Causal relationship between basal metabolic rate and kidney function: a bidirectional two-sample mendelian randomization study.

Background: The relationship between basal metabolic rate (BMR) and Chronic kidney disease (CKD) remains unclear and controversial. In this study, we investigated the causal role of BMR in renal injury, and inversely, whether altered renal function causes changes in BMR. Methods: In this two-sample mendelian randomization (MR) study, Genetic data were accessed from published genome-wide association studies (GWAS) for BMR ((n = 454,874) and indices of renal function, i.e. estimated glomerular filtration rate (eGFR) based on creatinine (n =1, 004, 040), CKD (n=480, 698), and blood urea nitrogen (BUN) (n =852, 678) in European. The inverse variance weighted (IVW) random-effects MR method serves as the main analysis, accompanied by several sensitivity MR analyses. We also performed a reverse MR to explore the causal effects of the above indices of renal function on the BMR. Results: We found that genetically predicted BMR was negatively related to eGFR, (ß= -0.032, P = 4.95*10-12). Similar results were obtained using the MR-Egger (ß= -0.040, P = 0.002), weighted median (ß= -0.04, P= 5.35×10-11) and weighted mode method (ß= -0.05, P=9.92×10-7). Higher BMR had a causal effect on an increased risk of CKD (OR =1.36, 95% CI = 1.11-1.66, P =0.003). In reverse MR, lower eGFR was related to higher BMR (ß= -0.64, P = 2.32×10-6, IVW analysis). Bidirectional MR supports no causal association was observed between BMR and BUN. Sensitivity analyses confirmed these findings, indicating the robustness of the results. Conclusion: Genetically predicted high BMR is associated with impaired kidney function. Conversely, genetically predicted decreased eGFR is associated with higher BMR.

Effect of basal metabolic rate on lifespan: a sex-specific Mendelian randomization study.

Observationally, the association of basal metabolic rate (BMR) with mortality is mixed, although some ageing theories suggest that higher BMR should reduce lifespan. It remains unclear whether a causal association exists. In this one-sample Mendelian randomization study, we aimed to estimate the casual effect of BMR on parental attained age, a proxy for lifespan, using two-sample Mendelian randomization methods. We obtained genetic variants strongly (p-value < 5 × 10-8) and independently (r2 < 0.001) predicting BMR from the UK Biobank and applied them to a genome-wide association study of parental attained age based on the UK Biobank. We meta-analyzed genetic variant-specific Wald ratios using inverse-variance weighting with multiplicative random effects by sex, supplemented by sensitivity analysis. A total of 178 and 180 genetic variants predicting BMR in men and women were available for father's and mother's attained age, respectively. Genetically predicted BMR was inversely associated with father's and mother's attained age (years of life lost per unit increase in effect size of genetically predicted BMR, 0.46 and 1.36; 95% confidence interval 0.07-0.85 and 0.89-1.82), with a stronger association in women than men. In conclusion, higher BMR might reduce lifespan. The underlying pathways linking to major causes of death and relevant interventions warrant further investigation.

A bidirectional Mendelian randomization study supports the causal effects of a high basal metabolic rate on colorectal cancer risk.

PURPOSE: We conducted a bidirectional two-sample Mendelian randomization (MR) study to determine whether genetically predicted basal metabolic rate (BMR) was a causal risk factor for colorectal cancer (CRC) or whether a genetically predicted CRC risk can influence the BMR level (i.e., reverse causation). METHODS: We employed 1,040 genetic variants as proxies for BMR to obtain effect estimates on CRC risk. Another 58 CRC-associated variants were used to estimate effects on BMR levels. Stratified analysis by tumor site was used to examine the causal associations between BMR and colon/rectal cancer risk. RESULTS: The inverse variance weighted (IVW) method indicated a significant causal effect of genetically determined BMR on CRC risk (ORSD = 1.27, 95% CI = 1.07-1.51). No significant reverse causal association was identified between genetically increased CRC risk and BMR levels [IVW (ß = 0, 95% CI = -0.01 to 0)]. The results of MR-Egger and the weighted median method were consistent with the IVW method. Stratified analysis by CRC sites identified significant causal associations between BMR and colon cancer [IVW (ORSD = 1.45, 95% CI = 1.16-1-80)], and null evidence of a causal association between BMR and rectal cancer risk was found (p > 0.05). CONCLUSION: Our findings add to the current literature by validating a positive relationship between high BMR levels and CRC risk instead of reverse causality. The genetically predicted BMR level was causally associated with colon cancer risk but not rectal cancer risk.

Interaction of MC4R rs17782313 variants and dietary carbohydrate quantity and quality on basal metabolic rate and general and central obesity in overweight/obese women: a cross-sectional study.

BACKGROUND: Recent studies have shown that dietary carbohydrate quantity and quality as well as genetic variants may contribute to determining the metabolic rate and general and central obesity. This study aimed to examine interactions between melanocortin 4 receptor gene (MC4R) rs17782313 and dietary carbohydrate intake, glycemic index (GI), and glycemic load (GL) on body mass index (BMI), waist circumferences (WC), basal metabolic rate (BMR), and BMR/kg in overweight/obese women. METHODS: A total of 282 Iranian women (BMI ≥ 25) aged 18-56 years were enrolled in this cross-sectional study. All participants were assessed for blood parameters, body composition, BMR, and dietary intake. Dietary carbohydrate intake, GI, and GL were determined using a valid, reliable 147-item food frequency questionnaire. MC4R rs17782313 was genotyped by the restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: After adjustment for age and energy intake, significant interactions were observed between carbohydrate intake and MC4R rs17782313 in terms of BMI (P Interaction = 0.007), WC (P Interaction = 0.02), and BMR/kg (P Interaction = 0.003) in this way that higher carbohydrate intake, compared with lower intake, was associated with an increase in BMI and WC for individuals with C allele carriers (TC + CC genotypes), while related to an increase in BMR/kg for those carrying the TT genotype. No significant interaction was found between MC4R rs17782313 and GI and GL on BMI, WC, BMR/kg, and BMR. CONCLUSIONS: Interactions between the MC4R rs17782313 and carbohydrate intake probably can have an effect on BMI, WC, and BMR/kg in overweight/obese women.

Basal metabolic rate and risk of multiple sclerosis: a Mendelian randomization study.

To determine the relationship between basal metabolic rate (BMR) and multiple sclerosis (MS) susceptibility, we analyzed genome-wide association study (GWAS) summary statistics data from the International Multiple Sclerosis Genetics Consortium on a total of 115,803 participants of European descent, including 47,429 patients with MS and 68,374 controls. We selected 378 independent genetic variants strongly associated with BMR in a GWAS involving 454,874 participants as instrumental variables to examine a potential causal relationship between BMR and MS. A genetically predicted higher BMR was associated with a greater risk of MS (odds ratio [OR]: 1.283 per one standard deviation increase in BMR, 95% confidence interval [CI]: 1.108-1.486, P = 0.001). Moreover, we used the lasso method to eliminate heterogeneity (Q statistic = 384.58, P = 0.370). There was no pleiotropy in our study and no bias was found in the sensitivity analysis using the leave-one-out test. We provide novel evidence that a higher BMR is an independent causal risk factor in the development of MS. Further work is warranted to elucidate the potential mechanisms.

Association Between Adipose Tissue Proton Density Fat Fraction, Resting Metabolic Rate and FTO Genotype in Humans.

Background: The difference of proton density fat fraction (PDFF) between supraclavicular and gluteal adipose tissue might indicate the presence of brown adipose tissue (BAT). Aim of this cross-sectional study was to investigate the association between PDFF over the supraclavicular fat region as a proxy of BAT proportion and resting metabolic rate (RMR). In addition, the association between the single nucleotide polymorphism (SNP) rs1421085 at the fat mass and obesity associated (FTO) gene locus and both PDFF and RMR was investigated. Methods: Anthropometric, clinical, and lifestyle data from 92 healthy adults (66.3% females, mean age: 36.2 ± 13.0 years, mean body mass index: 24.9 ± 5.4 kg/m2) were included in the analysis. The RMR was measured by indirect calorimetry. The magnetic resonance imaging (MRI) was used for the measurement of visceral and subcutaneous adipose tissue (VAT, SAT) volumes and for the measurement of adipose tissue PDFF. Results: Mean RMR of the whole group was 1 474.8 ± 242.2 kcal. Genotype data was available for 90 participants. After adjustment for age, sex, weight change and fat-free mass (FFM), no association was found between supraclavicular PDFF (p = 0.346) and gluteal PDFF (p = 0.252), respectively, and RMR, whereas statistically significant evidence for a negative association between delta PDFF (difference between gluteal PDFF and supraclavicular PDFF) and RMR (p = 0.027) was obtained. No statistically significant evidence was observed for per FTO risk allele change in RMR, gluteal and supraclavicular PDFF maps or volumes of VAT and SAT. Conclusions: Supraclavicular PDFF as a surrogate marker of BAT presence is not a determinant of RMR under basal conditions. In the present study, the FTO rs1421085 variant is not associated with either RMR or PDFF. Further studies are needed to elucidate the effect of BAT on RMR.

A quantitative genetics perspective on the body-mass scaling of metabolic rate.

Widely observed allometric scaling (log-log slope<1) of metabolic rate (MR) with body mass (BM) in animals has been frequently explained using functional mechanisms, but rarely studied from the perspective of multivariate quantitative genetics. This is unfortunate, given that the additive genetic slope (bA) of the MR-BM relationship represents the orientation of the 'line of least genetic resistance' along which MR and BM may most likely evolve. Here, we calculated bA in eight species. Although most bA values were within the range of metabolic scaling exponents reported in the literature, uncertainty of each bA estimate was large (only one bA was significantly lower than 3/4 and none were significantly different from 2/3). Overall, the weighted average for bA (0.667±0.098 95% CI) is consistent with the frequent observation that metabolic scaling exponents are negatively allometric in animals (b<1). Although bA was significantly positively correlated with the phenotypic scaling exponent (bP) across the sampled species, bP was usually lower than bA, as reflected in a (non-significantly) lower weighted average for bP (0.596±0.100). This apparent discrepancy between bA and bP resulted from relatively shallow MR-BM scaling of the residuals [weighted average residual scaling exponent (be)=0.503±0.128], suggesting regression dilution (owing to measurement error and within-individual variance) causing a downward bias in bP. Our study shows how the quantification of the genetic scaling exponent informs us about potential constraints on the correlated evolution of MR and BM, and by doing so has the potential to bridge the gap between micro- and macro-evolutionary studies of scaling allometry.

Osteogenesis Imperfecta: The Impact of Genotype and Clinical Phenotype on Adiposity and Resting Energy Expenditure.

CONTEXT: Mutations in type I collagen or collagen-related proteins cause osteogenesis imperfecta (OI). Energy expenditure and body composition in OI could reflect reduced mobility or intrinsic defects in osteoblast differentiation increasing adipocyte development. OBJECTIVE: This study compares adiposity and resting energy expenditure (REE) in OI and healthy controls (HC), for OI genotype- and Type-associated differences. METHODS: We studied 90 participants, 30 with OI (11 COL1A1 Gly, 8 COL1A2 Gly, 4 COL1A1 non-Gly, 1 COL1A2 non-Gly, 6 non-COL; 8 Type III, 16 Type IV, 4 Type VI, 1 Type VII, 1 Type XIV) and 60 HC with sociodemographic characteristics/BMI/BMIz similar to the OI group. Participants underwent dual-energy x-ray absorptiometry to determine lean mass and fat mass percentage (FM%) and REE. FM% and REE were compared, adjusting for covariates, to examine the relationship of OI genotypes and phenotypic Types. RESULTS: FM% did not differ significantly in all patients with OI vs HC (OI: 36.6% ± 1.9%; HC: 32.7% ± 1.2%; P = 0.088). FM% was, however, greater than HC for those with non-COL variants (P = 0.016). FM% did not differ from HC among OI Types (P values > 0.05).Overall, covariate-adjusted REE did not differ significantly between OI and HC (OI: 1376.5 ± 44.7 kcal/d; HC: 1377.0 ± 96 kcal/d; P = 0.345). However, those with non-COL variants (P = 0.016) and Type VI OI (P = 0.04) had significantly lower REE than HC. CONCLUSION: Overall, patients with OI did not significantly differ in either extra-marrow adiposity or REE from BMI-similar HC. However, reduced REE among those with non-COL variants may contribute to greater adiposity.

Variants of the cry 1 gene may influence the effect of fat intake on resting metabolic rate in women with overweight of obesity: a cross-sectional study.

BACKGROUND: Previous studies have shown that the minor allele (C allele) for Cry 1 rs2287161, may be associated with increased risk of cardiovascular diseases (CVDs). Low resting metabolic rate (RMR) caused by the diet has been shown to have, potentially, unfavorable effects on obesity. This study sought to investigate the interactions between the Cry 1 Gene and fat intake on RMR in women with overweight of obesity. METHODS: This comparative cross-sectional study was conducted on 377 Iranian women with overweight of obesity. A food frequency questionnaire (FFQ), with 147 items, was used to assess dietary intake. Individuals were categorized into two groups based on the rs2287161 genotype. Body composition, dietary intake, and RMR were assessed for all participants. RESULTS: There was a significant difference between genotypes for fasting blood sugar (FBS) (P = 0.04), fat free mass (FFM) (P = 0.0009), RMR per FFM (P = 0.05), RMR per body mass index (BMI) (P = 0.02), and RMR deviation (P = 0.01). Our findings also showed significant interactions between total fat and C allele carrier group on RMR per kg body weight, RMR per body surface area (BSA), RMR per FFM, and RMR deviation (P for interaction < 0.1), in addition to a significant interaction between CC + CG group genotype and polyunsaturated fatty acids (PUFA) intake on RMR per BMI (P for interaction =0.00) and RMR per kg (P for interaction = 0.02) and RMR per BSA (P = 0.07), compared to the GG group, after control for confounder factors. CONCLUSION: These results highlight that dietary compositions, gene variants, and their interaction, should be acutely considered in lower RMR.

Repeatability and heritability of resting metabolic rate in a long-lived amphibian.

Resting metabolic rate (RMR), i.e. spent energy necessary to maintain basic life functions, is a basic component of energy budget in ectotherms. The evolution of RMR through natural selection rests on the premise of its non-zero repeatability and heritability, i.e. consistent variation within individual lifetimes and resemblance between parents and their offspring, respectively. Joint estimates of RMR repeatability and heritability are missing in ectotherms, however, which precludes estimations of the evolutionary potential of this trait. We examined RMR repeatability and heritability in a long-lived ectotherm, the alpine newt (Ichthyosaura alpestris). Individual RMR was repeatable over both six-month (0.28 ±â€¯0.09 [SE]) and five-year (0.16 ±â€¯0.07) periods. While there was no resemblance between parent and offspring RMR (0.21 ±â€¯0.34), the trait showed similarity among offspring within families (broad-sense heritability; 0.25 ±â€¯0.09). Similar repeatability and broad-sense heritability values in parental and offspring generations, respectively, and non-conclusive narrow-sense heritability suggest the contribution of non-additive genetic factors to total phenotypic variance in this trait. We conclude that RMR evolutionary trajectories are shaped by other processes than natural selection in this long-lived ectotherm.

Growth Performance and Transcriptomic Response of Warm-Acclimated Hybrid Abalone Haliotis rufescens (♀) × H. corrugata (♂).

Along the Pacific coast of the Baja California Peninsula (Mexico), abalone represents one of the most lucrative fisheries. As wild populations are currently depleted, abalone farm production aims to balance the decreasing populations with the increasing demand. The Mexican abalone aquaculture is almost entirely based on red abalone (Haliotis rufescens). However, the increasing frequency of extreme temperature events is hampering this activity. The use interspecific hybrids can potentially improve abalone culture, as species have differences in their thermal tolerance. Therefore, the hybrid progeny between H. rufescens (♀) and pink abalone H. corrugata (♂), a temperate and a warmer water abalone species, respectively, will naturally support higher temperature. To test this hypothesis, growth rate, mortality and metabolic rate of both pure (RR) and hybrid abalone (RP) were assessed under the H. rufescens' optimum (18 °C) and thermally stressed (22 °C) conditions. To unveil the molecular pathways involved in the heat response, transcriptional profiling of both crosses was also investigated. At high temperature, we observed constrained growth and survival in RR while RP showed a significant increase in both rates, supporting the improved performance of the hybrid compared. These results match with the transcriptional profiling of hybrids showing higher expression of genes involved in growth and calcification, whereas in the pure red progeny, the transcriptional profile was mainly associated with the regulation of necroptosis process. Our results may contribute to propose new management plans to increase farm abalone production in Baja California.

Quantifying selection on standard metabolic rate and body mass in Drosophila melanogaster.

Standard metabolic rate (SMR), defined as the minimal energy expenditure required for self-maintenance, is a key physiological trait. Few studies have estimated its relationship with fitness, most notably in insects. This is presumably due to the difficulty of measuring SMR in a large number of very small individuals. Using high-throughput flow-through respirometry and a Drosophila melanogaster laboratory population adapted to a life cycle that facilitates fitness measures, we quantified SMR, body mass, and fitness in 515 female and 522 male adults. We used a novel multivariate approach to estimate linear and nonlinear selection differentials and gradients from the variance-covariance matrix of fitness, SMR, and body mass, allowing traits specific covariates to be accommodated within a single model. In males, linear selection differentials for mass and SMR were positive and individually significant. Selection gradients were also positive but, despite substantial sample sizes, were nonsignificant due to increased uncertainty given strong SMR-mass collinearity. In females, only nonlinear selection was detected and it appeared to act primarily on body size, although the individual gradients were again nonsignificant. Selection did not differ significantly between sexes although differences in the fitness surfaces suggest sex-specific selection as an important topic for further study.

Sub-nanowatt resolution direct calorimetry for probing real-time metabolic activity of individual C. elegans worms.

Calorimetry has been widely used in metabolic studies, but direct measurements from individual small biological model organisms such as C. elegans or isolated single cells have been limited by poor sensitivity of existing techniques and difficulties in resolving very small heat outputs. Here, by careful thermal engineering, we developed a robust, highly sensitive and bio-compatible calorimetric platform that features a resolution of ~270 pW-more than a 500-fold improvement over the most sensitive calorimeter previously used for measuring the metabolic heat output of C. elegans. Using this calorimeter, we demonstrate time-resolved metabolic measurements of single C. elegans worms from larval to adult stages. Further, we show that the metabolic output is significantly lower in long-lived C. elegans daf-2 mutants. These demonstrations clearly highlight the broad potential of this tool for studying the role of metabolism in disease, development and aging of small model organisms and single cells.

Characterization of basal and estrogen-regulated antisense transcription in breast cancer cells: Role in regulating sense transcription.

Estrogen-responsive breast cancer cells exhibit both basal and estrogen-regulated transcriptional programs, which lead to the transcription of many different transcription units (i.e., genes), including those that produce coding and non-coding sense (e.g., mRNA, lncRNA) and antisense (i.e., asRNA) transcripts. We have previously characterized the global basal and estrogen-regulated transcriptomes in estrogen receptor alpha (ERα)-positive MCF-7 breast cancer cells. Herein, we have mined genomic data to define three classes of antisense transcription in MCF-7 cells based on where their antisense transcription termination sites reside relative to their cognate sense mRNA and lncRNA genes. These three classes differ in their response to estrogen treatment, the enrichment of a number of genomic features associated with active promoters (H3K4me3, RNA polymerase II, open chromatin architecture), and the biological functions of their cognate sense genes as analyzed by DAVID gene ontology. We further characterized two estrogen-regulated antisense transcripts arising from the MYC gene in MCF-7 cells, showing that these antisense transcripts are 5'-capped, 3'-polyadenylated, and localized to different compartments of the cell. Together, our analyses have revealed distinct classes of antisense transcription correlated to different biological processes and response to estrogen stimulation, uncovering another layer of hormone-regulated gene regulation.

Improved polygenic prediction by Bayesian multiple regression on summary statistics.

Accurate prediction of an individual's phenotype from their DNA sequence is one of the great promises of genomics and precision medicine. We extend a powerful individual-level data Bayesian multiple regression model (BayesR) to one that utilises summary statistics from genome-wide association studies (GWAS), SBayesR. In simulation and cross-validation using 12 real traits and 1.1 million variants on 350,000 individuals from the UK Biobank, SBayesR improves prediction accuracy relative to commonly used state-of-the-art summary statistics methods at a fraction of the computational resources. Furthermore, using summary statistics for variants from the largest GWAS meta-analysis (n ≈ 700, 000) on height and BMI, we show that on average across traits and two independent data sets that SBayesR improves prediction R2 by 5.2% relative to LDpred and by 26.5% relative to clumping and p value thresholding.

Mitochondria, sex and variation in routine metabolic rate.

Variation in the metabolic costs associated with organismal maintenance may play a key role in determining fitness, and thus these differences among individuals are likely to be subject to natural selection. Although the evolvability of maintenance metabolism depends on its underlying genetic architecture, relatively little is known about the nature of genetic variation that underlies this trait. To address this, we measured variation in routine metabolic rate (MO2routine ), an index of maintenance metabolism, within and among three populations of Atlantic killifish, Fundulus heteroclitus, including a population from a region of genetic admixture between two subspecies. Polygenic association tests among individuals from the admixed population identified 54 single nucleotide polymorphisms (SNPs) that were associated with MO2routine , and these SNPs accounted for 43% of interindividual variation in this trait. However, genetic associations with MO2routine involved different SNPs if females and males were analysed separately, and there was a sex-dependent effect of mitochondrial genotype on variation in routine metabolism. These results imply that there are sex-specific genetic mechanisms, and potential mitonuclear interactions, that underlie variation in MO2routine . Additionally, there was evidence for epistatic interactions between 17% of the possible pairs of trait-associated SNPs, suggesting that epistatic effects on MO2routine are common. These data demonstrate not only that phenotypic variation in this ecologically important trait has a polygenic basis with considerable epistasis among loci, but also that these underlying genetic mechanisms, and particularly the role of mitochondrial genotype, may be sex-specific.

Stimulation of histamine H4 receptor participates in cold-induced browning of subcutaneous white adipose tissue.

Although many studies have shown that histamine and its signaling regulate energy homeostasis through the central nervous system, their roles in adipose tissues remain poorly understood. Here, we identified that the histamine H4 receptor (HrH4) was highly expressed in adipocytes at a level higher than that of the other three receptors (i.e., HrH1, HrH2, and HrH3). The HrH4 expression in adipocytes responded to cold through thermogenesis and lipolysis, supported by results from both mouse and cell models. When HrH4 expression was knocked down in the subcutaneous white adipose tissue (scWAT), browning and lipolysis effects triggered by cold were ablated, and the oxygen consumption was also lowered both at the normal and cold conditions. Moreover, mice exhibited browned scWAT, accelerated metabolic rates, and tolerance to hypothermia when 4-methylhistamine (4MH), a selective HrH4 agonist, was adjacently injected to the scWAT. Consistent with these findings, 4MH also triggered the browning and lipolytic effects in cultured C3H10T1/2 adipocytes. Mechanically, we demonstrated that p38/MAPK and ERK/MAPK pathways were involved in these processes. In conclusion, our findings have uncovered an effective role of HrH4 in adipose tissue browning.

Oligo-carrageenan kappa increases glucose, trehalose and TOR-P and subsequently stimulates the expression of genes involved in photosynthesis, and basal and secondary metabolisms in Eucalyptus globulus.

BACKGROUND: It has been previously shown that oligo-carrageenan (OC) kappa increases growth, photosynthesis and activities of enzymes involved in basal and secondary metabolisms in Eucalyptus globulus. However, it is not known whether OC kappa may induce the activation of TOR pathway and the increase in expression of genes encoding proteins involved in photosynthesis and enzymes of basal and secondary metabolisms. RESULTS: E. globulus trees were sprayed on leaves with water (control) or with OC kappa 1 mg mL- 1, once a week, four times in total, and cultivated for 17 additional weeks (21 weeks in total). Treated trees showed a higher level of net photosynthesis than controls, beginning at week 3, a higher height, beginning at week 9, and those differences remained until week 21. In addition, treated trees showed an increase in the level of glucose beginning at week 1, trehalose at weeks 1-3, and in TOR-P level at week 1-2. On the other hand, transcripts encoding proteins involved in photosynthesis, and enzymes involved in glucose accumulation, C, N and S assimilation, and synthesis of secondary metabolites began at weeks 3-4 and with additional peaks at weeks 5-6, 8-11,13-14 and 17-19. Thus, OC kappa induced initial increases in glucose, trehalose and TOR-P levels that were followed by oscillatory increases in the level of transcripts coding for proteins involved in photosynthesis, and in basal and secondary metabolisms suggesting that initial increases in glucose, trehalose and TOR-P may trigger activation of gene expression. CONCLUSIONS: The stimulation of growth induced by OC kappa in E. globulus trees is due, at least in part, to activation of TOR pathway and the increase in expression of genes encoding proteins involved in photosynthesis and enzymes of basal metabolism.

A novel polymorphism in the fatty acid desaturase 2 gene (Fads2): A possible role in the basal metabolic rate.

Fatty acyl composition of cell membrane lipids, particularly the abundance of highly unsaturated docosahexaenoic fatty acid (22:6n-3, DHA), is likely to be an important predictor of basal metabolic rate (BMR). Our study was performed using two lines of laboratory mice divergently selected for either high or low BMR. We describe a novel single nucleotide polymorphism in the Fads2 gene encoding Δ6-desaturase, a key enzyme in the metabolic pathways of polyunsaturated fatty acids (PUFAs). The allele frequencies of Fads2 were significantly different in both lines of mice. The analysis of genetic distances revealed that the genetic differentiation between the two studied lines developed significantly faster at the Fads2 locus than it did at neutral loci. Such a pattern suggests that the Fads2 polymorphism is related to the variation in BMR, i.e. the direct target of selection. The Fads2 polymorphism significantly affected abundance of several PUFAs; however, the differences in PUFA composition between lines were compatible with the difference in frequency of Fads2 alleles only for DHA. We hypothesize that the polymorphism in the Fads2 gene affects the BMR through modification of DHA abundance in cell membranes. This may be the first example of a significant link between a polymorphism in a gene responsible for fatty acyl composition and variation in BMR.

A systematic review and meta-analysis reveals pervasive effects of germline mitochondrial replacement on components of health.

BACKGROUND: Mitochondrial replacement, a form of nuclear transfer, has been proposed as a germline therapy to prevent the transmission of mitochondrial diseases. Mitochondrial replacement therapy has been licensed for clinical application in the UK, and already carried out in other countries, but little is known about negative or unintended effects on the health of offspring born using this technique. OBJECTIVE AND RATIONALE: Studies in invertebrate models have used techniques that achieve mitochondrial replacement to create offspring with novel combinations of mitochondrial and nuclear genotype. These have demonstrated that the creation of novel mitochondrial-nuclear interactions can lead to alterations in offspring characteristics, such as development rates, fertility and longevity. However, it is currently unclear whether such interactions could similarly affect the outcomes of vertebrate biomedical studies, which have sought to assess the efficacy of the replacement therapy. SEARCH METHODS: This systematic review addresses whether the effects of mitochondrial replacement on offspring characteristics differ in magnitude between biological (conducted on invertebrate models, with an ecological or evolutionary focus) and biomedical studies (conducted on vertebrate models, with a clinical focus). Studies were selected based on a key-word search in 'Web of Science', complemented by backward searches of reviews on the topic of mitochondrial-nuclear (mito-nuclear) interactions. In total, 43 of the resulting 116 publications identified in the search contained reliable data to estimate effect sizes of mitochondrial replacement. We found no evidence of publication bias when examining effect-size estimates across sample sizes. OUTCOMES: Mitochondrial replacement consistently altered the phenotype, with significant effects at several levels of organismal performance and health, including gene expression, anatomy, metabolism and life-history. Biomedical and biological studies, while differing in the methods used to achieve mitochondrial replacement, showed only marginally significant differences in effect-size estimates (-0.233 [CI: -0.495 to -0.011]), with larger effect-size estimates in biomedical studies (0.697 [CI: 0.450-0.956]) than biological studies (0.462 [CI: 0.287-0.688]). Humans showed stronger effects than other species. Effects of mitochondrial replacement were also stronger in species with a higher basal metabolic rate. Based on our results, we conducted the first formal risk analysis of mitochondrial replacement, and conservatively estimate negative effects in at least one in every 130 resulting offspring born to the therapy. WIDER IMPLICATIONS: Our findings suggest that mitochondrial replacement may routinely affect offspring characteristics across a wide array of animal species, and that such effects are likely to extend to humans. Studies in invertebrate models have confirmed mito-nuclear interactions as the underpinning cause of organismal effects following mitochondrial replacement. This therefore suggests that mito-nuclear interactions are also likely to be contributing to effects seen in biomedical studies, on vertebrate models, whose effect sizes exceeded those of biological studies. Our results advocate the use of safeguards that could offset any negative effects (defining any unintended effect as being negative) mediated by mito-nuclear interactions following mitochondrial replacement in humans, such as mitochondrial genetic matching between donor and recipient. Our results also suggest that further research into the molecular nature of mito-nuclear interactions would be beneficial in refining the clinical application of mitochondrial replacement, and in establishing what degree of variation between donor and patient mitochondrial DNA haplotypes is acceptable to ensure 'haplotype matching'.