scholarly journals OLGenie: Estimating Natural Selection to Predict Functional Overlapping Genes

2019 ◽  
Author(s):  
Chase W. Nelson ◽  
Zachary Ardern ◽  
Xinzhu Wei
Keyword(s):  
Natural Selection ◽  
Purifying Selection ◽  
Biological Sequences ◽  
Overlapping Genes ◽  
Protein Coding ◽  
Discriminatory Ability ◽  
Viral Genomes ◽  
Protein Coding Genes ◽  
Scalable Methods ◽  
Hiv 1

AbstractPurifying (negative) natural selection is a hallmark of functional biological sequences, and can be detected in protein-coding genes using the ratio of nonsynonymous to synonymous substitutions per site (dN/dS). However, when two genes overlap the same nucleotide sites in different frames, synonymous changes in one gene may be nonsynonymous in the other, perturbing dN/dS. Thus, scalable methods are needed to estimate functional constraint specifically for overlapping genes (OLGs). We propose OLGenie, which implements a modification of the Wei-Zhang method. Assessment with simulations and controls from viral genomes (58 OLGs and 176 non-OLGs) demonstrates low false positive rates and good discriminatory ability in differentiating true OLGs from non-OLGs. We also apply OLGenie to the unresolved case of HIV-1’s putative antisense protein gene, showing significant purifying selection. OLGenie can be used to study known OLGs and to predict new OLGs in genome annotation. Software and example data are freely available at https://github.com/chasewnelson/OLGenie.

scholarly journals OLGenie: Estimating Natural Selection to Predict Functional Overlapping Genes

2020 ◽  
Author(s):  
Chase W Nelson ◽  
Zachary Ardern ◽  
Xinzhu Wei
Keyword(s):  
Natural Selection ◽  
Protein Gene ◽  
Purifying Selection ◽  
Biological Sequences ◽  
Overlapping Genes ◽  
Protein Coding ◽  
Discriminatory Ability ◽  
Viral Genomes ◽  
Scalable Methods ◽  
Hiv 1

Abstract Purifying (negative) natural selection is a hallmark of functional biological sequences, and can be detected in protein-coding genes using the ratio of nonsynonymous to synonymous substitutions per site (dN/dS). However, when two genes overlap the same nucleotide sites in different frames, synonymous changes in one gene may be nonsynonymous in the other, perturbing dN/dS. Thus, scalable methods are needed to estimate functional constraint specifically for overlapping genes (OLGs). We propose OLGenie, which implements a modification of the Wei-Zhang method. Assessment with simulations and controls from viral genomes (58 OLGs and 176 non-OLGs) demonstrates low false positive rates and good discriminatory ability in differentiating true OLGs from non-OLGs. We also apply OLGenie to the unresolved case of HIV-1’s putative antisense protein gene, showing significant purifying selection. OLGenie can be used to study known OLGs and to predict new OLGs in genome annotation. Software and example data are freely available at https://github.com/chasewnelson/OLGenie.

scholarly journals Analysis of Stop Codons within Prokaryotic Protein-Coding Genes Suggests Frequent Readthrough Events

2021 ◽  
Vol 22 (4) ◽  
pp. 1876
Author(s):  
Frida Belinky ◽  
Ishan Ganguly ◽  
Eugenia Poliakov ◽  
Vyacheslav Yurchenko ◽  
Igor B. Rogozin
Keyword(s):  
Stop Codon ◽  
Purifying Selection ◽  
Protein Product ◽  
Intermediate Step ◽  
Protein Coding ◽  
Stop Codons ◽  
Protein Coding Genes ◽  
Synonymous Sites ◽  
Prokaryotic Protein ◽  
Sense Codon

Nonsense mutations turn a coding (sense) codon into an in-frame stop codon that is assumed to result in a truncated protein product. Thus, nonsense substitutions are the hallmark of pseudogenes and are used to identify them. Here we show that in-frame stop codons within bacterial protein-coding genes are widespread. Their evolutionary conservation suggests that many of them are not pseudogenes, since they maintain dN/dS values (ratios of substitution rates at non-synonymous and synonymous sites) significantly lower than 1 (this is a signature of purifying selection in protein-coding regions). We also found that double substitutions in codons—where an intermediate step is a nonsense substitution—show a higher rate of evolution compared to null models, indicating that a stop codon was introduced and then changed back to sense via positive selection. This further supports the notion that nonsense substitutions in bacteria are relatively common and do not necessarily cause pseudogenization. In-frame stop codons may be an important mechanism of regulation: Such codons are likely to cause a substantial decrease of protein expression levels.

scholarly journals Overlapping protein-coding genes in human genome and their coincidental expression in tissues

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chao-Hsin Chen ◽  
Chao-Yu Pan ◽  
Wen-chang Lin
Keyword(s):  
Human Genome ◽  
Expression Profiles ◽  
Tissue Expression ◽  
Human Protein ◽  
Clear Understanding ◽  
Overlapping Genes ◽  
Genome Sequences ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Overlapping Gene

Abstract The completion of human genome sequences and the advancement of next-generation sequencing technologies have engendered a clear understanding of all human genes. Overlapping genes are usually observed in compact genomes, such as those of bacteria and viruses. Notably, overlapping protein-coding genes do exist in human genome sequences. Accordingly, we used the current Ensembl gene annotations to identify overlapping human protein-coding genes. We analysed 19,200 well-annotated protein-coding genes and determined that 4,951 protein-coding genes overlapped with their adjacent genes. Approximately a quarter of all human protein-coding genes were overlapping genes. We observed different clusters of overlapping protein-coding genes, ranging from two genes (paired overlapping genes) to 22 genes. We also divided the paired overlapping protein-coding gene groups into four subtypes. We found that the divergent overlapping gene subtype had a stronger expression association than did the subtypes of 5ʹ-tandem overlapping and 3ʹ-tandem overlapping genes. The majority of paired overlapping genes exhibited comparable coincidental tissue expression profiles; however, a few overlapping gene pairs displayed distinctive tissue expression association patterns. In summary, we have carefully examined the genomic features and distributions about human overlapping protein-coding genes and found coincidental expression in tissues for most overlapping protein-coding genes.

scholarly journals Standard codon substitution models overestimate purifying selection for non-stationary data

2016 ◽  
Author(s):  
Benjamin D Kaehler ◽  
Von Bing Yap ◽  
Gavin A Huttley
Keyword(s):  
Natural Selection ◽  
De Novo ◽  
Purifying Selection ◽  
Neutral Evolution ◽  
Protein Coding ◽  
Synonymous Substitutions ◽  
New Model ◽  
Sequence Composition ◽  
Codon Substitution ◽  
Substitution Models

Estimation of natural selection on protein-coding sequences is a key comparative genomics approach for de novo prediction of lineage specific adaptations. Selective pressure is measured on a per-gene basis by comparing the rate of non-synonymous substitutions to the rate of neutral evolution, typically assumed to be the rate of synonymous substitutions. All published codon substitution models have been time-reversible and thus assume that sequence composition does not change over time. We previously demonstrated that if time-reversible DNA substitution models are applied blindly in the presence of changing sequence composition, the number of substitutions is systematically biased towards overestimation. We extend these findings to the case of codon substitution models and further demonstrate that the ratio of non-synonymous to synonymous rates of substitution tends to be underestimated over three data sets of insects, mammals, and vertebrates. Our basis for comparison is a non-stationary codon substitution model that allows sequence composition to change. Model selection and model fit results demonstrate that our new model tends to fit the data better. Direct measurement of non-stationarity shows that bias in estimates of natural selection and genetic distance increases with the degree of violation of the stationarity assumption. Additionally, inferences drawn under time-reversible models are systematically affected by compositional divergence. As genomic sequences accumulate at an accelerating rate, the importance of accurate de novo estimation of natural selection increases. Our results establish that our new model provides a more robust perspective on this fundamental quantity.

scholarly journals Protein-Coding Genes of Helicobacter pylori Predominantly Present Purifying Selection though Many Membrane Proteins Suffer from Selection Pressure: A Proposal to Analyze Bacterial Pangenomes

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 377
Author(s):  
Alejandro Rubio ◽  
Antonio Pérez-Pulido
Keyword(s):  
Helicobacter Pylori ◽  
Membrane Proteins ◽  
Selection Pressure ◽  
Purifying Selection ◽  
Protein Coding ◽  
Evolutionary Selection ◽  
Protein Coding Genes ◽  
The Core ◽  
Genes Encoding ◽  
Selection For

The current availability of complete genome sequences has allowed knowing that bacterial genomes can bear genes not present in the genome of all the strains from a specific species. So, the genes shared by all the strains comprise the core of the species, but the pangenome can be much greater and usually includes genes appearing in one only strain. Once the pangenome of a species is estimated, other studies can be undertaken to generate new knowledge, such as the study of the evolutionary selection for protein-coding genes. Most of the genes of a pangenome are expected to be subject to purifying selection that assures the conservation of function, especially those in the core group. However, some genes can be subject to selection pressure, such as genes involved in virulence that need to escape to the host immune system, which is more common in the accessory group of the pangenome. We analyzed 180 strains of Helicobacter pylori, a bacterium that colonizes the gastric mucosa of half the world population and presents a low number of genes (around 1500 in a strain and 3000 in the pangenome). After the estimation of the pangenome, the evolutionary selection for each gene has been calculated, and we found that 85% of them are subject to purifying selection and the remaining genes present some grade of selection pressure. As expected, the latter group is enriched with genes encoding for membrane proteins putatively involved in interaction to host tissues. In addition, this group also presents a high number of uncharacterized genes and genes encoding for putative spurious proteins. It suggests that they could be false positives from the gene finders used for identifying them. All these results propose that this kind of analyses can be useful to validate gene predictions and functionally characterize proteins in complete genomes.

scholarly journals Evolution of Pulmonate Gastropod Mitochondrial Genomes: Comparisons of Gene Organizations of Euhadra, Cepaea and Albinaria and Implications of Unusual tRNA Secondary Structures

Genetics ◽  
1997 ◽  
Vol 145 (3) ◽  
pp. 749-758 ◽  
Author(s):  
Nika Yamazaki ◽  
Rei Ueshima ◽  
Jonathan A Terrett ◽  
Shin-ichi Yokobori ◽  
Masayuki Kaifu ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Rrna Genes ◽  
Mitochondrial Genomes ◽  
Trna Genes ◽  
Overlapping Genes ◽  
Protein Coding ◽  
Cepaea Nemoralis ◽  
Protein Coding Genes ◽  
Editing Process ◽  
Pulmonate Gastropod

Complete gene organizations of the mitochondrial genomes of three pulmonate gastropods, Euhadra herklotsi, Cepaea nemoralis and Albinaria coerulea, permit comparisons of their gene organizations. Euhadra and Cepaea are classified in the same superfamily, Helicoidea, yet they show several differences in the order of tRNA and protein coding genes. Albinaria is distantly related to the other two genera but shares the same gene order in one part of its mitochondrial genome with Euhadra and in another part with Cepaea. Despite their small size (14.1 – 14.5 kbp), these snail mtDNAs encode 13 protein genes, two rRNA genes and at least 22 tRNA genes. These genomes exhibit several unusual or unique features compared to other published metazoan mitochondrial genomes, including those of other molluscs. Several tRNAs predicted from the DNA sequences possess bizarre structures lacking either the T stem or the D stem, similar to the situation seen in nematode mt-tRNAs. The acceptor stems of many tRNAs show a considerable number of mismatched basepairs, indicating that the RNA editing process recently demonstrated in Euhadra is widespread in the pulmonate gastropods. Strong selection acting on mitochondrial genomes of these animals would have resulted in frequent occurrence of the mismatched basepairs in regions of overlapping genes.

scholarly journals Extreme purifying selection against point mutations in the human genome

2021 ◽  
Author(s):  
Noah Dukler ◽  
Mehreen R Mughal ◽  
Ritika Ramani ◽  
Yi-Fei Huang ◽  
Adam Siepel
Keyword(s):  
Human Genome ◽  
De Novo ◽  
Point Mutations ◽  
Purifying Selection ◽  
Selection Coefficient ◽  
Sequencing Data ◽  
Protein Coding ◽  
Coding Regions ◽  
Protein Coding Genes ◽  
Selective Effects

Genome sequencing of tens of thousands of human individuals has recently enabled the measurement of large selective effects for mutations to protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring similar selective effects at individual sites in noncoding as well as in coding regions of the human genome. ExtRaINSIGHT estimates the prevalance of strong purifying selection, or "ultraselection" (λs), as the fractional depletion of rare single-nucleotide variants (minor allele frequency <0.1%) in a target set of genomic sites relative to matched sites that are putatively neutrally evolving, in a manner that controls for local variation and neighbor-dependence in mutation rate. We show using simulations that, above an appropriate threshold, λs is closely related to the average site-specific selection coefficient against heterozygous point mutations, as predicted at mutation-selection balance. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find particularly strong evidence of ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. Moreover, our estimated selection coefficient against heterozygous amino-acid replacements across the genome (at 1.4%) is substantially larger than previous estimates based on smaller sample sizes. By contrast, we find weak evidence of ultraselection in other noncoding RNAs and transcription factor binding sites, and only modest evidence in ultraconserved elements and human accelerated regions. We estimate that ~0.3-0.5% of the human genome is ultraselected, with one third to one half of ultraselected sites falling in coding regions. These estimates suggest ~0.3-0.4 lethal or nearly lethal de novo mutations per potential human zygote, together with ~2 de novo mutations that are more weakly deleterious. Overall, our study sheds new light on the genome-wide distribution of fitness effects for new point mutations by combining deep new sequencing data sets and classical theory from population genetics.

scholarly journals Patterns of Natural Selection on Mitochondrial Protein-Coding Genes in Lungless Salamanders: Relaxed Purifying Selection and Presence of Positively Selected Codon Sites in the Family Plethodontidae

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Ryosuke Kakehashi ◽  
Atsushi Kurabayashi
Keyword(s):  
Mitochondrial Protein ◽  
Purifying Selection ◽  
Recent Common Ancestor ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Most Recent Common Ancestor ◽  
Plethodontid Salamander ◽  
Branch Model ◽  
The Family ◽  
Oxygen Requirements

There are two distinct lungless groups in caudate amphibians (salamanders and newts) (the family Plethodontidae and the genus Onychodactylus, from the family Hynobiidae). Lunglessness is considered to have evolved in response to environmental and/or ecological adaptation with respect to oxygen requirements. We performed selection analyses on lungless salamanders to elucidate the selective patterns of mitochondrial protein-coding genes associated with lunglessness. The branch model and RELAX analyses revealed the occurrence of relaxed selection (an increase of the dN/dS ratio = ω value) in most mitochondrial protein-coding genes of plethodontid salamander branches but not in those of Onychodactylus. Additional branch model and RELAX analyses indicated that direct-developing plethodontids showed the relaxed pattern for most mitochondrial genes, although metamorphosing plethodontids had fewer relaxed genes. Furthermore, aBSREL analysis detected positively selected codons in three plethodontid branches but not in Onychodactylus. One of these three branches corresponded to the most recent common ancestor, and the others corresponded with the most recent common ancestors of direct-developing branches within Hemidactyliinae. The positive selection of mitochondrial protein-coding genes in Plethodontidae is probably associated with the evolution of direct development.

scholarly journals Convergent evolution as an indicator for selection during acute HIV-1 infection

2017 ◽  
Author(s):  
Frederic Bertels ◽  
Karin J. Metzner ◽  
Roland Regoes
Keyword(s):  
Convergent Evolution ◽  
Adaptive Immune System ◽  
Purifying Selection ◽  
Selective Advantage ◽  
Single Individual ◽  
Viral Genomes ◽  
Acute Hiv ◽  
Different Populations ◽  
Neutral Models ◽  
Hiv 1

AbstractConvergent evolution describes the process of different populations acquiring similar phenotypes or genotypes. Complex organisms with large genomes only rarely and only under very strong selection converge to the same genotype. In contrast, independent virus populations with very small genomes often acquire identical mutations. Here we test the hypothesis of whether convergence in early HIV-1 infection is common enough to serve as an indicator for selection. To this end, we measure the number of convergent mutations in a well-studied dataset of full-length HIV-1envgenes sampled from HIV-1 infected individuals during early infection. We compare this data to a neutral model and find an excess of convergent mutations. Convergent mutations are not evenly distributed across the env gene, but more likely to occur in gp41, which suggests that convergent mutations provide a selective advantage and hence are positively selected. In contrast, mutations that are only found in an HIV-1 population of a single individual are significantly affected by purifying selection. Our analysis suggests that comparisons between convergent and private mutations with neutral models allow us to identify positive and negative selection in small viral genomes. Our results also show that selection significantly shapes HIV-1 populations even before the onset of the adaptive immune system.

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