Interindividual Variation In Levels Research Articles

THU397 Homeostatic Regulation Of 1,25-dihydroxyvitamin D: Critical Role Of 24-hydroxylation (CYP24A1)

Abstract Disclosure: Z. Shahidzadeh Yazdi: None. E.A. Streeten: Grant Recipient; Self; Regeneron Pharmaceuticals. H.B. Whitlatch: Grant Recipient; Self; Regeneron Pharmaceuticals. M.E. Montasser: Grant Recipient; Self; Regeneron Pharmaceuticals. A.L. Beitelshees: None. S.I. Taylor: Consulting Fee; Self; Ionis Pharmaceuticals Inc. The VITAL study raised substantial questions whether current Endocrine Society guidelines provide optimal criteria to identify patients whose bone health would benefit from vitamin D (VitD) supplements. We investigated the impact of VitD supplements on levels of VitD metabolites and other biomarkers in the context of studying interactions between VitD and canagliflozin. 11 healthy Amish participants with 25-hydroxyvitamin-D (25(OH)D) levels ≤20 ng/mL were recruited in the context of our ongoing pharmacogenomic study of canagliflozin. RESULTS: VitD supplements increased mean levels of 25(OH)D from 16.5±1.6 ng/mL to 44.3±5.5 ng/mL (p=0.0006) and 24,25(OH)2D from 1.0±0.1 ng/mL to 4.3±0.6 ng/mL (p=0.0002). Mean levels of 1,25(OH)2D and PTH were unchanged: 43.8±3.6 vs. 44.9±4.1 pg/mL for 1,25(OH)2D and 47.5±4.8 vs. 48.4±5.1 pg/mL for PTH. We applied mathematical modeling, which suggested that regulation of 24-hydroxylation was the principal mechanism responsible for maintaining 1,25(OH)2D levels within a narrow range in our mildly VitD deficient research participants [25(OH)D levels: 10-20 ng/mL]. When 25(OH)D levels were low (<20 ng/mL), 24-hydroxylation was maximally suppressed. Low levels of 24-hydroxylase activity tend to sustain levels of 1,25(OH)2D by decreasing its rate of metabolic clearance. VitD supplementation induced 24-hydroxylase activity by ∼5-fold – reaching a plateau when 25(OH)D levels >60 ng/mL. As suggested in the literature (JCY Tang et al, Sci Rep, 9:6974, 2019), we calculated ratios of 1,25(OH)2D/24,25(OH)2D as an index for the homeostatic response to VitD status. When we plotted the 1,25(OH)2D/24,25(OH)2D ratio as a function of 25(OH)D/1,25(OH)2D, we observed an extremely high degree of correlation (Spearman correlation coefficient of -0.94; p=10-10). DISCUSSION: Clinical assessment of thyroid status provides a highly relevant historical precedent. 50 years ago, thyroid status was assessed by measurement of total serum thyroxine (T4) levels. Diagnostic accuracy was greatly improved when total T4 was replaced by laboratory measurement of either free T4 or TSH (an index of the homeostatic response to thyroid status). Current clinical guidelines recommend assessment of VitD status by measuring total levels of 25(OH)D, which unfortunately are confounded by inter-individual variation in levels of VitD binding proteins (VDBP). We anticipate that diagnostic accuracy would be greatly enhanced if clinicians replaced measurement of total 25(OH)D by laboratory measurements that are not affected by variation in levels of VDBP. By analogy to the approach to clinical assessment of thyroid status, we recommend consideration of VDBP-independent indices of VitD status including 25(OH)D/1,25(OH)2D as an index of VitD stores and 1,25(OH)2D/24,25(OH)2D as an index for the body’s homeostatic response to VitD status. Presentation: Thursday, June 15, 2023

Exploiting Underutilised crops

Exploiting Underutilised crops

Anxiety trajectories: An observational study of women undergoing chemotherapy for breast or gynecological cancer

While anxiety is prevalent among women who undergo chemotherapy for breast or gynecologic cancer, research on its predictors has focused primarily on cross-sectional evaluations or on assessments of anxiety prior to and after receipt of chemotherapy. Few studies have evaluated for predictors of inter-individual variability in levels of anxiety during chemotherapy. This study evaluated for inter-individual differences in anxiety across two cycles of chemotherapy and identified demographic, clinical, symptom, and psychological adjustment (e.g., stress, coping) characteristics associated with initial levels and trajectories of anxiety. Patients with breast (n=530) or gynecologic (n=233) cancer completed the Spielberger State Anxiety Inventory six times over two cycles of chemotherapy. At enrollment, self-report measures were used to assess demographic, symptom, stress, and coping characteristics. Hierarchical linear modeling was used to evaluate for risk factors associated with initial levels and trajectories of state anxiety. At enrollment, demographic, clinical, symptom, and psychological adjustment characteristics associated with inter-individual differences of anxiety were: marital status, functional status, sleep disturbance, cognitive function, global stress, cancer-specific stress, resilience, sense of coherence, and the coping strategies of venting and self-blame. Employment status and morning fatigue were the only characteristics associated with inter-individual differences in the trajectories of anxiety. Denial was the only characteristic associated with both initial levels and the trajectories of anxiety. A variety of patient characteristics predicted initial levels of anxiety. Fewer characteristics predicted trajectories of anxiety. Identification of specific risk factors, such as avoidant coping, suggests the need for targeted interventions among higher-risk patients.

Opioids and obstructive sleep apnea.

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

Quantitative Measurement of Anti-SARS-CoV-2 Antibodies: Analytical and Clinical Evaluation.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Molecular-based testing is used to diagnose COVID-19, and serologic testing of antibodies specific to SARS-CoV-2 is used to detect past infection. While most serologic assays are qualitative, a quantitative serologic assay was recently developed that measures antibodies against the S protein, the target of vaccines. Quantitative antibody determination may help determine antibody titer and facilitate longitudinal monitoring of the antibody response, including antibody response to vaccines. We evaluated the quantitative Roche Elecsys anti-SARS-CoV-2 S assay. Specimens from 167 PCR-positive patients and 103 control specimens were analyzed using the Elecsys anti-SARS-CoV-2 S assay on the cobas e411 (Roche Diagnostics). Analytical evaluation included assessing linearity, imprecision, and analytical sensitivity. Clinical evaluation included assessing clinical sensitivity, specificity, cross-reactivity, positive predictive value (PPV), negative predictive value (NPV), and serial sampling from the same patient. The Elecsys anti-SARS-CoV-2 S assay exhibited its highest sensitivity (84.0%) at 15 to 30 days post-PCR positivity and exhibited no cross-reactivity, a specificity and PPV of 100%, and an NPV between 98.3% and 99.8% at ≥14 days post-PCR positivity, depending on the seroprevalence estimate. Imprecision was <2% at 9.06 U/ml across 6 days, the negative quality control (QC) was consistently negative (<0.40 U/ml), the manufacturer's claimed limit of quantitation of 0.40 U/ml was verified, and linearity across the analytical measuring range was observed, except at the low end (<20 U/ml). Lastly, antibody response showed high interindividual variation in level and time of peak antibody titer and trends over time.

Long-term behavioural rewriting of maladaptive drinking memories via reconsolidation-update mechanisms.

Alcohol use disorders can be conceptualised as a learned pattern of maladaptive alcohol-consumption behaviours. The memories encoding these behaviours centrally contribute to long-term excessive alcohol consumption and are therefore an important therapeutic target. The transient period of memory instability sparked during memory reconsolidation offers a therapeutic window to directly rewrite these memories using targeted behavioural interventions. However, clinically-relevant demonstrations of the efficacy of this approach are few. We examined key retrieval parameters for destabilising naturalistic drinking memories and the ability of subsequent counterconditioning to effect long-term reductions in drinking. Hazardous/harmful beer-drinking volunteers (N = 120) were factorially randomised to retrieve (RET) or not retrieve (No RET) alcohol reward memories with (PE) or without (No PE) alcohol reward prediction error. All participants subsequently underwent disgust-based counterconditioning of drinking cues. Acute responses to alcohol were assessed pre- and post-manipulation and drinking levels were assessed up to 9 months. Greater long-term reductions in drinking were found when counterconditioning was conducted following retrieval (with and without PE), despite a lack of short-term group differences in motivational responding to acute alcohol. Large variability in acute levels of learning during counterconditioning was noted. 'Responsiveness' to counterconditioning predicted subsequent responses to acute alcohol in RET + PE only, consistent with reconsolidation-update mechanisms. The longevity of behavioural interventions designed to reduce problematic drinking levels may be enhanced by leveraging reconsolidation-update mechanisms to rewrite maladaptive memory. However, inter-individual variability in levels of corrective learning is likely to determine the efficacy of reconsolidation-updating interventions and should be considered when designing and assessing interventions.

Exploring Overlap of Feather Molting and Migration in Tundra Swans Using δ2H Analysis

AbstractDetermining the processes that shape the relative timing of energetically-costly events in the annual cycle of migrating birds is important to our understanding of avian phenology and ecology. We paired satellite tracking and hydrogen stable isotope analysis (δ2H) to examine the relative timing of two such events – migration and feather molting – in tundra swans from four breeding areas in Alaska, USA. Our results show a trend of increasing intra-individual variability in breast feather δ2H values with increasing migration distance, suggesting the overlap of breast feather molting and migration. However, when individual samples were pooled by breeding area, the δ2H values of breast and head feathers showed no trend with migration distance, presumably resulting from high levels of inter-individual variability in δ2H values within each breeding area. We explore potential reasons for this variability, propose potential mechanisms influencing feather δ2H values of tundra swans, and recommend further research into methods for exploring the temporal configuration of events in the annual cycle of migrating birds.

Epigenética: la relación del medio ambiente con el genoma y su influencia en la salud mental.

El estudio del genoma humano, cuando efectuado solo a través de la información secuencial de ADN, no explica del todo el alto nivel de variación inter-individual usualmente observado. Es la epigenética la que permite explicar aquellas variaciones de expresión génica como un proceso reversible y hereditario en el corto plazo, bajo la influencia del medio ambiente durante diversas etapas del desarrollo y la edad adulta, sin modificar la secuencia genética. Las alteraciones epigenéticas están siendo ya incorporadas como elementos valiosos en la posible identificación de biomarcadores. Además, debido a su naturaleza reversible, pueden constituirse en factores de mejoría de síntomas de enfermedad mediante el uso de enfoques terapéuticos. El presente artículo explica los mecanismos de inhibición de la expresión génica, su relación con el medio ambiente, la dieta y su influencia en la evolución, la ocurrencia de enfermedades, la conducta humana y la salud mental.

Measures of Strength and Jump Performance Can Predict 30-m Sprint Time in Rugby Union Players.

Furlong, L-AM, Harrison, AJ, and Jensen, RL. Measures of strength and jump performance can predict 30-m sprint time in Rugby Union players. J Strength Cond Res 35(9): 2579-2583, 2021-Performance and fitness monitoring in Rugby Union often include jumping, sprinting, and strength tests, but repeatability of and relationships between these measures are unclear. The level of interindividual variability in these relationships and their sprint time predictive capabilities are also unknown. This study examined the reliability of, and relationship between, countermovement (CMJJH), squat (SJJH), and rebound (RBJJH) jump heights, rebound jump contact time (RBJCT), estimated 1 repetition maximum back squat relative to body mass (SQBM), and reactive strength index (RSI) to 30-m sprint time of subelite, semiprofessional Rugby Union players. Measurement reliability was very good, with high average intraclass correlation coefficients (≥0.9) and low coefficient of variation (<10.1%). All variables were significantly (p < 0.01) correlated to each other (r > 0.575), except for SQBM (only related to CMJJH, r = 0.621) and RBJCT (only related to RSI, r = -0.727). SJJH and SQBM were the strongest and most consistent predictors of time to 30 m (R = 0.754 ± 0.081; SEE = 0.166 ± 0.025), but variability in SEE magnitude was observed across the group during bootstrapping. Cross-validation showed a mean difference between actual and predicted 30 m times equivalent to 0.22% of the group average time to 30 m. These results support the importance of multiple aspects of fitness training in Rugby Union players for improving performance in short-duration sprinting activities, but highlight the individual nature of their relative importance. Measures of strength and power can be used to predict short sprint performance by the strength and conditioning professional.

Inter-individual variability and consistency of saccade adaptation in oblique saccades: Amplitude increase and decrease in the horizontal or vertical saccade component

Despite changes in the physical structures controlling the eyes, saccades, the rapid eye movements used to explore the visual environment, remain accurate throughout the lifetime. The process underlying this sensorimotor adaptation is studied using a double step paradigm: an intra-saccadic target displacement introduces a systematic position error which triggers changes in saccadic amplitude or direction across trials. Numerous researches on this saccade adaptation have been conducted, but the level of inter-individual variability and consistency in saccade gain change and how it relates to increase- or decrease-amplitude paradigms is not fully described. We conducted experiments in four groups of 25 participants with 800 trials per participant, including 200 baseline trials and 200 recovery trials. We used four distinct double-step paradigms that differed by the intra-saccadic target-step leading to either a horizontal (Backward or Forward) or vertical (Upward or Downward) gain modulation. Across experiments 95% of the participants exhibited adaptation, revealing the consistency of this phenomenon. We observed strong inter-individual differences, both in the extent and rate of adaptation, which were not correlated with the individual baseline saccades characteristics. As previously reported, the rates of adaptation were higher for gain decrease than for gain increase experiments but the final extent of adaptation were similar. Our results also support the view that adaptation of oblique saccades occurs where the saccade command is represented as a vector. Finally, at the individual level, we did not observe systematic changes in the saccade metrics in relation to adaptation.

Social Integration and Terminal Decline in Life Satisfaction Among Older Japanese.

Well-being typically exhibits pronounced deteriorations with approaching death, with sizeable interindividual variations in levels and changes. It is less well understood how psychosocial factors contribute to these individual differences. We examined whether and how social integration is associated with terminal trajectories of well-being, indexed as life satisfaction. Data were drawn from 1,119 deceased Japanese participants of a 15-year longitudinal study (age at death: M = 79.2 years; SD = 7.7 years; 43.1% women). Life satisfaction, structural and functional features of social integration (e.g., frequency of contact with family and nonfamily, and perceived overall support, respectively), sociodemographic characteristics, and physical function were assessed. Social integration predicted individual differences in terminal decline in life satisfaction, after controlling for age at death, gender, education, and physical function: More diverse social relationships were associated with higher levels of life satisfaction at 1 year before death. In addition, individuals who exhibited more decline in social participation and perceived less support showed more pronounced decline with increasing proximity of death. This study suggests that social integration plays a protective role in late-life well-being and that sustaining an active social life and supportive social interactions may help mitigate terminal decline in well-being.

Performance comparison of first-order conditional estimation with interaction and Bayesian estimation methods for estimating the population parameters and its distribution from data sets with a low number of subjects

BackgroundExploratory preclinical, as well as clinical trials, may involve a small number of patients, making it difficult to calculate and analyze the pharmacokinetic (PK) parameters, especially if the PK parameters show very high inter-individual variability (IIV). In this study, the performance of a classical first-order conditional estimation with interaction (FOCE-I) and expectation maximization (EM)-based Markov chain Monte Carlo Bayesian (BAYES) estimation methods were compared for estimating the population parameters and its distribution from data sets having a low number of subjects.MethodsIn this study, 100 data sets were simulated with eight sampling points for each subject and with six different levels of IIV (5%, 10%, 20%, 30%, 50%, and 80%) in their PK parameter distribution. A stochastic simulation and estimation (SSE) study was performed to simultaneously simulate data sets and estimate the parameters using four different methods: FOCE-I only, BAYES(C) (FOCE-I and BAYES composite method), BAYES(F) (BAYES with all true initial parameters and fixed ω2), and BAYES only. Relative root mean squared error (rRMSE) and relative estimation error (REE) were used to analyze the differences between true and estimated values. A case study was performed with a clinical data of theophylline available in NONMEM distribution media. NONMEM software assisted by Pirana, PsN, and Xpose was used to estimate population PK parameters, and R program was used to analyze and plot the results.ResultsThe rRMSE and REE values of all parameter (fixed effect and random effect) estimates showed that all four methods performed equally at the lower IIV levels, while the FOCE-I method performed better than other EM-based methods at higher IIV levels (greater than 30%). In general, estimates of random-effect parameters showed significant bias and imprecision, irrespective of the estimation method used and the level of IIV. Similar performance of the estimation methods was observed with theophylline dataset.ConclusionsThe classical FOCE-I method appeared to estimate the PK parameters more reliably than the BAYES method when using a simple model and data containing only a few subjects. EM-based estimation methods can be considered for adapting to the specific needs of a modeling project at later steps of modeling.

Assessment the Exposure Level of Rare Earth Elements in Workers Producing Cerium, Lanthanum Oxide Ultrafine and Nanoparticles.

In order to assess occupational exposure level of 15 rare earth elements (REEs) and identify the associated influence, we used inductively coupled plasma mass spectrometry (ICP-MS) based on closed-vessel microwave-assisted wet digestion procedure to determinate the concentration of Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu in urinary samples obtained from workers producing ultrafine and nanoparticles containing cerium and lanthanum oxide. The results suggest that La and Ce were the primary component, together accounting for 97% of total REEs in workers. The urinary levels of La, and Ce among the workers (6.36, 15.32μg.g-1 creatinine, respectively) were significantly enriched compared to those levels measured in the control subjects (1.52, 4.04μg.g-1 creatinine, respectively) (p<0.05). This study simultaneously identified the associated individual factors, the results indicate that the concentrations in over 5years group (11.64±10.93 for La, 27.83±24.38 for Ce) were significantly elevated compared to 1-5years group (2.58±1.51 for La, 6.87±3.90 for Ce) (p<0.05). Compared the urinary levels of La and Ce at the separation and packaging locations (9.10±9.51 for La, 22.29±21.01 for Ce) with the other locations (2.85±0.98 for La, 6.37±2.12 for Ce), the results show urinary concentrations were significantly higher in workers at separation and packaging locations (p<0.01). Inter-individual variation in levels of La and Ce in urine is the result of multi-factorial comprehensive action. Further researches should focus on the multiple factors contributing to the REEs levels of the occupationally exposed workers.

Upscaling the niche variation hypothesis from the intra- to the inter-specific level.

The "niche variation hypothesis" (NVH) predicts that populations with wider niches should display higher among-individual variability. This prediction originally stated at the intra-specific level may be extended to the inter-specific level: individuals of generalist species may differ to a greater extent than individuals of a specialist species. We tested the NVH at intra- and inter-specific levels based on a large diet database of three large herbivore feces collected in the field and analyzed using DNA metabarcoding. The three herbivores (roe deer Capreolus capreolus, chamois Rupicapra rupicapra and mouflon Ovis musimon) are highly contrasted in terms of sociality (solitary to highly gregarious) and diet. The NVH at the intraspecific level was tested by relating, for the same population, diet breadth and inter-individual variation across the four seasons. Compared to null models, our data supported the NVH both at the intra- and inter-specific levels. Inter-individual variation of the diet of solitary species was not larger than in social species, although social individuals feed together and could therefore have more similar diets. Hence, the NVH better explained diet breadth than other factors such as sociality. The expansion of the population niche of the three species was driven by resource availability, and achieved by an increase in inter-individual variation, and the level of inter-individual variability was larger in the generalist species (mouflon) than in the specialist one (roe deer). This mechanism at the base of the NVH appears at play at different levels of biological organization, from populations to communities.

Brain structure correlates of emotion-based rash impulsivity

Negative urgency (the tendency to engage in rash, ill-considered action in response to intense negative emotions), is a personality trait that has been linked to problematic involvement in several risky and impulsive behaviours, and to various forms of disinhibitory psychopathology, but its neurobiological correlates are poorly understood. Here, we explored whether inter-individual variation in levels of trait negative urgency was associated with inter-individual variation in regional grey matter volumes. Using voxel-based morphometry (VBM) in a sample (n=152) of healthy participants, we found that smaller volumes of the dorsomedial prefrontal cortex and right temporal pole, regions previously linked to emotion appraisal, emotion regulation and emotion-based decision-making, were associated with higher levels of trait negative urgency. When controlling for other impulsivity linked personality traits (sensation seeking, lack of planning/perseverance) and negative emotionality per se (neuroticism), these associations remained, and an additional relationship was found between higher levels of trait negative urgency and smaller volumes of the left ventral striatum. This latter finding mirrors recent VBM findings in an animal model of impulsivity. Our findings offer novel insight into the brain structure correlates of one key source of inter-individual differences in impulsivity.

Ocean Acidification and Fertilization in the Antarctic Sea UrchinSterechinus neumayeri: the Importance of Polyspermy

Ocean acidification (OA), the reduction of the seawater pH as a result of increasing levels of atmospheric CO2, is an important climate change stressor in the Southern Ocean and Antarctic. We examined the impact of OA on fertilization success in the Antarctic sea urchin Sterechinus neumayeri using pH treatment conditions reflective of the current and near-future "pH seascape" for this species: current (control: pH 8.052, 384.1 μatm of pCO2), a high CO2 treatment approximating the 0.2-0.3 unit decrease in pH predicted for 2100 (high CO2: pH 7.830, 666.0 μatm of pCO2), and an intermediate medium CO2 (pH 7.967, 473.4 μatm of pCO2). Using a fertilization kinetics approach and mixed-effect models, we observed significant variation in the OA response between individual male/female pairs (N = 7) and a significant population-level increase (70-100%) in tb (time for a complete block to polyspermy) at medium and high CO2, a mechanism that potentially explains the higher levels of abnormal development seen in OA conditions. However, two pairs showed higher fertilization success with CO2 treatment and a nonsignificant effect. Future studies should focus on the mechanisms and levels of interindividual variability in OA response, so that we can consider the potential for selection and adaptation of organisms to a future ocean.

MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms

High intra- and interindividual variations in the expression levels of the human O6-methylguanine-DNA methyltransferase (MGMT) gene have been observed. This DNA repair enzyme can be a cause of resistance of cancer cells to alkylating chemotherapy. It has been studied the association of single nucleotide polymorphisms (SNPs) of MGMT with the risk for different types of cancer, progression-free survival in patients with cancer treated with alkylating chemotherapy, as well as an effect of SNPs on the MGMT gene expression and activity of the enzyme. SNPs have been suggested to be the factors which influence the levels of interindividual variability of the MGMT expression. Therefore, the aim of this paper was to review the experimental data on SNPs of the human MGMT gene, which are associated with cancer, as well as on location of MGMT-SNPs in regulatory and protein-coding regions of the gene in relation to its regulation. Lots of MGMT SNPs, which could affect the gene expression and result in interindividual MGMT variability or the enzyme resistance to pseudosubstrate inhibitors, have been revealed within the promoter and enhancer regions, the 5'- and 3'-UTRs and introns of the MGMT gene, as well as within the protein-coding region. Many of them may have regulatory effect.

BEYOND COMPARING MEANS: THE USEFULNESS OF ANALYZING INTERINDIVIDUAL VARIATION IN GENE EXPRESSION FOR IDENTIFYING GENES ASSOCIATED WITH CANCER DEVELOPMENT

Identifying genes associated with cancer development is typically accomplished by comparing mean expression values in normal and tumor tissues, which identifies differentially expressed (DE) genes. Interindividual variation (IV) in gene expression is indirectly included in DE gene identification because given the same absolute differences in means, genes with lower variance tend to have lower p-values. We explored the direct use of IV in gene expression to identify candidate genes associated with cancer development. We focused on prostate (PCa) and lung (LC) cancers and compared IV in the expression level of genes shown to be cancer related with that in all other genes in the human genome. Compared with all those other genes, cancer-related genes tended to have greater IV in normal tissues and a greater increase in IV during the transition from normal to tumorous tissue. Genes without significantly different mean expression values between tumor and normal tissues but with greater IV in tumor than in normal tissue (note: the DE-based approach completely ignores those genes) had stronger associations with clinically important features like Gleason score in PCa or tumor histology in LC than all other genes were. Our results suggest that analyzing IV in gene expression level is useful in identifying novel candidate genes associated with cancer development.

Genetic variation shapes protein networks mainly through non-transcriptional mechanisms.

Author SummaryThe level of protein produced by each gene corresponds approximately to the level of mRNA transcript produced by that gene: so high-abundance proteins, like those involved in protein synthesis, are represented by high-abundance transcripts, whereas low-abundance proteins, like those involved in signaling pathways, are represented by low-abundance transcripts. Furthermore, genetic variation can cause variation in transcript levels for the same gene between different individuals. These two observations have led to the assumption that inter-individual variation in transcript levels for any particular gene causes corresponding variation in protein levels. However, this need not be the case, because protein levels could be controlled not only by regulating transcript levels but also by regulating protein translation and stability. Because inter-individual variation in the levels of the transcript for any particular gene is typically less than 3-fold, rather than orders of magnitude, it is possible that the predominant cause of inter-individual variation in levels of any particular protein is transcription-independent regulation of protein levels. Here, we look in a genetically diverse population of 95 yeast strains at the genetic variation that leads in turn to variation in levels of 354 proteins that function within co-regulated networks. We find that the between-strain variation predominantly reflects transcription-independent mechanisms. If this result is typical of the proteome as a whole, it suggests that protein levels in genetically diverse populations cannot be accurately inferred from levels of their underlying transcripts.

DNA methylation: A source of random variation in natural populations

Epigenetic processes (e.g., DNA methylation) have been proposed as potentially important evolutionary mechanisms. However, before drawing conclusions about their evolutionary relevance, we need to evaluate the independence of epigenetic variation from genetic variation, as well as the extent of methylation polymorphism in nature. We evaluated these in natural populations of a clonal fish, Chrosomus eos-neogaeus, for which genetically identical individuals may be found in distinct environments. A genomic survey confirms the genetic uniformity of individuals, whereas a substantial level of inter-individual variation results in DNA methylation. Survey of the methylation status of the CpG dinucleotides of a fragment of a retrotransposon confirmed a marked difference in epiallelic composition among tissues, as well as among individuals. This study provides further evidence of epigenetic variation in the absence of genetic variation and demonstrates that this process can be a source of random variation in natural populations.