scholarly journals Thermodynamic stability of G-quadruplex and overlapping m6A: Position-dependent collaborators in allele frequency and fitness?

2021 ◽  
Author(s):  
Cagri Gulec
Keyword(s):  
Statistical Analysis ◽  
Allele Frequency ◽  
Gene Product ◽  
Thermodynamic Stability ◽  
Rna Processing ◽  
Genetic Variants ◽  
Common Variants ◽  
Unequal Distribution ◽  
Human Genes ◽  
G Quadruplex

AbstractBackgroundPost-transcriptional modifications like m6A, and secondary structures like G-quadruplex (G4), play an important role in RNA processing. Despite an emerging number of studies focusing on m6A and G4 separately, there are less studies about their synergy.AimSince m6A is known to be enzymatically created in DRACH-motif, and genetic variants may create a novel DRACH-motif or abolish a pre-existing DRACH-motif, we can suppose that the variants may affect gene product level through modulating m6A-G4 colocalization, which consequently may affect fitness and change allele frequency. To test this hypothesis, rare and common variants in selected human genes were investigated in terms of their effect on m6A-G4 colocalization.MethodsGenomic sequences and variant features were fetched from GRCh37/hg19 and Biomart-Ensembl databases, respectively. Counting the number of putative m6A- and G4-motifs in sequences and statistical analysis were performed with appropriate libraries of Python3.7.ResultsCommon variants creating novel m6A-motif were found more frequently inside than outside G4, and displayed unequal distribution throughout pre-mRNA. Unequal distribution of m6A-creating variants seemed to be related to their effect on thermodynamic stability of the overlapping-G4.DiscussionSelective m6A-G4 colocalization suggests that m6A-motif is favorable when overlapping with G4. Besides, thermodynamic stability may lead to unequal distribution of m6A-G4 colocalization, because m6A-creating alleles seem to have lower frequency if stabilizes overlapping-G4 in 3-prime-side, but not in 5-prime-side. We can conclude that the fitness, and consequently frequency of an m6A-creating variant is prone to become higher or lower depending on its position and effect on the overlapping-G4 stability.

scholarly journals Genetic profiling of Vietnamese population from large-scale genomic analysis of non-invasive prenatal testing data

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ngoc Hieu Tran ◽  
Thanh Binh Vo ◽  
Van Thong Nguyen ◽  
Nhat-Thang Tran ◽  
Thu-Huong Nhat Trinh ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Frequency Distribution ◽  
Genetic Variants ◽  
Large Scale ◽  
Genomic Analysis ◽  
Prenatal Testing ◽  
Allele Frequency Distribution ◽  
Genetic Studies ◽  
Non Invasive ◽  
Vietnamese Population

Abstract The under-representation of several ethnic groups in existing genetic databases and studies have undermined our understanding of the genetic variations and associated traits or diseases in many populations. Cost and technology limitations remain the challenges in performing large-scale genome sequencing projects in many developing countries, including Vietnam. As one of the most rapidly adopted genetic tests, non-invasive prenatal testing (NIPT) data offers an alternative untapped resource for genetic studies. Here we performed a large-scale genomic analysis of 2683 pregnant Vietnamese women using their NIPT data and identified a comprehensive set of 8,054,515 single-nucleotide polymorphisms, among which 8.2% were new to the Vietnamese population. Our study also revealed 24,487 disease-associated genetic variants and their allele frequency distribution, especially 5 pathogenic variants for prevalent genetic disorders in Vietnam. We also observed major discrepancies in the allele frequency distribution of disease-associated genetic variants between the Vietnamese and other populations, thus highlighting a need for genome-wide association studies dedicated to the Vietnamese population. The resulted database of Vietnamese genetic variants, their allele frequency distribution, and their associated diseases presents a valuable resource for future genetic studies.

scholarly journals Properties of human genes guided by their enrichment in rare and common variants

2017 ◽  
Vol 39 (3) ◽  
pp. 365-370 ◽  
Author(s):  
Eman Alhuzimi ◽  
Luis G. Leal ◽  
Michael J.E. Sternberg ◽  
Alessia David
Keyword(s):  
Common Variants ◽  
Human Genes

scholarly journals Automated design of CRISPR prime editors for thousands of human pathogenic variants

2020 ◽  
Author(s):  
John A. Morris ◽  
Jahan A. Rahman ◽  
Xinyi Guo ◽  
Neville E. Sanjana
Keyword(s):  
Genetic Variants ◽  
Gene Editing ◽  
Genome Engineering ◽  
Disease Modeling ◽  
Automated Design ◽  
Common Variants ◽  
Therapeutic Gene ◽  
Web Based ◽  
Pathogenic Variants ◽  
Automated Pipeline

AbstractPrime editors (PEs) are CRISPR-based genome engineering tools that can introduce precise base-pair edits at specific locations in the genome. These programmable gene editors have been predicted to repair 89% of known human pathogenic variants in the ClinVar database, although these PE constructs do not presently exist. Towards this end, we developed an automated pipeline to correct (therapeutic editing) or introduce (disease modeling) human pathogenic variants that optimizes the design of several RNA constructs required for prime editing and avoids predicted off-targets in the human genome. However, using optimal PE design criteria, we find that only a small fraction of these pathogenic variants can be targeted. Through the use of alternative Cas9 enzymes and extended templates, we increase the number of targetable pathogenic variants to >50,000 variants and make these pre-designed PE constructs accessible through a web-based portal (http://primeedit.nygenome.org). Given the tremendous potential for therapeutic gene editing, we also assessed the possibility of developing universal PE constructs. By examining the overlap of different PE components with common human genetic variants in dbSNP, we find that common variants affect only a small minority of designed PEs.

scholarly journals The genetic architecture of medication-use

2020 ◽  
Author(s):  
Palle Duun Rohde ◽  
Peter Sørensen ◽  
Mette Nyegaard
Keyword(s):  
Medical Treatment ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Genetic Variants ◽  
Genetic Architecture ◽  
Association Studies ◽  
Medication Use ◽  
Minor Allele ◽  
Genome Wide Association Studies ◽  
Common Genetic Variants

AbstractGenomics has been forecasted to revolutionise human health by improving medical treatment through a better understanding of the molecular mechanisms of human diseases. Despite great successes of the last decade’s genome-wide association studies (GWAS), the results have to a limited extent been translated to genomic medicine. We propose, that one route to get closer to improved medical treatment is by understanding the genetics of medication-use. Here we obtained entire medication profiles from 335,744 individuals from the UK Biobank and performed a GWAS to identify which common genetic variants are major drivers of medication-use. We analysed 9 million imputed genetic variants, estimated SNP heritability, partitioned the genomic variance across functional categories, and constructed genetic scores for medication-use. In total, 59 independent loci were identified for medication-use and approximately 18% of the total variation was attributable to common genetic (minor allele frequency >0.01) variants. The largest fraction of variance was captured by variants with low to medium minor allele frequency. In particular coding and conserved regions, as well as transcription start sites, displayed significantly enrichment of heritability. The average correlation between medication-use and predicted genetic scores was 0.14. These results demonstrate that medication-use per se is a highly polygenic complex trait and that individuals with higher genetic liability are on average more diseased and have a higher risk for adverse drug reactions. These results provide an insight into the genetic architecture of medication use and pave the way for developments of multicomponent genetic risk models that includes the genetically informed medication-use.

scholarly journals Ultra-rare, rare, and common genetic variant analysis converge to implicate negative selection and neuronal processes in the aetiology of schizophrenia

2021 ◽  
Author(s):  
Wonuola A Akingbuwa ◽  
Anke R Hammerschlag ◽  
Meike Bartels ◽  
Michel G Nivard ◽  
Christel M Middeldorp
Keyword(s):  
Allele Frequency ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Cell Types ◽  
Brain Cell ◽  
Synaptic Function ◽  
Human Brain Tissue ◽  
Gene Sets ◽  
Cell Gene ◽  
Brain Cell Types

Both common and rare genetic variants (minor allele frequency > 1% and < 0.1% respectively) have been implicated in the aetiology of schizophrenia. In this study, we integrate single-cell gene expression data with publicly available Genome-Wide Association Study (GWAS) and exome sequenced data in order to investigate in parallel, the enrichment of common and (ultra-)rare variants related to schizophrenia in several functionally relevant gene sets. Four types of gene sets were constructed 1) protein-truncating variant (PTV)-intolerant (PI) genes 2) genes expressed in brain cell types and neurons ascertained from mouse and human brain tissue 3) genes defined by synaptic function and location and 4) intersection genes, i.e., PI genes that are expressed in the human and mouse brain cell gene sets. We show that common as well as (ultra-)rare schizophrenia-associated variants are overrepresented in PI genes, in excitatory neurons from the prefrontal cortex and hippocampus, medium spiny neurons, and genes enriched for synaptic processes. We also observed stronger enrichment in the intersection genes. Our findings suggest that across the allele frequency spectrum, genes and genetic variants likely to be under stringent selection, and those expressed in particular brain cell types, are involved in the same biological pathways influencing the risk for schizophrenia.

scholarly journals Sex-biased reduction in reproductive success drives selective constraint on human genes

2020 ◽  
Author(s):  
Eugene J. Gardner ◽  
Matthew D. C. Neville ◽  
Kaitlin E. Samocha ◽  
Kieron Barclay ◽  
Martin Kolk ◽  
...  
Keyword(s):  
Sexual Selection ◽  
Reproductive Success ◽  
Genetic Variants ◽  
Purifying Selection ◽  
Female Mate Choice ◽  
Selective Constraint ◽  
Human Populations ◽  
Protein Coding ◽  
Genome Wide ◽  
Human Genes

SummaryGenome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants. While genes under the strongest selective constraint are highly enriched for Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known. Here we show that genetic variants that damage these genes reduce reproductive success substantially in males but much less so in females. We present evidence that this reduction is mediated primarily by cognitive and behavioural traits, which renders male carriers of such variants less likely to find mating partners. These findings represent strong genetic evidence that sexual selection mediated through female mate choice is shaping the gene pool of contemporary human populations. Furthermore, these results suggest that sexual selection accounts for 21% of purifying selection against heterozygous variants that ablate protein-coding genes.

scholarly journals Cell Type-Specific Annotation and Fine Mapping of Variants Associated With Brain Disorders

2020 ◽  
Vol 11 ◽  
Author(s):  
Abolfazl Doostparast Torshizi ◽  
Iuliana Ionita-Laza ◽  
Kai Wang
Keyword(s):  
Genetic Variants ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Brain Disorders ◽  
Common Variants ◽  
Cell Type ◽  
Tissue Specific ◽  
Common Genetic Variants ◽  
Functional Consequences ◽  
Context Free

Common genetic variants confer susceptibility to a large number of complex brain disorders. Given that such variants predominantly localize in non-coding regions of the human genome, there is a significant challenge to predict and characterize their functional consequences. More importantly, most available computational methods, generally defined as context-free methods, output prediction scores regarding the functionality of genetic variants irrespective of the context, i.e., the tissue or cell-type affected by a disease, limiting the ability to predict the functional consequences of common variants on brain disorders. In this study, we introduce a comparative multi-step pipeline to investigate the relative effectiveness of context-specific and context-free approaches to prioritize disease causal variants. As an experimental case, we focused on schizophrenia (SCZ), a debilitating neuropsychiatric disease for which a large number of susceptibility variants is identified from genome-wide association studies. We tested over two dozen available methods and examined potential associations between the cell/tissue-specific mapping scores and open chromatin accessibility, and provided a prioritized map of SCZ risk loci for in vitro or in-vivo functional analysis. We found extensive differences between context-free and tissue-specific approaches and showed how they may play complementary roles. As a proof of concept, we found a few sets of genes, through a consensus mapping of both categories, including FURIN to be among the top hits. We showed that the genetic variants in this gene and related genes collectively dysregulate gene expression patterns in stem cell-derived neurons and characterize SCZ phenotypic manifestations, while genes which were not shared among highly prioritized candidates in both approaches did not demonstrate such characteristics. In conclusion, by combining context-free and tissue-specific predictions, our pipeline enables prioritization of the most likely disease-causal common variants in complex brain disorders.

Metaphors in Polish, English, Russian, and French perfumery discourse

2021 ◽  
Vol 11 (1) ◽  
pp. 143-170
Author(s):  
Magdalena Zawisławska ◽  
Marta Falkowska
Keyword(s):  
Statistical Analysis ◽  
Unequal Distribution

Abstract This paper examines metaphors in perfume reviews in four languages, namely Polish, English, Russian, and French. Some typical features of the perfumery discourse, similar across the four languages, have been highlighted, such as clustering, extension, and mixing metaphors. The authors also discuss the most typical schemata used in the conceptualization of perfumes. Although the analyzed texts exhibit a certain similarity, a statistical analysis of the reviews identifies some interesting discrepancies between the languages, that is: unequal distribution of metaphorical types, preferences in usage of perceptual and non-perceptual source frames, and variance in perfume conceptualization (perfume is a woman vs. perfume is a man).

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