The mitochondria are essential organelles and are the location of cellular respiration, which is responsible for the majority of ATP production. Each cell contains multiple mitochondria, and each ...mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. The regulation of mitochondrial copy number by nuclear genes has been studied extensively. While mitochondrial variation has been associated with longevity and some of the diseases known to have reduced mitochondrial copy number, the role that the mitochondrial genome itself has in regulating mitochondrial copy number remains poorly understood.
We analyzed the complete mitochondrial genomes from 1007 individuals randomly selected from the Cache County Study on Memory Health and Aging utilizing the inferred evolutionary history of the mitochondrial haplotypes present in our dataset to identify sequence variation and mitochondrial haplotypes associated with changes in mitochondrial copy number. Three variants belonging to mitochondrial haplogroups U5A1 and T2 were significantly associated with higher mitochondrial copy number in our dataset.
We identified three variants associated with higher mitochondrial copy number and suggest several hypotheses for how these variants influence mitochondrial copy number by interacting with known regulators of mitochondrial copy number. Our results are the first to report sequence variation in the mitochondrial genome that causes changes in mitochondrial copy number. The identification of these variants that increase mtDNA copy number has important implications in understanding the pathological processes that underlie these phenotypes.
The color-word Stroop is a popular measure in psychological assessments. Evidence suggests that Stroop performance relies heavily on reading, an ability that improves over childhood. One way to ...influence reading proficiency is by orthographic manipulations. To determine the degree of interference posed by orthographic manipulations with development, in addition to standard color-Words (purple) we manipulated letter-positions: First/last letter in correct place (prulpe) and Scrambled (ulrpep). We tested children 7-16 years (n = 128) and adults (n = 23). Analyses showed that Word- and First/last-incongruent were qualitatively similar, whereas Word-congruent was different than other conditions. Results suggest that for children and adults, performance was hindered the most for incongruent and incorrectly spelled words and was most facilitated when words were congruent with the ink color and correctly spelled. Implications on visual word recognition and reading are discussed.
•Cigarette use during adolescence is associated with increased risk for insomnia during adulthood.•Cigarette use is associated with increased anxiety symptoms characterized by physiological arousal, ...and anxiety symptoms and insomnia are bidirectionally associated.•Anxiety symptoms characterized by physiological arousal exert an indirect effect on the association between cigarette use during adolescence and insomnia symptoms in early adulthood.•The associations remained after adjusting for baseline depressive symptoms, health, and alcohol use.
Cigarette use during adolescence has been linked to increased risk for insomnia symptoms, but limited work has examined factors that may account for this association. Adolescent cigarette use and anxiety symptoms characterized by physiological hyperarousal evidence bidirectional associations, as do anxiety symptoms and insomnia symptoms. This suggests that adolescent cigarette use, anxiety symptoms characterized by physiological hyperarousal, and insomnia symptoms may increase and maintain one another. The current study tests physiological hyperarousal anxiety symptoms as a potential indirect effect in the cigarette-insomnia symptoms link across adolescence and young adulthood. Methods: We examined data from adolescents and young adults from Waves 1, 2, 3 and 4 of the National Longitudinal Study of Adolescent to Adult Health (N = 2,432 with full data). Insomnia symptoms were assessed at baseline (ages 12–16 years), 1 year later (13–17 years), and 14 years after baseline (26 – 30 years) among a nationally representative sample of adolescents. Cigarette use was assessed at baseline, 1 year later, 6 years after baseline, and 14 years after baseline. Anxiety symptoms were assessed at baseline and 1 year later. Results: Structural equation models indicated that anxiety symptoms exerted an indirect effect on the longitudinal associations between adolescent cigarette use and adult insomnia symptoms. Anxiety symptoms and cigarette use evidenced bidirectional associations during adolescence. Conclusions: These results suggest that increases in anxiety symptoms characterized by physiological hyperarousal may be one mechanism whereby cigarette use during adolescence is associated with increased insomnia symptoms during early adulthood. Prevention efforts aimed at reducing cigarette use during adolescence may have long term additional benefits for anxiety symptoms and insomnia symptoms.
Genetic factors play an important role in the etiology of late-onset Alzheimer's disease (LOAD). We tested gene-centric single nucleotide polymorphisms (SNPs) on chromosome 9 and identified two SNPs ...in the death-associated protein kinase, DAPK1, that show significant association with LOAD. SNP rs4878104 was significantly associated with LOAD in our discovery case–control sample set (WU) and replicated in each of two initial validation case–control sample sets (P<0.05, UK1, SD). The risk-allele frequency of this SNP showed a similar direction in three other case–control sample sets. A meta-analysis of the six sample sets combined, totaling 2012 cases and 2336 controls, showed an allelic P-value of 0.0016 and an odds ratio (OR) of 0.87 (95%CI: 0.79–0.95). Minor allele homozygotes had a consistently lower risk than major allele homozygotes in the discovery and initial two replication sample sets, which remained significant in the meta-analysis of all six sample sets (OR=0.7, 95%CI: 0.58–0.85), whereas the risk for heterozygous subjects was not significantly different from that of major allele homozygotes. A second SNP, rs4877365, which is in high linkage disequilibrium with rs4878104 (r2=0.64), was also significantly associated with LOAD (meta P=0.0017 in the initial three sample sets). Furthermore, DAPK1 transcripts show differential allelic gene expression, and both rs4878104 and rs4877365 were significantly associated with DAPK1 allele-specific expression (P=0.015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD.
It is known that sequencing error can bias estimation of evolutionary or population genetic parameters. This problem is more prominent in deep resequencing studies because of their large sample size ...n, and a higher probability of error at each nucleotide site. We propose a new method based on the composite likelihood of the observed SNP configurations to infer population mutation rate theta = 4N(e)micro, population exponential growth rate R, and error rate epsilon, simultaneously. Using simulation, we show the combined effects of the parameters, theta, n, epsilon, and R on the accuracy of parameter estimation. We compared our maximum composite likelihood estimator (MCLE) of theta with other theta estimators that take into account the error. The results show the MCLE performs well when the sample size is large or the error rate is high. Using parametric bootstrap, composite likelihood can also be used as a statistic for testing the model goodness-of-fit of the observed DNA sequences. The MCLE method is applied to sequence data on the ANGPTL4 gene in 1832 African American and 1045 European American individuals.
Objective: Emerging adulthood is characterized by maturation of executive functions (EF) and changes in health behaviors (HB). Interestingly, EF are bi-directionally related to many specific HB; yet ...how EF performs in relation to overall patterns of HB engagement is unclear. Groupings of HB and the relationship between these HB groupings and EF were examined. Participants. Full-time college students were recruited from three large Mid- and Southwest universities (N = 1,387). Methods. Online self-report questionnaires assessing demographics, HB, and EF were completed. Results. Latent class analysis of HB revealed three classes: (1) High Substance Use, (2) Moderately Healthy, (3) Healthy. In general, the Healthy class had significantly greater EF compared to no significant differences between the other two classes. Conclusions. Collective engagement in HB is associated with EF. Interventions targeting both HB and EF simultaneously may be most efficacious.
Although the current obesity epidemic is of environmental origin, there is substantial genetic variation in individual response to an obesogenic environment. In this study, we perform a genome‐wide ...scan for quantitative trait loci (QTLs) affecting obesity per se, or an obese response to a high‐fat diet in mice from the LG/J by SM/J Advanced Intercross (AI) Line (Wustl:LG, SM‐G16). A total of 1,002 animals from 78 F16 full sibships were weaned at 3 weeks of age and half of each litter placed on high‐ and low‐fat diets. Animals remained on the diet until 20 weeks of age when they were necropsied and the weights of the reproductive, kidney, mesenteric, and inguinal fat depots were recorded. Effects on these phenotypes, along with total fat depot weight and carcass weight at necropsy, were mapped across the genome using 1,402 autosomal single‐nucleotide polymorphism (SNP) markers. Haplotypes were reconstructed and additive, dominance, and imprinting genotype scores were derived every 1 cM along the F16 map. Analysis was performed using a mixed model with additive, dominance, and imprinting genotype scores, their interactions with sex, diet, and with sex‐by‐diet as fixed effects and with family and its interaction with sex, diet, and sex‐by‐diet as random effects. We discovered 95 trait‐specific QTLs mapping to 40 locations. Most QTLs had additive effects with dominance and imprinting effects occurring at two‐thirds of the loci. Nearly every locus interacted with sex and/or diet in important ways demonstrating that gene effects are primarily context dependent, changing depending on sex and/or diet.
Since genome size and the number of duplicate genes observed in genomes increase from haploid to diploid organisms, diploidy might provide more evolutionary probabilities through gene duplication. It ...is still unclear how diploidy promotes genomic evolution in detail. In this study, we explored the evolution of segmental gene duplication in haploid and diploid populations by analytical and simulation approaches. Results show that (1) under the double null recessive (DNR) selective model, given the same recombination rate, the evolutionary trajectories and consequences are very similar between the same-size gene-pool haploid vs. diploid populations; (2) recombination enlarges the probability of preservation of duplicate genes in either haploid or diploid large populations, and haplo-insufficiency reinforces this effect; and (3) the loss of duplicate genes at the ancestor locus is limited under recombination while under complete linkage the loss of duplicate genes is always random at the ancestor and newly duplicated loci. Therefore, we propose a model to explain the advantage of diploidy: diploidy might facilitate the increase of recombination rate, especially under sexual reproduction; more duplicate genes are preserved under more recombination by originalization (by which duplicate genes are preserved intact at a special quasi-mutation-selection balance under the DNR or haplo-insufficient selective model), so genome sizes and the number of duplicate genes in diploid organisms become larger. Additionally, it is suggested that small genomic rearrangements due to the random loss of duplicate genes might be limited under recombination.
Variation in serum cholesterol, free-fatty acids, and triglycerides is associated with cardiovascular disease (CVD) risk factors. There is great interest in characterizing the underlying genetic ...architecture of these risk factors, because they vary greatly within and among human populations and between the sexes. We present results of a genome-wide scan for quantitative trait loci (QTL) affecting serum cholesterol, free-fatty acids, and triglycerides in an F₁₆ advanced intercross line of LG/J and SM/J (Wustl:LG,SM-G16). Half of the population was fed a high-fat diet and half was fed a relatively low-fat diet. Context-dependent genetic (additive and dominance) and epigenetic (imprinting) effects were characterized by partitioning animals into sex, diet, and sex-by-diet cohorts. Here we examine genetic, environmental, and genetic-by-environmental interactions of QTL overlapping previously identified loci associated with CVD risk factors, and we add to the serum lipid QTL landscape by identifying new loci.
Variations in diabetic phenotypes are caused by complex interactions of genetic effects, environmental factors, and the interplay between the two. We tease apart these complex interactions by ...examining genome-wide genetic and epigenetic effects on diabetes-related traits among different sex, diet, and sex-by-diet cohorts in a
Mus musculus
model. We conducted a genome-wide scan for quantitative trait loci that affect serum glucose and insulin levels and response to glucose stress in an F
16
Advanced Intercross Line of the LG/J and SM/J intercross (Wustl:LG,SM-G16). Half of each sibship was fed a high-fat diet and half was fed a relatively low-fat diet. Context-dependent genetic (additive and dominance) and epigenetic (parent-of-origin imprinting) effects were characterized by partitioning animals into sex, diet, and sex-by-diet cohorts. We found that different cohorts often have unique genetic effects at the same loci, and that genetic signals can be masked or erroneously assigned to specific cohorts if they are not considered individually. Our data demonstrate that the effects of genes on complex trait variation are highly context-dependent and that the same genomic sequence can affect traits differently depending on an individual’s sex and/or dietary environment. Our results have important implications for studies of complex traits in humans.
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