200 research outputs found
The Increasing Importance of Gene-Based Analyses.
No full textIn recent years, genome and exome sequencing studies have implicated a plethora of new disease genes with rare causal variants. Here, I review 150 exome sequencing studies that claim to have discovered that a disease can be caused by different rare variants in the same gene, and I determine whether their methods followed the current best-practice guidelines in the interpretation of their data. Specifically, I assess whether studies appropriately assess controls for rare variants throughout the entire gene or implicated region as opposed to only investigating the specific rare variants identified in the cases, and I assess whether studies present sufficient co-segregation data for statistically significant linkage. I find that the proportion of studies performing gene-based analyses has increased with time, but that even in 2015 fewer than 40% of the reviewed studies used this method, and only 10% presented statistically significant co-segregation data. Furthermore, I find that the genes reported in these papers are explaining a decreasing proportion of cases as the field moves past most of the low-hanging fruit, with 50% of the genes from studies in 2014 and 2015 having variants in fewer than 5% of cases. As more studies focus on genes explaining relatively few cases, the importance of performing appropriate gene-based analyses is increasing. It is becoming increasingly important for journal editors and reviewers to require stringent gene-based evidence to avoid an avalanche of misleading disease gene discovery papers
Genetic and Environmental Contributions to Baseline Cognitive Ability and Cognitive Response to Topiramate
No full textAlthough much research has focused on cognitive ability and the genetic and environmental factors that might influence it, this aspect of human nature is still far from being well understood. It has been well-established that certain factors such as age and education have significant impacts on performance on most cognitive tests, but the effects of variables such as cognitive pastimes and strategies used during testing have generally not been assessed. Additionally, no genetic variant has yet been unequivocally shown to influence the normal variation in cognitive ability of healthy individuals. Candidate gene studies of cognition have produced conflicting results that have not been replicable, and genome-wide association studies have not found common variants with large influences on this trait.Here, we have recruited a large cohort of healthy volunteers (n=1,887) and administered a brief cognitive battery utilizing diverse, common, and well-known tests. In addition to providing standard demographic information, the subjects also filled out a questionnaire that was designed to assess novel factors such as whether they had seen the test before, in what cognitive pastimes they participated, and what strategies they had used during testing. Linear regression models were built to assess the effects of these variables on the test scores. I found that the addition of novel covariates to standard ones increased the percent of the variation in test score that was explained for all tests; for some tests, the increase was as high as 70%.Next, I examined the effects of genetic variants on test scores. I first performed a genome-wide association study using the Illumina HumanHap 550 and 610 chips. These chips are designed to directly genotype or tag the vast majority of the common variants in the genome. Despite having 80% power to detect a common variant explaining at least 3-6% (depending on the test) of the variation in the trait, I did not find any genetic variants that were significantly associated after correction for multiple testing. This is in line with the general findings from GWA studies that single common variants have a limited impact on complex traits.Because of the recent technological advances in next-generation sequencing and the apparently limited role of very common variants, many human geneticists are making a transition from genome-wide association study to whole-genome and whole-exome sequencing, which allow for the identification of rarer variants. Because these methods are currently costly, it is important to utilize study designs that have the best chance of finding causal variants in a small sample size. One such method is the extreme-trait design, where individuals from one or both ends of a trait distribution are sequenced and variants that are enriched in the group(s) are identified. Here, I have sequenced the exomes of 20 young individuals of European ethnicity: 10 that performed at the top of the distribution for the cognitive battery and 10 that performed at the bottom. I identified rare genetic variants that were enriched in one extreme group as compared to the other and performed follow-up genotyping of the best candidate variant that emerged from this analysis. Unfortunately, this variant was not found to be associated in a larger sample of individuals. This pilot study indicates that a larger sample size will be needed to identify variants enriched in cognition extremes.Finally, I assessed the effect of topiramate, an antiepileptic drug that causes marked side effects in certain cognitive areas in certain individuals, on some of the healthy volunteers (n=158) by giving them a 100 mg dose and then administering the cognitive test two hours later. I compared their scores at this testing session to those at the previous session and calculated the overall level to which they were affected by topiramate. I found that the topiramate blood levels, which were highly dependent on weight and the time from dosing to testing, varied widely between individuals after this acute dose, and that this variation explained 35% of the variability in topiramate response. A genome-wide association study of the remaining variability in topiramate response did not identify a genome-wide significant association.In sum, I studied the contributions of both environmental and genetic variables to cognitive ability and cognitive response to topiramate. I found that I could identify environmental variables explaining large proportions of the variation in these traits, but that I could not identify genetic variants that influenced the traits. My analysis of genetic variants was for the most part restricted to the very common ones found on genotyping chips, and this and other studies have generally found that single common genetic variants do not have large affects on complex traits. As we move forward into studies that involve the sequencing of whole exomes and genomes, genetic variants with large effects on these complex traits may finally be found.</p
Gene-based collapsing analysis.
No full textShown is the basic schematic for a gene-based collapsing analysis. A gene is completely sequenced in cases and controls, and the number of cases and controls with rare mutations (lightning bolts) in the gene is compared. In contrast, many published articles only use controls to look for the specific variants found in the cases. For example, here the red lightning bolt indicates a variant that is found in both a case and a control. If only case variants are considered, then there are seven cases with different mutations in this gene, and only one of these mutations is found in controls. However, if all variants in the gene are considered, then there are an equal number of cases and controls with mutations in this gene. This collapsing technique can also be used to assess and implicate a gene region instead of an entire gene, for example in S1 Fig and in [16,17].</p
Coverage imbalances can create false signals.
No full textThe coverage profile of each exon of the gene is shown for cases and controls, with greater filled-in area indicating higher coverage. Mutations are shown with lightning bolts. In this example, the amount of the gene well covered in the cases is much higher than the amount well covered in the controls. As fewer variants are called in regions with poor coverage, the coverage pattern in this gene makes it predisposed to showing more mutations in cases than in controls. One method that can be used to reduce this problem is to prune exons or regions from analysis that show a high case-control imbalance in their coverage patterns [8].</p
Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet.
No full textTrends in exome sequencing disease gene discovery papers.
No full text(A) Proportion of studies performing gene-based comparisons and statistical analyses. There has been a trend for more papers to use gene-based comparisons versus controls with time (p = 0.44, or 0.18 if restricting to studies with at least ten unrelated cases) and a statistically significant increase in the proportion of papers using gene-based statistical analyses (p = 0.008, or 0.001 if restricting to studies with at least ten unrelated cases). (B) Proportion of cases with qualifying variants in each implicated gene. Studies with fewer than ten unrelated cases have continued to have a very high proportion of cases with qualifying variants in the implicated gene, while studies with more cases have had a progressively lower proportion of cases with qualifying variants over time (p = 0.009 for change over time). (C) Proportion of studies that include co-segregation data from families with multiple affected individuals, that present co-segregation data that appears consistent with a significant LOD score (>3.3), and that report a significant LOD score. The proportion of studies in all three of these categories has been decreasing with time (p = 0.001, 0.002, and 0.08, respectively), and the proportion of studies with co-segregation data that present data consistent with a significant LOD score has tended to decrease as well (p = 0.06; dropped from 53% in 2010/2011 to 27% in 2015; S5 Fig). (D) Proportion of studies that follow best-practice guidelines [1] in terms of either gene-based analysis or linkage analysis. The less stringent category includes studies that either perform gene-based comparisons or present co-segregation data consistent with significant linkage, and the more stringent category includes papers that perform a gene-based statistical analysis or report a significant LOD score. The total proportion of gene discovery papers following best-practice guidelines does not appear to be changing with time. Plotted are the means and 95% confidence intervals. 2010 and 2011 are merged due to only four studies being from 2010.</p
Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet.
No full textFocus on Building & Real Estate piece on Stoneham-based Crowell Construction,
No full textFocus on Building & Real Estate piece on Stoneham-based Crowell Construction, owned by Gary Crowell, 49. Author Stephen King tapped Crowell to be project manager for a $1 million renovation of the Charles P. Brown house next to the Kings\u27 Bangor home. Because he was committed to projects in the Kezar Lake area, Crowell could not do the actual work on the house. As the Lovell/Stoneham area has become a destination spot for vacationers, Crowell\u27s custom projects have increased in size and value from the camps he once built. Crowell has a skilled team, and compared with other area builders, he subcontracts far less. He tries to persuade his customers to build at a distance from the lake\u27s shore to preserve the views for others
Individual Variation in Contagious Yawning Susceptibility Is Highly Stable and Largely Unexplained by Empathy or Other Known Factors
No full textThe contagious aspect of yawning is a well-known phenomenon that exhibits variation in the human population. Despite the observed variation, few studies have addressed its intra-individual reliability or the factors modulating differences in the susceptibility of healthy volunteers. Due to its obvious biological basis and impairment in diseases like autism and schizophrenia, a better understanding of this trait could lead to novel insights into these conditions and the general biological functioning of humans. We administered 328 participants a 3-minute yawning video stimulus, a cognitive battery, and a comprehensive questionnaire that included measures of empathy, emotional contagion, circadian energy rhythms, and sleepiness. Individual contagious yawning measurements were found to be highly stable across testing sessions, both in a lab setting and if administered remotely online, confirming that certain healthy individuals are less susceptible to contagious yawns than are others. Additionally, most individuals who failed to contagiously yawn in our study were not simply suppressing their reaction, as they reported not even feeling like yawning in response to the stimulus. In contrast to previous studies indicating that empathy, time of day, or intelligence may influence contagious yawning susceptibility, we found no influence of these variables once accounting for the age of the participant. Participants were less likely to show contagious yawning as their age increased, even when restricting to ages of less than 40 years. However, age was only able to explain 8% of the variability in the contagious yawn response. The vast majority of the variability in this extremely stable trait remained unexplained, suggesting that studies of its inheritance are warranted
PIER PAOLO PASOLINI AND THE SPACE OF THE “RIVOLUZIONE ANTROPOLOGICA”
No full textI propose in my dissertation a broadened reading of Pasolini’s idea of an anthropological revolution taking place in Italy during the 1970s, assuming spatial studies as the privileged perspective for my analysis. The expression “rivoluzione antropologica” occurs only in Pasolini’s production of the last years, and it refers to a sudden transformation of human nature that Pasolini recognizes as being particularly effective in the lower strata of society. I argue that most of Pasolini’s production, even before the coining of the expression “rivoluzione antropologica,” can be connected to this concept, since it makes of the transformation and the homogenization of the Italian, Western, and global societies one of its paramount topics. In addition, I highlight how such transformation is portrayed by the space that the protagonists of this revolution inhabit. I divide Pasolini’s production into four parts based on the setting, discussing for each of them how the anthropological revolution is connected to, and supported by, changes involving the environment that highlight the persistent dialogue existing in Pasolini between nature and culture. Finally, I consider how the Italian author fostered in his work resistance to the anthropological revolution, and how, once again, such resistance is promoted through techniques involving the relationship between his characters and their surrounding space.Doctor of Philosoph
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