the comparison between modeled and measured proxy data in paleoclimate archives. However, the variability and drivers of measured and modeled water isotopologues, as well as the diversity of their representation in different models, are not well constrained. Improving our understanding of this variability in past and present climates will help to better constrain future climate change projections and decrease their range of uncertainty. Speleothems are a precisely datable terrestrial paleoclimate archives and provide well-preserved (semi-)continuous multivariate isotope time series in the lower latitudes and mid-latitudes and are therefore well suited to assess climate and isotope variability on decadal and longer timescales. However, the relationships of speleothem oxygen and carbon isotopes to climate variables are influenced by site-specific parameters, and their comparison to GCMs is not always straightforward. Here we compare speleothem oxygen and carbon isotopic signatures from the Speleothem Isotopes Synthesis and Analysis database version 2 (SISALv2) to the output of five different water-isotope-enabled GCMs (ECHAM5-wiso, GISSE2-R, iCESM, iHadCM3, and isoGSM) over the last millennium (850–1850 CE). We systematically evaluate differences and commonalities between the standardized model simulation outputs. The goal is to distinguish climatic drivers of variability for modeled isotopes and compare them to those of measured isotopes. We find strong regional differences in the oxygen isotope signatures between models that can partly be attributed to differences in modeled surface temperature. At low latitudes, precipitation amount is the dominant driver for stable water isotope variability; however, at cave locations the agreement between modeled temperature variability is higher than for precipitation variability. While modeled isotopic signatures at cave locations exhibited extreme events coinciding with changes in volcanic and solar forcing, such fingerprints are not apparent in the speleothem isotopes. This may be attributed to the lower temporal resolution of speleothem records compared to the events that are to be detected. Using spectral analysis, we can show that all models underestimate decadal and longer variability compared to speleothems (albeit to varying extents). We found that no model excels in all analyzed comparisons, although some perform better than the others in either mean or variability. Therefore, we advise a multi-model approach whenever comparing proxy data to modeled data. Considering karst and cave internal processes, e.g., through isotope-enabled karst models, may alter the variability in speleothem isotopes and play an important role in determining the most appropriate model. By exploring new ways of analyzing the relationship between the oxygen and carbon isotopes, their variability, and co-variability across timescales, we provide methods that may serve as a baseline for future studies with different models using, e.g., different isotopes, different climate archives, or different time periods