Quasi-neutral molecular evolution — When positive and negative selection cancel out

AbstractIn the absence of both positive and negative selection, DNA sequences evolve at the neutral rate, R = 1. Due to the prevalence of negative selection, R∼1 is rarely achieved in organismal evolution. However, when R ∼ 1 is observed, it does not necessarily indicate neutral evolution because positive and negative selection could be equally strong but in opposite directions - hereby referred to as quasi-neutrality. We now show that somatic-cell evolution could be the paradigm of quasi-neutral evolution for these reasons: 1) Quasi-neutrality is much more likely in small populations (size N < 50) than in large ones; 2) Stem cell population sizes in single niches of normal tissues, from which tumors likely emerges, have small N’s (usually < 50); 3) the genome-wide evolutionary rate across tissue types is close to R = 1; 4) Relative to the average of R ∼ 1, many genes evolve at a much higher or lower rate, thus hinting both positive and negative selection; 5) When N < 50, selection efficacy decreases rapidly as N decreases even when the selection intensity stays constant; 6) Notably, N is smaller in the small intestine (SmI) than in the colon (CO); hence, the ∼ 70 fold higher rate of phenotypic evolution (observed as cancer risk) in the latter can be explained by the greater efficacy of selection, which then leads to the fixation of more advantageous mutations and fewer deleterious ones in the CO. Under quasineutrality, positive and negative selection can be measured in the same system as the two forces are simultaneously present or absent.

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Large Number of Replacement Polymorphisms in Rapidly Evolving Genes of Drosophila: Implications for Genome-Wide Surveys of DNA Polymorphism

Genetics ◽

10.1093/genetics/153.4.1717 ◽

1999 ◽

Vol 153 (4) ◽

pp. 1717-1729 ◽

Cited By ~ 4

Author(s):

Karl J Schmid ◽

Loredana Nigro ◽

Charles F Aquadro ◽

Diethard Tautz

Keyword(s):

Recombination Rate ◽

Current Knowledge ◽

Purifying Selection ◽

Neutral Evolution ◽

Nucleotide Polymorphism ◽

Effective Population ◽

Nucleotide Substitutions ◽

Large Numbers ◽

Genome Wide ◽

Population Sizes

AbstractWe present a survey of nucleotide polymorphism of three novel, rapidly evolving genes in populations of Drosophila melanogaster and D. simulans. Levels of silent polymorphism are comparable to other loci, but the number of replacement polymorphisms is higher than that in most other genes surveyed in D. melanogaster and D. simulans. Tests of neutrality fail to reject neutral evolution with one exception. This concerns a gene located in a region of high recombination rate in D. simulans and in a region of low recombination rate in D. melanogaster, due to an inversion. In the latter case it shows a very low number of polymorphisms, presumably due to selective sweeps in the region. Patterns of nucleotide polymorphism suggest that most substitutions are neutral or nearly neutral and that weak (positive and purifying) selection plays a significant role in the evolution of these genes. At all three loci, purifying selection of slightly deleterious replacement mutations appears to be more efficient in D. simulans than in D. melanogaster, presumably due to different effective population sizes. Our analysis suggests that current knowledge about genome-wide patterns of nucleotide polymorphism is far from complete with respect to the types and range of nucleotide substitutions and that further analysis of differences between local populations will be required to understand the forces more completely. We note that rapidly diverging and nearly neutrally evolving genes cannot be expected only in the genome of Drosophila, but are likely to occur in large numbers also in other organisms and that their function and evolution are little understood so far.

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Faculty Opinions recommendation of Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1026953.326505 ◽

2005 ◽

Author(s):

Charles Auffray

Keyword(s):

Expression Profiles ◽

Normal Tissues ◽

Genome Wide ◽

Genome Wide Survey

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Bayes Estimation of Species Divergence Times and Ancestral Population Sizes Using DNA Sequences From Multiple Loci

Genetics ◽

10.1093/genetics/164.4.1645 ◽

2003 ◽

Vol 164 (4) ◽

pp. 1645-1656 ◽

Cited By ~ 3

Author(s):

Bruce Rannala ◽

Ziheng Yang

Keyword(s):

Dna Sequences ◽

Gene Tree ◽

Species Tree ◽

Bayes Estimation ◽

Ancestral Population ◽

Divergence Times ◽

Gene Trees ◽

Species Divergence ◽

Multiple Loci ◽

Population Sizes

Abstract The effective population sizes of ancestral as well as modern species are important parameters in models of population genetics and human evolution. The commonly used method for estimating ancestral population sizes, based on counting mismatches between the species tree and the inferred gene trees, is highly biased as it ignores uncertainties in gene tree reconstruction. In this article, we develop a Bayes method for simultaneous estimation of the species divergence times and current and ancestral population sizes. The method uses DNA sequence data from multiple loci and extracts information about conflicts among gene tree topologies and coalescent times to estimate ancestral population sizes. The topology of the species tree is assumed known. A Markov chain Monte Carlo algorithm is implemented to integrate over uncertain gene trees and branch lengths (or coalescence times) at each locus as well as species divergence times. The method can handle any species tree and allows different numbers of sequences at different loci. We apply the method to published noncoding DNA sequences from the human and the great apes. There are strong correlations between posterior estimates of speciation times and ancestral population sizes. With the use of an informative prior for the human-chimpanzee divergence date, the population size of the common ancestor of the two species is estimated to be ∼20,000, with a 95% credibility interval (8000, 40,000). Our estimates, however, are affected by model assumptions as well as data quality. We suggest that reliable estimates have yet to await more data and more realistic models.

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DNABERT: pre-trained Bidirectional Encoder Representations from Transformers model for DNA-language in genome

Bioinformatics ◽

10.1093/bioinformatics/btab083 ◽

2021 ◽

Author(s):

Yanrong Ji ◽

Zhihan Zhou ◽

Han Liu ◽

Ramana V Davuluri

Keyword(s):

Dna Sequences ◽

Regulatory Elements ◽

Ease Of Use ◽

Fine Tuning ◽

Supplementary Information ◽

Sequence Motifs ◽

Semantic Relationship ◽

Accurate Identification ◽

Conserved Sequence ◽

Genome Wide

Abstract Motivation Deciphering the language of non-coding DNA is one of the fundamental problems in genome research. Gene regulatory code is highly complex due to the existence of polysemy and distant semantic relationship, which previous informatics methods often fail to capture especially in data-scarce scenarios. Results To address this challenge, we developed a novel pre-trained bidirectional encoder representation, named DNABERT, to capture global and transferrable understanding of genomic DNA sequences based on up and downstream nucleotide contexts. We compared DNABERT to the most widely used programs for genome-wide regulatory elements prediction and demonstrate its ease of use, accuracy and efficiency. We show that the single pre-trained transformers model can simultaneously achieve state-of-the-art performance on prediction of promoters, splice sites and transcription factor binding sites, after easy fine-tuning using small task-specific labeled data. Further, DNABERT enables direct visualization of nucleotide-level importance and semantic relationship within input sequences for better interpretability and accurate identification of conserved sequence motifs and functional genetic variant candidates. Finally, we demonstrate that pre-trained DNABERT with human genome can even be readily applied to other organisms with exceptional performance. We anticipate that the pre-trained DNABERT model can be fined tuned to many other sequence analyses tasks. Availability and implementation The source code, pretrained and finetuned model for DNABERT are available at GitHub (https://github.com/jerryji1993/DNABERT). Supplementary information Supplementary data are available at Bioinformatics online.

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Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors

Nature Communications ◽

10.1038/s41467-021-24967-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Karen R. Mifsud ◽

Clare L. M. Kennedy ◽

Silvia Salatino ◽

Eshita Sharma ◽

Emily M. Price ◽

...

Keyword(s):

Dna Sequences ◽

Glucocorticoid Receptors ◽

Acute Stress ◽

Circadian Variation ◽

Rna Seq ◽

Physiological Regulation ◽

Behavioural Adaptation ◽

Neuronal Progenitor ◽

Genome Wide ◽

Transcriptional Changes

AbstractGlucocorticoid hormones (GCs) — acting through hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) — are critical to physiological regulation and behavioural adaptation. We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress. In a subset of genes, these physiological conditions resulted in enhanced MR and/or GR binding to DNA sequences and associated transcriptional changes. Binding of MR at a substantial number of sites however remained unchanged. MR and GR binding occur at overlapping as well as distinct loci. Moreover, although the GC response element (GRE) was the predominant motif, the transcription factor recognition site composition within MR and GR binding peaks show marked differences. Pathway analysis uncovered that MR and GR regulate a substantial number of genes involved in synaptic/neuro-plasticity, cell morphology and development, behavior, and neuropsychiatric disorders. We find that MR, not GR, is the predominant receptor binding to >50 ciliary genes; and that MR function is linked to neuronal differentiation and ciliogenesis in human fetal neuronal progenitor cells. These results show that hippocampal MRs and GRs constitutively and dynamically regulate genomic activities underpinning neuronal plasticity and behavioral adaptation to changing environments.

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Genome-Wide Transcriptomic Analysis of Non-Tumorigenic Tissues Reveals Aging-Related Prognostic Markers and Drug Targets in Renal Cell Carcinoma

Cancers ◽

10.3390/cancers13123045 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3045

Author(s):

Euiyoung Oh ◽

Jun-Hyeong Kim ◽

JungIn Um ◽

Da-Woon Jung ◽

Darren R. Williams ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cancer Patient ◽

Immune Cells ◽

Renal Cell ◽

Prognostic Markers ◽

Patient Survival ◽

Survival Outcome ◽

Normal Tissues ◽

Genome Wide ◽

The Relationship

The relationship between expression of aging-related genes in normal tissues and cancer patient survival has not been assessed. We developed a genome-wide transcriptomic analysis approach for normal tissues adjacent to the tumor to identify aging-related transcripts associated with survival outcome, and applied it to 12 cancer types. As a result, five aging-related genes (DUSP22, MAPK14, MAPKAPK3, STAT1, and VCP) in normal tissues were found to be significantly associated with a worse survival outcome in patients with renal cell carcinoma (RCC). This computational approach was investigated using nontumorigenic immune cells purified from young and aged mice. Aged immune cells showed upregulated expression of all five aging-related genes and promoted RCC invasion compared to young immune cells. Further studies revealed DUSP22 as a regulator and druggable target of metastasis. DUSP22 gene knockdown reduced RCC invasion and the small molecule inhibitor BML-260 prevented RCC dissemination in a tumor/immune cell xenograft model. Overall, these results demonstrate that deciphering the relationship between aging-related gene expression in normal tissues and cancer patient survival can provide new prognostic markers, regulators of tumorigenesis and novel targets for drug development.

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Recombination Can Evolve in Large Finite Populations Given Selection on Sufficient Loci

Genetics ◽

10.1093/genetics/165.4.2249 ◽

2003 ◽

Vol 165 (4) ◽

pp. 2249-2258 ◽

Cited By ~ 9

Author(s):

Mark M Iles ◽

Kevin Walters ◽

Chris Cannings

Keyword(s):

Experimental Evidence ◽

Genetic Drift ◽

Finite Population ◽

Selective Advantage ◽

Indirect Selection ◽

Small Populations ◽

Finite Populations ◽

Population Sizes ◽

Population Recombination

AbstractIt is well known that an allele causing increased recombination is expected to proliferate as a result of genetic drift in a finite population undergoing selection, without requiring other mechanisms. This is supported by recent simulations apparently demonstrating that, in small populations, drift is more important than epistasis in increasing recombination, with this effect disappearing in larger finite populations. However, recent experimental evidence finds a greater advantage for recombination in larger populations. These results are reconciled by demonstrating through simulation without epistasis that for m loci recombination has an appreciable selective advantage over a range of population sizes (am, bm). bm increases steadily with m while am remains fairly static. Thus, however large the finite population, if selection acts on sufficiently many loci, an allele that increases recombination is selected for. We show that as selection acts on our finite population, recombination increases the variance in expected log fitness, causing indirect selection on a recombination-modifying locus. This effect is enhanced in those populations with more loci because the variance in phenotypic fitnesses in relation to the possible range will be smaller. Thus fixation of a particular haplotype is less likely to occur, increasing the advantage of recombination.

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Genome-Wide Identification of 5-Methylcytosine Sites in Bacterial Genomes By High-Throughput Sequencing of MspJI Restriction Fragments

10.1101/2021.02.10.430591 ◽

2021 ◽

Author(s):

Brian P. Anton ◽

Alexey Fomenkov ◽

Victoria Wu ◽

Richard J. Roberts

Keyword(s):

Single Molecule ◽

Dna Sequences ◽

High Throughput Sequencing ◽

Cost Effective ◽

Restriction Enzymes ◽

Specific Sequence ◽

Genome Wide ◽

Cost Effective Alternative ◽

Simple Column ◽

Sequencing Platforms

ABSTRACTSingle-molecule Real-Time (SMRT) sequencing can easily identify sites of N6-methyladenine and N4-methylcytosine within DNA sequences, but similar identification of 5-methylcytosine sites is not as straightforward. In prokaryotic DNA, methylation typically occurs within specific sequence contexts, or motifs, that are a property of the methyltransferases that “write” these epigenetic marks. We present here a straightforward, cost-effective alternative to both SMRT and bisulfite sequencing for the determination of prokaryotic 5-methylcytosine methylation motifs. The method, called MFRE-Seq, relies on excision and isolation of fully methylated fragments of predictable size using MspJI-Family Restriction Enzymes (MFREs), which depend on the presence of 5-methylcytosine for cleavage. We demonstrate that MFRE-Seq is compatible with both Illumina and Ion Torrent sequencing platforms and requires only a digestion step and simple column purification of size-selected digest fragments prior to standard library preparation procedures. We applied MFRE-Seq to numerous bacterial and archaeal genomic DNA preparations and successfully confirmed known motifs and identified novel ones. This method should be a useful complement to existing methodologies for studying prokaryotic methylomes and characterizing the contributing methyltransferases.

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Genome-wide identification of 5-methylcytosine sites in bacterial genomes by high-throughput sequencing of MspJI restriction fragments

PLoS ONE ◽

10.1371/journal.pone.0247541 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0247541

Author(s):

Brian P. Anton ◽

Alexey Fomenkov ◽

Victoria Wu ◽

Richard J. Roberts

Keyword(s):

Single Molecule ◽

Dna Sequences ◽

High Throughput Sequencing ◽

Cost Effective ◽

Restriction Enzymes ◽

Specific Sequence ◽

Genome Wide ◽

Cost Effective Alternative ◽

Simple Column ◽

Sequencing Platforms

Single-molecule Real-Time (SMRT) sequencing can easily identify sites of N6-methyladenine and N4-methylcytosine within DNA sequences, but similar identification of 5-methylcytosine sites is not as straightforward. In prokaryotic DNA, methylation typically occurs within specific sequence contexts, or motifs, that are a property of the methyltransferases that “write” these epigenetic marks. We present here a straightforward, cost-effective alternative to both SMRT and bisulfite sequencing for the determination of prokaryotic 5-methylcytosine methylation motifs. The method, called MFRE-Seq, relies on excision and isolation of fully methylated fragments of predictable size using MspJI-Family Restriction Enzymes (MFREs), which depend on the presence of 5-methylcytosine for cleavage. We demonstrate that MFRE-Seq is compatible with both Illumina and Ion Torrent sequencing platforms and requires only a digestion step and simple column purification of size-selected digest fragments prior to standard library preparation procedures. We applied MFRE-Seq to numerous bacterial and archaeal genomic DNA preparations and successfully confirmed known motifs and identified novel ones. This method should be a useful complement to existing methodologies for studying prokaryotic methylomes and characterizing the contributing methyltransferases.

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