Testing the effects of oxidative stress on genomic recombination in the honey bee, Apis mellifera

It has become increasingly evident that genomic recombination is an evolved trait that varies between and within species. The honey bee has an extremely high genomic recombination rate but the responsible mechanisms have not been studied. Based on the hypothesis that meiotic recombination and DNA damage repair share common mechanisms in honey bees, I predicted that oxidative stress leads to a further increase in recombination rate. This prediction was directly tested by subjecting honey bee queens to oxidative stress by paraquat injection and measuring the rates of genomic recombination in select genome intervals of their offspring before and after injection. Of 27 intervals compared only 13 experienced an increase in the rate of recombination in the post-injection sample set as compared to the pre-injection set, suggesting no significant experimental effect. This result was confirmed when the analysis was restricted to the 16 intervals whose pre-injection recombination fractions were within ±8% of the value that was predicted based on a pre-existing linkage map. Intervals did not see consistent upregulation in all colony sample sets where upregulation occurred either. Overall the evidence does not support the hypothesis that oxidative stress induces an increase in the rate of genomic recombination

An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI≥30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI≥30 kg/m(2) (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI\u3e30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI\u3e30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN

The Effect of ACACB cis-Variants on Gene Expression and Metabolic Traits

Acetyl Coenzyme A carboxylase β (ACACB) is the rate-limiting enzyme in fatty acid oxidation, and continuous fatty acid oxidation in Acacb knock-out mice increases insulin sensitivity. Systematic human studies have not been performed to evaluate whether ACACB variants regulate gene expression and insulin sensitivity in skeletal muscle and adipose tissues. We sought to determine whether ACACB transcribed variants were associated with ACACB gene expression and insulin sensitivity in non-diabetic African American (AA) and European American (EA) adults.ACACB transcribed single nucleotide polymorphisms (SNPs) were genotyped in 105 EAs and 46 AAs whose body mass index (BMI), lipid profiles and ACACB gene expression in subcutaneous adipose and skeletal muscle had been measured. Allelic expression imbalance (AEI) was assessed in lymphoblast cell lines from heterozygous subjects in an additional EA sample (n = 95). Selected SNPs were further examined for association with insulin sensitivity in a cohort of 417 EAs and 153 AAs.ACACB transcribed SNP rs2075260 (A/G) was associated with adipose ACACB messenger RNA expression in EAs and AAs (p = 3.8×10(-5), dominant model in meta-analysis, Stouffer method), with the (A) allele representing lower gene expression in adipose and higher insulin sensitivity in EAs (p = 0.04). In EAs, adipose ACACB expression was negatively associated with age and sex-adjusted BMI (r = -0.35, p = 0.0002).Common variants within the ACACB locus appear to regulate adipose gene expression in humans. Body fat (represented by BMI) may further regulate adipose ACACB gene expression in the EA population

Phospholipid Biosynthesis Genes and Susceptibility to Obesity: Analysis of Expression and Polymorphisms

<div><p>Recent studies have identified links between phospholipid composition and altered cellular functions in animal models of obesity, but the involvement of phospholipid biosynthesis genes in human obesity are not well understood. We analyzed the transcript of four phospholipid biosynthesis genes in adipose and muscle from 170 subjects. We examined publicly available genome-wide association data from the GIANT and MAGIC cohorts to investigate the association of SNPs in these genes with obesity and glucose homeostasis traits, respectively. Trait-associated SNPs were genotyped to evaluate their roles in regulating expression in adipose. In adipose tissue, expression of <i>PEMT</i>, <i>PCYT1A</i>, and <i>PTDSS2</i> were positively correlated and <i>PCYT2</i> was negatively correlated with percent fat mass and body mass index (BMI). Among the polymorphisms in these genes, SNP rs4646404 in <i>PEMT</i> showed the strongest association (p = 3.07E-06) with waist-to-hip ratio (WHR) adjusted for BMI. The WHR-associated intronic SNP rs4646343 in the <i>PEMT</i> gene showed the strongest association with its expression in adipose. Allele “C” of this SNP was associated with higher WHR (p = 2.47E-05) and with higher expression (p = 4.10E-04). Our study shows that the expression of <i>PEMT</i> gene is high in obese insulin-resistant subjects. Intronic <i>cis</i>-regulatory polymorphisms may increase the genetic risk of obesity by modulating <i>PEMT</i> expression.</p></div

Characteristics of study population.

*<p>, Metabolic traits from FSIVGT evaluation of non-diabetic individuals. S_I, insulin sensitivity index, Units are taken from MINMOD program. C, Caucasian; AA, African American; WHR, waist-to-hip ratio; BMI, body mass index; PFAT, percent of fat mass (measured by DEXA).</p

WHR-associated SNPs in <i>PEMT</i> modulate its transcript level expression in subcutaneous adipose tissue.

*<p>, Allele 1, Trait increasing allele; P, ANOVA P-value for transcript expression level; P adj, statistical significance of genotypic association from univariate analysis of variance using a general linear model (GLM) procedure that included age as covariates and genotype, gender, ethnicity as fixed factors; WHR P-value, P-value for WHR adjusted for BMI as in GIANT data.</p