PURPOSEUnderstanding seasonal variation in physical activity is important for informing public health surveillance and intervention design. The aim of the current study was to describe seasonal ...variation in children’s objectively measured physical activity and sedentary time.
METHODSData are from the UK Millennium Cohort Study. Participants were invited to wear an accelerometer for 7 d on five occasions between November 2008 and January 2010. Outcome variables were sedentary time (<100 counts per minute, min·d) and moderate to vigorous physical activity (MVPA) (>2241 counts per minute, min·d). The season was characterized using a categorical variable (spring, summer, autumn, or winter) and a continuous function of day of the year. Cross-classified linear regression models were used to estimate the association of each of these constructs with the outcome variables. Modification of the seasonal variation by sex, weight status, urban/rural location, parental income, and day of the week (weekday/weekend) was examined using interaction terms in regression models.
RESULTSAt least one wave of valid accelerometer data was obtained from 704 participants (47% male; baseline age, 7.6 (0.3) yr). MVPA was lower in autumn and winter relative to spring, with the magnitude of this difference varying by weekday/weekend, sex, weight status, urban/rural location, and family income (P for interaction <0.05 in all cases). Total sedentary time was greater in autumn and winter compared with spring; the seasonal effect was stronger during the weekend than during the weekday (P for interaction <0.01).
CONCLUSIONSLower levels of MVPA and elevated sedentary time support the implementation of intervention programs during autumn and winter. Evidence of greater seasonal variation in weekend behavior and among certain sociodemographic subgroups highlights targets for tailored intervention programs.
The contribution of repetitive elements to quantitative human traits is largely unknown. Here we report a genome-wide survey of the contribution of short tandem repeats (STRs), which constitute one ...of the most polymorphic and abundant repeat classes, to gene expression in humans. Our survey identified 2,060 significant expression STRs (eSTRs). These eSTRs were replicable in orthogonal populations and expression assays. We used variance partitioning to disentangle the contribution of eSTRs from that of linked SNPs and indels and found that eSTRs contribute 10-15% of the cis heritability mediated by all common variants. Further functional genomic analyses showed that eSTRs are enriched in conserved regions, colocalize with regulatory elements and may modulate certain histone modifications. By analyzing known genome-wide association study (GWAS) signals and searching for new associations in 1,685 whole genomes from deeply phenotyped individuals, we found that eSTRs are enriched in various clinically relevant conditions. These results highlight the contribution of STRs to the genetic architecture of quantitative human traits.
Three cross sectional studies suggest that neighbourhood greenspace may protect against incident diabetes. This study uses data from a longitudinal study with a large sample size to investigate the ...association between greenspace and the occurrence of incident diabetes over time.
Data was from the European Prospective Investigation of Cancer Norfolk, UK, cohort, recruitment 1993-2007 (N = 23,865). Neighbourhoods were defined as 800 m circular buffers around participants' home locations, according to their home postcode (zip code). Greenspace exposure was defined as the percentage of the home neighbourhood that was woodland, grassland, arable land, mountain, heath and bog, according to the UK Land Cover Map. Cox proportional hazards regression examined the association between neighbourhood greenspace exposure and incident diabetes. The population attributable fraction assessed the proportion of diabetes cases attributable to exposure to least green neighbourhoods. Mediation analysis assessed if physical activity explained associations between greenspace and diabetes. Interaction analysis was used to test for the modifying effect of rurality and socio-economic status on the relationship between greenspace and diabetes. Models were adjusted for known and hypothesised confounders.
The mean age of participants was 59 years at baseline and 55.1% were female. The mean follow-up time was 11.3 years. Individuals living in the greenest neighbourhood quartile had a 19% lower relative hazard of developing diabetes (HR 0.81; 95% CI 0.67, 0.99; p = 0.035; linear trend p = 0.010). The hazard ratio remained similar (HR 0.81; 95% CI 0.65, 0.99; p = 0.042) after adjusting for age, sex, BMI, whether a parent had been diagnosed with diabetes and socio-economic status at the individual and neighbourhood level. A HR of 0.97 was attributed to the pathway through physical activity in a fully adjusted model, although this was non-significant (95% CI 0.88, 1.08; p = 0.603). The incidence of diabetes in the least green neighbourhoods (with 20% greenspace on average) would fall by 10.7% (95% CI -2.1%, 25.2%; p = 0.106) if they were as green as the average neighbourhood observed across the whole cohort (59% greenspace on average). There were no significant interactions between rurality or socio-economic status and level of greenspace.
Greener home neighbourhoods may protect against risk of diabetes in older adults, although this study does not support a mediation role for physical activity. Causal mechanisms underlying the associations require further investigation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Physical activity (PA) declines during adolescence but change in different PA intensities across population subgroups is rarely explored. We describe change in sedentary (SED) time, light (LPA), ...moderate (MPA) and vigorous PA (VPA) assessed at three time points over 4 years.
Accelerometer-assessed PA (min) was obtained at baseline (N=2064), 1 and 4 years later among British children (baseline mean±SD 10.2±0.3-year-old; 42.5% male). Change in SED (<100 counts/min (cpm)), LPA (101-1999 cpm), MPA (2000-3999 cpm) and VPA (≥4000 cpm) was studied using three-level (age, individual and school) mixed-effects linear regression including participants with data at ≥2 time points (N=990). Differences in change by sex, home location and weight status were explored with interactions for SED, LPA and moderate and vigorous PA (MVPA).
SED increased by 10.6 (95% CI 9.1 to 12.2) min/day/year. MPA and VPA decreased by 1.4 (1.0 to 1.8) and 1.5 (1.1 to 1.8) min/day/year, respectively. VPA decreased more than MPA as a percentage of the baseline value. MVPA declined more steeply among boys (3.9 (3.0 to 4.8)) versus girls (2.0 (1.2 to 2.7) min/day/year) despite lower MVPA among girls at all ages; rural (4.4 (3.5 to 5.2)) versus urban individuals (1.3 (0.4 to 2.3) min/day/year) and on weekends (6.7 (5.2 to 8.1)) versus weekdays (2.8 (1.9 to 3.7) min/day/year). MVPA was consistently lower among overweight/obese individuals (-17.5 (-3.9 to -2.5) min/day/year).
PA decreases and is replaced by SED during early adolescence in British youth. Results indicate the urgency of PA promotion among all adolescents but especially girls and in rural areas. Increasing VPA and targeting PA promotion during weekends appear important.
Open reading frames (ORFs) with fewer than 100 codons are generally not annotated in genomes, although bona fide genes of that size are known. Newer biochemical studies have suggested that thousands ...of small protein-coding ORFs (smORFs) may exist in the human genome, but the true number and the biological significance of the micropeptides they encode remain uncertain. Here, we used a comparative genomics approach to identify high-confidence smORFs that are likely protein-coding. We identified 3,326 high-confidence smORFs using constraint within human populations and evolutionary conservation as additional lines of evidence. Next, we validated that, as a group, our high-confidence smORFs are conserved at the amino-acid level rather than merely residing in highly conserved non-coding regions. Finally, we found that high-confidence smORFs are enriched among disease-associated variants from GWAS. Overall, our results highlight that smORF-encoded peptides likely have important functional roles in human disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A fundamental initiative for evolutionary biologists is to understand the molecular basis underlying phenotypic diversity. A long-standing hypothesis states that species-specific traits may be ...explained by differences in gene regulation rather than differences at the protein level. Over the past few years, evolutionary studies have shifted from mere sequence comparisons to integrative analyses in which gene regulation is key to understanding species evolution. DNA methylation is an important epigenetic modification involved in the regulation of numerous biological processes. Nevertheless, the evolution of the human methylome and the processes driving such changes are poorly understood. Here, we review the close interplay between Cytosine-phosphate-Guanine (CpG) methylation and the underlying genome sequence, as well as its evolutionary impact. We also summarize the latest advances in the field, revisiting the main literature on human and nonhuman primates. We hope to encourage the scientific community to address the many challenges posed by the field of comparative epigenomics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Using the Illumina 450K array and a stringent statistical analysis with age and gender correction, we report genome-wide differences in DNA methylation between pathology-free regions derived from ...human multiple sclerosis-affected and control brains. Differences were subtle, but widespread and reproducible in an independent validation cohort. The transcriptional consequences of differential DNA methylation were further defined by genome-wide RNA-sequencing analysis and validated in two independent cohorts. Genes regulating oligodendrocyte survival, such as BCL2L2 and NDRG1, were hypermethylated and expressed at lower levels in multiple sclerosis-affected brains than in controls, while genes related to proteolytic processing (for example, LGMN, CTSZ) were hypomethylated and expressed at higher levels. These results were not due to differences in cellular composition between multiple sclerosis and controls. Thus, epigenomic changes in genes affecting oligodendrocyte susceptibility to damage are detected in pathology-free areas of multiple sclerosis-affected brains.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
DNA methylation is an epigenetic modification involved in regulatory processes such as cell differentiation during development, X-chromosome inactivation, genomic imprinting and susceptibility to ...complex disease. However, the dynamics of DNA methylation changes between humans and their closest relatives are still poorly understood. We performed a comparative analysis of CpG methylation patterns between 9 humans and 23 primate samples including all species of great apes (chimpanzee, bonobo, gorilla and orangutan) using Illumina Methylation450 bead arrays. Our analysis identified ∼800 genes with significantly altered methylation patterns among the great apes, including ∼170 genes with a methylation pattern unique to human. Some of these are known to be involved in developmental and neurological features, suggesting that epigenetic changes have been frequent during recent human and primate evolution. We identified a significant positive relationship between the rate of coding variation and alterations of methylation at the promoter level, indicative of co-occurrence between evolution of protein sequence and gene regulation. In contrast, and supporting the idea that many phenotypic differences between humans and great apes are not due to amino acid differences, our analysis also identified 184 genes that are perfectly conserved at protein level between human and chimpanzee, yet show significant epigenetic differences between these two species. We conclude that epigenetic alterations are an important force during primate evolution and have been under-explored in evolutionary comparative genomics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
While population studies have resulted in detailed maps of genetic variation in humans, to date there are few robust maps of epigenetic variation. We identified sites containing clusters of CpGs with ...high inter-individual epigenetic variation, termed Variably Methylated Regions (VMRs) in five purified cell types. We observed that VMRs occur preferentially at enhancers and 3' UTRs. While the majority of VMRs have high heritability, a subset of VMRs within the genome show highly correlated variation in trans, forming co-regulated networks that have low heritability, differ between cell types and are enriched for specific transcription factor binding sites and biological pathways of functional relevance to each tissue. For example, in T cells we defined a network of 95 co-regulated VMRs enriched for genes with roles in T-cell activation; in fibroblasts a network of 34 co-regulated VMRs comprising all four HOX gene clusters enriched for control of tissue growth; and in neurons a network of 18 VMRs enriched for roles in synaptic signaling. By culturing genetically-identical fibroblasts under varying environmental conditions, we experimentally demonstrated that some VMR networks are responsive to the environment, with methylation levels at these loci changing in a coordinated fashion in trans dependent on cellular growth. Intriguingly these environmentally-responsive VMRs showed a strong enrichment for imprinted loci (p<10-80), suggesting that these are particularly sensitive to environmental conditions. Our study provides a detailed map of common epigenetic variation in the human genome, showing that both genetic and environmental causes underlie this variation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Short tandem repeats (STRs) contribute significantly to genetic diversity in humans, including disease-causing variation. Although the effect of STR variation on gene expression has been extensively ...assessed, their impact on epigenetics has been poorly studied and limited to specific genomic regions. Here, we investigated the hypothesis that some STRs act as independent regulators of local DNA methylation in the human genome and modify risk of common human traits. To address these questions, we first analyzed two independent data sets comprising PCR-free whole-genome sequencing (WGS) and genome-wide DNA methylation levels derived from whole-blood samples in 245 (discovery cohort) and 484 individuals (replication cohort). Using genotypes for 131,635 polymorphic STRs derived from WGS using HipSTR, we identified 11,870 STRs that associated with DNA methylation levels (mSTRs) of 11,774 CpGs (Bonferroni
< 0.001) in our discovery cohort, with 90% successfully replicating in our second cohort. Subsequently, through fine-mapping using CAVIAR we defined 585 of these mSTRs as the likely causal variants underlying the observed associations (fm-mSTRs) and linked a fraction of these to previously reported genome-wide association study signals, providing insights into the mechanisms underlying complex human traits. Furthermore, by integrating gene expression data, we observed that 12.5% of the tested fm-mSTRs also modulate expression levels of nearby genes, reinforcing their regulatory potential. Overall, our findings expand the catalog of functional sequence variants that affect genome regulation, highlighting the importance of incorporating STRs in future genetic association analysis and epigenetics data for the interpretation of trait-associated variants.
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