scholarly journals Selection against archaic hominin genetic variation in regulatory regions

2019 ◽  
Author(s):  
Natalie Telis ◽  
Robin Aguilar ◽  
Kelley Harris
Keyword(s):  
Conditional Random Field ◽  
Fetal Brain ◽  
Purifying Selection ◽  
Hybrid Fitness ◽  
Regulatory Regions ◽  
Gene Dysregulation ◽  
Genomic Regions ◽  
Harmful Effects ◽  
New Mutations ◽  
Fetal Muscle

AbstractTraces of archaic hominin DNA persist in the human gene pool, but are systematically depleted around genes and other functionally important genomic regions. This suggests that many Neandertal and Denisovan alleles had harmful effects on hybrid fitness. We hypothesized that if some harmful effects were mediated by gene dysregulation in specific tissues, alleles previously flagged as archaic using a conditional random field (CRF) should be depleted from those tissues’ regulatory enhancers compared to “control” alleles matched for allele frequency and the strength of background selection. By this metric, both Neandertal and Denisovan variation appear depleted from enhancers, particularly enhancers that show pleiotropic activity across tissues. This depletion is driven by young archaic SNPs that the CRF confidently identifies as private to Neandertals or Denisovans; older variants that were likely present in both archaic species are not depleted from enhancers. We found that enhancer pleiotropy is not only a predictor of archaic SNP depletion, but also a predictor of intolerance to new mutations as measured by both phastCons scores and the frequency spectrum of African variation. In other respects, however, the landscape of selection against young archaic alleles appears qualitatively different from the landscape of ordinary purifying selection, suggesting that archaic alleles had a different distribution of fitness effects from ordinary new mutations. Most strikingly, fetal brain and muscle are the tissues most depleted of young archaic variation in their regulatory regions, but only brain enhancers appear commensurately intolerant to new mutations. In contrast, fetal muscle enhancers show no evidence of elevated purifying selection relative to other enhancers. This suggests that epistatic incompatibility between human and archaic alleles is needed to explain the degree of archaic variant depletion from fetal muscle enhancers, perhaps due to divergent selection for higher muscle mass in archaic hominins compared to humans.

scholarly journals Functional alterations caused by mutations reflect evolutionary trends of SARS-CoV-2

2021 ◽  
Author(s):  
Liang Cheng ◽  
Xudong Han ◽  
Zijun Zhu ◽  
Changlu Qi ◽  
Ping Wang ◽  
...  
Keyword(s):  
Reference Genome ◽  
Sequence Data ◽  
Purifying Selection ◽  
Virus Genome ◽  
Receptor Binding Domain ◽  
Evolutionary Trends ◽  
Synonymous Mutations ◽  
Almost All ◽  
Virus Strains ◽  
New Mutations

Abstract Since the first report of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the COVID-19 pandemic has spread rapidly worldwide. Due to the limited virus strains, few key mutations that would be very important with the evolutionary trends of virus genome were observed in early studies. Here, we downloaded 1809 sequence data of SARS-CoV-2 strains from GISAID before April 2020 to identify mutations and functional alterations caused by these mutations. Totally, we identified 1017 nonsynonymous and 512 synonymous mutations with alignment to reference genome NC_045512, none of which were observed in the receptor-binding domain (RBD) of the spike protein. On average, each of the strains could have about 1.75 new mutations each month. The current mutations may have few impacts on antibodies. Although it shows the purifying selection in whole-genome, ORF3a, ORF8 and ORF10 were under positive selection. Only 36 mutations occurred in 1% and more virus strains were further analyzed to reveal linkage disequilibrium (LD) variants and dominant mutations. As a result, we observed five dominant mutations involving three nonsynonymous mutations C28144T, C14408T and A23403G and two synonymous mutations T8782C, and C3037T. These five mutations occurred in almost all strains in April 2020. Besides, we also observed two potential dominant nonsynonymous mutations C1059T and G25563T, which occurred in most of the strains in April 2020. Further functional analysis shows that these mutations decreased protein stability largely, which could lead to a significant reduction of virus virulence. In addition, the A23403G mutation increases the spike-ACE2 interaction and finally leads to the enhancement of its infectivity. All of these proved that the evolution of SARS-CoV-2 is toward the enhancement of infectivity and reduction of virulence.

scholarly journals Impact of male trait exaggeration on sex-biased gene expression and genome architecture in a water strider

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
William Toubiana ◽  
David Armisén ◽  
Corentin Dechaud ◽  
Roberto Arbore ◽  
Abderrahman Khila
Keyword(s):  
Gene Expression ◽  
Sexual Selection ◽  
Enrichment Analysis ◽  
Purifying Selection ◽  
Genome Architecture ◽  
Water Strider ◽  
Secondary Sexual Traits ◽  
Genomic Regions ◽  
Small Clusters ◽  
Secondary Sexual

Abstract Background Exaggerated secondary sexual traits are widespread in nature and often evolve under strong directional sexual selection. Although heavily studied from both theoretical and empirical viewpoints, we have little understanding of how sexual selection influences sex-biased gene regulation during the development of exaggerated secondary sexual phenotypes, and how these changes are reflected in genomic architecture. This is primarily due to the limited availability of representative genomes and associated tissue and sex transcriptomes to study the development of these traits. Here we present the genome and developmental transcriptomes, focused on the legs, of the water strider Microvelia longipes, a species where males exhibit strikingly long third legs compared to females, which they use as weapons. Results We generated a high-quality genome assembly with 90% of the sequence captured in 13 scaffolds. The most exaggerated legs in males were particularly enriched in both sex-biased and leg-biased genes, indicating a specific signature of gene expression in association with trait exaggeration. We also found that male-biased genes showed patterns of fast evolution compared to non-biased and female-biased genes, indicative of directional or relaxed purifying selection. By contrast to male-biased genes, female-biased genes that are expressed in the third legs, but not the other legs, are over-represented in the X chromosome compared to the autosomes. An enrichment analysis for sex-biased genes along the chromosomes revealed also that they arrange in large genomic regions or in small clusters of two to four consecutive genes. The number and expression of these enriched regions were often associated with the exaggerated legs of males, suggesting a pattern of common regulation through genomic proximity in association with trait exaggeration. Conclusion Our findings indicate how directional sexual selection may drive sex-biased gene expression and genome architecture along the path to trait exaggeration and sexual dimorphism.

scholarly journals Allele frequency divergence reveals ubiquitous influence of positive selection in Drosophila

2021 ◽  
Author(s):  
Jason Bertram
Keyword(s):  
Allele Frequency ◽  
Evolutionary Biology ◽  
Polymorphic Locus ◽  
Purifying Selection ◽  
Allele Frequencies ◽  
Intermediate Allele ◽  
Genome Wide ◽  
Signature Of Selection ◽  
Basic Objective ◽  
Genomic Regions

Resolving the role of natural selection is a basic objective of evolutionary biology. It is generally difficult to detect the influence of selection because ubiquitous non-selective stochastic change in allele frequencies (genetic drift) degrades evidence of selection. As a result, selection scans typically only identify genomic regions that have undergone episodes of intense selection. Yet it seems likely such episodes are the exception; the norm is more likely to involve subtle, concurrent selective changes at a large number of loci. We develop a new theoretical approach that uncovers a previously undocumented genome-wide signature of selection in the collective divergence of allele frequencies over time. Applying our approach to temporally-resolved allele frequency measurements from laboratory and wild Drosophila populations, we quantify the selective contribution to allele frequency divergence and find that selection has substantial effects on much of the genome. We further quantify the magnitude of the total selection coefficient (a measure of the combined effects of direct and linked selection) at a typical polymorphic locus, and find this to be large (of order 1%) even though most mutations are not directly under selection. We find that selective allele frequency divergence is substantial at intermediate allele frequencies, which we argue is most parsimoniously explained by positive --- not purifying --- selection. Thus, in these populations most mutations are far from evolving neutrally in the short term (tens of generations), including mutations with neutral fitness effects, and the result cannot be explained simply as a purging of deleterious mutations.

scholarly journals Sites of active gene regulation in the prenatal frontal cortex and their role in neuropsychiatric disorders

2021 ◽  
Author(s):  
Manuela R. Kouakou ◽  
Darren Cameron ◽  
Eilis Hannon ◽  
Emma L. Dempster ◽  
Jonathan Mill ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Major Depressive Disorder ◽  
Genetic Variation ◽  
Frontal Cortex ◽  
Fetal Brain ◽  
Neuropsychiatric Disorders ◽  
Open Chromatin ◽  
Major Depressive ◽  
Genomic Regions ◽  
Neuropsychiatric Conditions

Common genetic variation appears to largely influence risk for neuropsychiatric disorders through effects on gene regulation. It is therefore possible to shed light on the biology of these conditions by testing for enrichment of associated genetic variation within regulatory genomic regions operating in specific tissues or cell types. Here, we have used ATAC-Seq to map open chromatin (an index of active regulatory genomic regions) in bulk tissue, NeuN+ and NeuN- nuclei from the prenatal human frontal cortex, and tested enrichment of SNP heritability for 5 neuropsychiatric disorders (autism spectrum disorder, ADHD, bipolar disorder, major depressive disorder and schizophrenia) within these regions. We observed significant enrichment of SNP heritability for ADHD, major depressive disorder and schizophrenia within open chromatin regions mapped in bulk fetal frontal cortex, and for all 5 tested neuropsychiatric conditions when we restricted these sites to those overlapping histone modifications indicative of enhancers (H3K4me1) or promoters (H3K4me3) in fetal brain. SNP heritability for neuropsychiatric disorders was significantly enriched in open chromatin regions identified in fetal frontal cortex NeuN- as well as NeuN+ nuclei overlapping fetal brain H3K4me1 or H3K4me3 sites. We additionally demonstrate the utility of our mapped open chromatin regions for prioritizing potentially functional SNPs at genome-wide significant risk loci for neuropsychiatric disorders. Our data provide evidence for an early neurodevelopmental component to a range of neuropsychiatric conditions and highlight an important role for regulatory genomic regions active within both NeuN+ and NeuN- cells of the prenatal brain.

scholarly journals Population genomic evidence of selection on structural variants in a natural hybrid zone

2022 ◽  
Author(s):  
Linyi Zhang ◽  
Samridhi Chaturvedi ◽  
Chris Nice ◽  
Lauren Lucas ◽  
Zachariah Gompert
Keyword(s):  
Reproductive Isolation ◽  
Hybrid Zone ◽  
Structural Variants ◽  
Hybrid Fitness ◽  
Genome Wide ◽  
Oxford Nanopore ◽  
Jackson Hole ◽  
Long Read ◽  
Genomic Regions

Structural variants (SVs) can promote speciation by directly causing reproductive isolation or by suppressing recombination across large genomic regions. Whereas examples of each mechanism have been documented, systematic tests of the role of SVs in speciation are lacking. Here, we take advantage of long-read (Oxford nanopore) whole-genome sequencing and a hybrid zone between two Lycaeides butterfly taxa (L. melissa and Jackson Hole Lycaeides) to comprehensively evaluate genome-wide patterns of introgression for SVs and relate these patterns to hypotheses about speciation. We found >100,000 SVs segregating within or between the two hybridizing species. SVs and SNPs exhibited similar levels of genetic differentiation between species, with the exception of inversions, which were more differentiated. We detected credible variation in patterns of introgression among SV loci in the hybrid zone, with 562 of 1419 ancestry-informative SVs exhibiting genomic clines that deviating from null expectations based on genome-average ancestry. Overall, hybrids exhibited a directional shift towards Jackson Hole Lycaeides ancestry at SV loci, consistent with the hypothesis that these loci experienced more selection on average then SNP loci. Surprisingly, we found that deletions, rather than inversions, showed the highest skew towards excess introgression from Jackson Hole Lycaeides. Excess Jackson Hole Lycaeides ancestry in hybrids was also especially pronounced for Z-linked SVs and inversions containing many genes. In conclusion, our results show that SVs are ubiquitous and suggest that SVs in general, but especially deletions, might contribute disproportionately to hybrid fitness and thus (partial) reproductive isolation.

scholarly journals Background selection and biased gene conversion affect more than 95% of the human genome and bias demographic inferences

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Fanny Pouyet ◽  
Simon Aeschbacher ◽  
Alexandre Thiéry ◽  
Laurent Excoffier
Keyword(s):  
Gene Conversion ◽  
Purifying Selection ◽  
Genomic Diversity ◽  
Background Selection ◽  
Recombination Rates ◽  
Biased Gene Conversion ◽  
Synonymous Sites ◽  
History Of ◽  
Demographic Inference ◽  
Genomic Regions

Disentangling the effect on genomic diversity of natural selection from that of demography is notoriously difficult, but necessary to properly reconstruct the history of species. Here, we use high-quality human genomic data to show that purifying selection at linked sites (i.e. background selection, BGS) and GC-biased gene conversion (gBGC) together affect as much as 95% of the variants of our genome. We find that the magnitude and relative importance of BGS and gBGC are largely determined by variation in recombination rate and base composition. Importantly, synonymous sites and non-transcribed regions are also affected, albeit to different degrees. Their use for demographic inference can lead to strong biases. However, by conditioning on genomic regions with recombination rates above 1.5 cM/Mb and mutation types (C↔G, A↔T), we identify a set of SNPs that is mostly unaffected by BGS or gBGC, and that avoids these biases in the reconstruction of human history.

scholarly journals Patterns of variation in cis-regulatory regions: examining evidence of purifying selection

BMC Genomics ◽  
2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Thijessen Naidoo ◽  
Per Sjödin ◽  
Carina Schlebusch ◽  
Mattias Jakobsson
Keyword(s):  
Purifying Selection ◽  
Regulatory Regions ◽  
In Cis

scholarly journals Identification of Novel Regulatory Regions Induced by Intrauterine Growth Restriction in Rat Islets

Endocrinology ◽  
2021 ◽  
Author(s):  
Yu-Chin Lien ◽  
Sara E Pinney ◽  
Xueqing Maggie Lu ◽  
Rebecca A Simmons
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Regulatory Regions ◽  
Binding Motifs ◽  
Intrauterine Growth ◽  
Gene Dysregulation ◽  
Transcription Factor Binding Motifs ◽  
Significant Expression

Abstract Intrauterine growth restriction (IUGR) leads to development of type 2 diabetes in adulthood and the permanent alterations in gene expression implicate an epigenetic mechanism. Using a rat model of IUGR, we performed TrueSeq-HELP Tagging to assess the association of DNA methylation changes and gene dysregulation in islets. We identified 511 differentially methylated regions (DMRs) and 4377 significantly altered single CpG sites. Integrating the methylome and our published transcriptome datasets resulted in the identification of pathways critical for islet function. The identified DMRs were enriched with transcription factor binding motifs, such as Elk1, Etv1, Foxa1, Foxa2, Pax7, Stat3, Hnf1, and AR. In silico analysis of 3D chromosomal interactions using human pancreas and islet Hi-C datasets identified interactions between 14 highly conserved DMRs and 35 genes with significant expression changes at an early age, many of which persisted in adult islets. In adult islets, there were far more interactions between DMRs and genes with significant expression changes identified with Hi-C and most of them were critical to islet metabolism and insulin secretion. The methylome was integrated with our published genome-wide histone modification datasets from IUGR islets resulting in further characterization of important regulatory regions of the genome altered by IUGR containing both significant changes in DNA methylation and specific histone marks. In summary we identified novel regulatory regions in islets after exposure to IUGR suggesting that epigenetic changes at key transcription factor binding motifs and other gene regulatory regions may contribute to gene dysregulation and an abnormal islet phenotype in IUGR rats.

scholarly journals SgTiler: a fast method to design tiling sgRNAs for CRISPR/Cas9 mediated screening

2017 ◽  
Author(s):  
Musaddeque Ahmed ◽  
Housheng Hansen He
Keyword(s):  
Source Code ◽  
Regions Of Interest ◽  
Fast Method ◽  
Command Line ◽  
Regulatory Regions ◽  
Guide Rnas ◽  
Command Line Tool ◽  
Genomic Regions ◽  
The Web ◽  
Target Effects

AbstractSummaryScreening of genomic regions of interest using CRISPR/Cas9 is getting increasingly popular. The system requires designing of single guide RNAs (sgRNAs) that can efficiently guide the Cas9 endonuclease to the targeted region with minimal off-target effects. Tiling sgRNAs is the most effective way to perturb regulatory regions, such as promoters and enhancers. sgTiler is the first tool that provides a fast method for designing tiling sgRNAs.Availability and ImplementationsgTiler is a command line tool that requires only one command to execute. Its source code is freely available on the web at https://github.com/HansenHeLab/sgTiler. sgTiler is implemented in Python and supported on any platform with Python and Bowtie.

scholarly journals Expected patterns of local ancestry in a hybrid zone

2018 ◽  
Author(s):  
Joel Smith ◽  
Bret Payseur ◽  
John Novembre
Keyword(s):  
Reproductive Isolation ◽  
Purifying Selection ◽  
Hybrid Zones ◽  
Qualitative Properties ◽  
Hybrid Fitness ◽  
Local Ancestry ◽  
Migration History ◽  
Local Patterns ◽  
Candidate Loci ◽  
Genomic Patterns

1AbstractThe initial drivers of reproductive isolation between species are poorly characterized. In cases where partial reproductive isolation exists, genomic patterns of variation in hybrid zones may provide clues about the barriers to gene flow which arose first during the early stages of speciation. Purifying selection against incompatible substitutions that reduce hybrid fitness has the potential to distort local patterns of ancestry relative to background patterns across the genome. The magnitude and qualitative properties of this pattern are dependent on several factors including migration history and the relative fitnesses for different combinations of incompatible alleles. We present a model which may account for these factors and highlight the potential for its use in verifying the action of natural selection on candidate loci implicated in reducing hybrid fitness.

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