scholarly journals Evidence of positive and negative selection associated with DNA methylation

2021 ◽  
Author(s):  
Charlie Hatcher ◽  
Gibran Hemani ◽  
Santiago Rodriguez ◽  
Tom R Gaunt ◽  
Daniel J Lawson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Complex Traits ◽  
Functional Role ◽  
Joint Distribution ◽  
Negative Selection ◽  
Selection Coefficient ◽  
Parents And Children ◽  
Selection For ◽  
Avon Longitudinal Study

Signatures of negative selection are pervasive amongst complex traits and diseases. However, it is unclear whether such signatures exist for DNA methylation (DNAm) that has been proposed to have a functional role in disease. We estimate polygenicity, SNP-based heritability and model the joint distribution of effect size and minor allele frequency (MAF) to estimate a selection coefficient (S) for 2000 heritable DNAm sites in 1774 individuals from the Avon Longitudinal Study of Parents and Children. Additionally, we estimate S for meta stable epi alleles and DNAm sites associated with aging and mortality, birthweight and body mass index. Quantification of MAF-dependent genetic architectures estimated from genotype and DNAm reveal evidence of positive (S>0) and negative selection (S<0) and confirm previous evidence of negative selection for birthweight. Evidence of both negative and positive selection highlights the role of DNAm as an intermediary in multiple biological pathways with competing function.

scholarly journals Epigenome-wide association study of seizures in childhood and adolescence

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Doretta Caramaschi ◽  
Charlie Hatcher ◽  
Rosa H. Mulder ◽  
Janine F. Felix ◽  
Charlotte A. M. Cecil ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Independent Study ◽  
Childhood And Adolescence ◽  
Parents And Children ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
The Brain ◽  
Avon Longitudinal Study

AbstractThe occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study, we analyzed the association of genome-wide blood DNA methylation with the occurrence of seizures in ~ 800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood, and adolescence (peripheral blood). We also analyzed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e., using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1–5% absolute methylation difference at pFDR < 0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In conclusion, we show a suggestive link between seizures and blood DNA methylation while at the same time exploring the limitations of conducting such study.

scholarly journals Use of signals of positive and negative selection to distinguish cancer genes and passenger genes

2020 ◽  
Author(s):  
László Bányai ◽  
Mária Trexler ◽  
Krisztina Kerekes ◽  
Orsolya Csuka ◽  
László Patthy
Keyword(s):  
Negative Selection ◽  
Cancer Genomics ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Human Genes ◽  
Strong Negative Selection ◽  
Selection For ◽  
Inactivating Mutations

AbstractA major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most approaches focused on genes that are positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution. In the present work we have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human genes. Our analyses have confirmed that tumor suppressor genes are positively selected for inactivating mutations. Oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells.

scholarly journals The Role of Exposure to Neighborhood and School Poverty in Understanding Educational Attainment

2021 ◽  
Author(s):  
Jaap Nieuwenhuis ◽  
Tom Kleinepier ◽  
Maarten van Ham
Keyword(s):  
Longitudinal Study ◽  
Educational Attainment ◽  
School Contexts ◽  
Neighborhood Poverty ◽  
Parents And Children ◽  
Longitudinal Approach ◽  
School Poverty ◽  
Avon Longitudinal Study ◽  
Observation Period

AbstractBecause the demographic composition of neighborhoods and schools overlaps, their effects on educational attainment are not independent of each other. Throughout the early teenage years, the timing and duration of exposure to neighborhood and school contexts can vary, advocating for a longitudinal approach when studying schooling outcomes. This study uses Avon Longitudinal Study of Parents and Children data (N = 4502; 49% female) to examine how exposure to poverty between ages 10–16 predicts educational attainment. The results indicate that enduring exposure to neighborhood poverty relates to educational attainment, while timing does not. For school poverty, longer exposure is related to lower attainment, but earlier exposure has a stronger impact than later exposure. Adolescents who were exposed to poverty in both contexts for the full observation period had the lowest educational attainment. The findings highlight the importance of understanding when and how long adolescents are exposed to contextual poverty.

scholarly journals Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data

2019 ◽  
Author(s):  
Yang Wu ◽  
Ting Qi ◽  
Huanwei Wang ◽  
Futao Zhang ◽  
Zhili Zheng ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Complex Traits ◽  
Analytical Approach ◽  
Human Peripheral Blood ◽  
Complex Trait ◽  
Trait Variation ◽  
Chromatin Interactions ◽  
Level Data ◽  
Trait Locus

AbstractPromoter-anchored chromatin interactions (PAIs) play a pivotal role in transcriptional regulation. Current high-throughput technologies for detecting PAIs, such as promoter capture Hi-C, are not scalable to large cohorts. Here, we present an analytical approach that uses summary-level data from cohort-based DNA methylation (DNAm) quantitative trait locus (mQTL) studies to predict PAIs. Using mQTL data from human peripheral blood (n=1,980), we predicted 34,797 PAIs which showed strong overlap with the chromatin contacts identified by previous experimental assays. The promoter-interacting DNAm sites were enriched in enhancers or near expression QTLs. Genes whose promoters were involved in PAIs were more actively expressed, and gene pairs with promoter-promoter interactions were enriched for co-expression. Integration of the predicted PAIs with GWAS data highlighted interactions among 601 DNAm sites associated with 15 complex traits. This study demonstrates the use of mQTL data to predict PAIs and provides insights into the role of PAIs in complex trait variation.

scholarly journals Optimizing the power to identify the genetic basis of complex traits with Evolve and Resequence studies

2019 ◽  
Author(s):  
Christos Vlachos ◽  
Robert Kofler
Keyword(s):  
Complex Traits ◽  
Quantitative Traits ◽  
Genetic Basis ◽  
Optimal Selection ◽  
Selection Regime ◽  
Higher Power ◽  
Powerful Approach ◽  
Selection For ◽  
Generation Sequencing

AbstractEvolve and Resequence (E&R) studies are frequently used to dissect the genetic basis of quantitative traits. By subjecting a population to truncating selection for several generations and estimating the allele frequency differences between selected and non-selected populations using Next Generation Sequencing, the loci contributing to the selected trait may be identified. The role of different parameters, such as, the population size or the number of replicate populations have been examined in previous works. However, the influence of the selection regime, i.e. the strength of truncating selection during the experiment, remains little explored. Using whole genome, individual based forward simulations of E&R studies, we found that the power to identify the causative alleles may be maximized by gradually increasing the strength of truncating selection during the experiment. Notably, such an optimal selection regime comes at no or little additional cost in terms of sequencing effort and experimental time. Interestingly, we also found that a selection regime which optimizes the power to identify the causative loci is not necessarily identical to a regime that maximizes the phenotypic response. Finally, our simulations suggest that an E&R study with an optimized selection regime may have a higher power to identify the genetic basis of quantitative traits than a GWAS, highlighting that E&R is a powerful approach for finding the loci underlying complex traits.

scholarly journals Paradoxical Signaling Pathways in Developing Thymocytes

2011 ◽  
Vol 14 (3) ◽  
pp. 378 ◽  
Author(s):  
Aws Alshamsan
Keyword(s):  
Cell Death ◽  
Positive Selection ◽  
Cell Fate ◽  
Negative Selection ◽  
Mapk Pathway ◽  
Erk Activation ◽  
Selection For ◽  
Kinetics Of ◽  
Level Order

ABSTRACT- Thymocytes are subjected to processes of selection during their life in the thymus; negative selection for autoreactive thymocytes and positive selection for self-MHC restricted self-tolerant cells. Interestingly, signals for positive or negative selection originate from the same receptor. More importantly, evidence showed that both death and survival signals are mediated by the MAPK pathway. The degree and order of ERK activation, but not other MAPK proteins, has been found to be different in either cases of cell fate. Therefore, it is suspected that the kinetics of ERK after activation may dictate cell death or survival. There are two important GEF proteins that are involved in Ras/ERK activation, RasGRP and SOS. It is thought that the level, order and kinetics of ERK are influenced upstream by the type of GEF. This review discusses the role of both GEF proteins in positive and negative selection and how this reflects on ERK activation. This article is open POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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