Abstract
Mitochondrial DNA (mtDNA) resides in a high ROS environment and suffers more mutations than its nuclear counterpart. Increasing evidence suggests that mtDNA mutations are not the results of ...direct oxidative damage, rather are caused, at least in part, by DNA replication errors. To understand how the mtDNA replicase, Pol γ, can give rise to elevated mutations, we studied the effect of oxidation of Pol γ on replication errors. Pol γ is a high fidelity polymerase with polymerase (pol) and proofreading exonuclease (exo) activities. We show that Pol γ exo domain is far more sensitive to oxidation than pol; under oxidative conditions, exonuclease activity therefore declines more rapidly than polymerase. The oxidized Pol γ becomes editing-deficient, displaying a 20-fold elevated mutations than the unoxidized enzyme. Mass spectrometry analysis reveals that Pol γ exo domain is a hotspot for oxidation. The oxidized exo residues increase the net negative charge around the active site that should reduce the affinity to mismatched primer/template DNA. Our results suggest that the oxidative stress induced high mutation frequency on mtDNA can be indirectly caused by oxidation of the mitochondrial replicase.
In males of many vertebrate species, sexual selection has led to the evolution of sexually dimorphic traits, which are often developmentally controlled by androgen signaling involving androgen ...response elements (AREs). Evolutionary changes in the number and genomic locations of AREs can modify patterns of receptor regulation and potentially alter gene expression. Here, we use recently sequenced primate genomes to evaluate the hypothesis that the strength of sexual selection is related to the genome-wide number of AREs in a diversifying lineage. In humans, we find a higher incidence of AREs near male-biased genes and androgen-responsive genes when compared with randomly selected genes from the genome. In a set of primates, we find that gains or losses of AREs proximal to genes are correlated with changes in male expression levels and the degree of sex-biased expression of those genes. In a larger set of primates, we find that an increase in one indicator of sexual selection, canine size sexual dimorphism, is correlated with genome-wide ARE counts. Our results suggest that the responsiveness of the genome to androgens in humans and their close relatives has been shaped by sexual selection that arises from competition among males for mating access to females.
Cross-sexual Transfer Revisited Anderson, Andrew P; Falk, Jay Jinsing
Integrative and comparative biology,
10/2023, Volume:
63, Issue:
4
Journal Article
Peer reviewed
Open access
Abstract
In her influential book “Developmental Plasticity and Evolution,” Mary Jane West-Eberhard introduced the concept of cross-sexual transfer, where traits expressed in one sex in an ancestral ...species become expressed in the other sex. Despite its potential ubiquity, we find that cross-sexual transfer has been under-studied and under-cited in the literature, with only a few experimental papers that have invoked the concept. Here, we aim to reintroduce cross-sexual transfer as a powerful framework for explaining sex variation and highlight its relevance in current studies on the evolution of sexual heteromorphism (different means or modes in trait values between the sexes). We discuss several exemplary studies of cross-sexual transfer that have been published in the past two decades, further building on West-Eberhard’s extensive review. We emphasize two scenarios as potential avenues of study, within-sex polymorphic and sex-role reversed species, and discuss the evolutionary and adaptive implications. Lastly, we propose future questions to expand our understanding of cross-sexual transfer, from nonhormonal mechanisms to the identification of broad taxonomic patterns. As evolutionary biologists increasingly recognize the nonbinary and often continuous nature of sexual heteromorphism, the cross-sexual framework has important utility for generating novel insights and perspectives on the evolution of sexual phenotypes across diverse taxa.
This protocol details the steps for data quality assessment and control that are typically carried out during case-control association studies. The steps described involve the identification and ...removal of DNA samples and markers that introduce bias. These critical steps are paramount to the success of a case-control study and are necessary before statistically testing for association. We describe how to use PLINK, a tool for handling SNP data, to perform assessments of failure rate per individual and per SNP and to assess the degree of relatedness between individuals. We also detail other quality-control procedures, including the use of SMARTPCA software for the identification of ancestral outliers. These platforms were selected because they are user-friendly, widely used and computationally efficient. Steps needed to detect and establish a disease association using case-control data are not discussed here. Issues concerning study design and marker selection in case-control studies have been discussed in our earlier protocols. This protocol, which is routinely used in our labs, should take approximately 8 h to complete.
Breakthrough Listen is the most comprehensive and sensitive search for extraterrestrial intelligence (SETI) to date, employing a collection of international observational facilities including both ...radio and optical telescopes. During the first three years of the Listen program, thousands of targets have been observed with the Green Bank Telescope (GBT), Parkes Telescope and Automated Planet Finder. At GBT and Parkes, observations have been performed ranging from 700 MHz to 26 GHz, with raw data volumes averaging over 1 PB day−1. A pseudo-real time software spectroscopy suite is used to produce multi-resolution spectrograms amounting to approximately 400 GB h−1 GHz−1 beam−1. For certain targets, raw baseband voltage data is also preserved. Observations with the Automated Planet Finder produce both two-dimensional and one-dimensional high-resolution (R ∼ 105) echelle spectral data. Although the primary purpose of Listen data acquisition is for SETI, a range of secondary science has also been performed with these data, including studies of fast radio bursts. Other current and potential research topics include spectral line studies, searches for certain kinds of dark matter, probes of interstellar scattering, pulsar searches, radio transient searches and investigations of stellar activity. Listen data are also being used in the development of algorithms, including machine-learning approaches to modulation scheme classification and outlier detection, that have wide applicability not just for astronomical research but for a broad range of science and engineering. In this paper, we describe the hardware and software pipeline used for collection, reduction, archival, and public dissemination of Listen data. We describe the data formats and tools, and present Breakthrough Listen Data Release 1.0 (BLDR 1.0), a defined set of publicly available raw and reduced data totaling 1 PB.
Intrusive memories, images, and hallucinations are hallmark symptoms of psychiatric disorders. Although often attributed to deficient inhibitory control by the prefrontal cortex, difficulty in ...controlling intrusive thoughts is also associated with hippocampal hyperactivity, arising from dysfunctional GABAergic interneurons. How hippocampal GABA contributes to stopping unwanted thoughts is unknown. Here we show that GABAergic inhibition of hippocampal retrieval activity forms a key link in a fronto-hippocampal inhibitory control pathway underlying thought suppression. Subjects viewed reminders of unwanted thoughts and tried to suppress retrieval while being scanned with functional magnetic resonance imaging. Suppression reduced hippocampal activity and memory for suppressed content.
H magnetic resonance spectroscopy revealed that greater resting concentrations of hippocampal GABA predicted better mnemonic control. Higher hippocampal, but not prefrontal GABA, predicted stronger fronto-hippocampal coupling during suppression, suggesting that interneurons local to the hippocampus implement control over intrusive thoughts. Stopping actions did not engage this pathway. These findings specify a multi-level mechanistic model of how the content of awareness is voluntarily controlled.
This protocol describes how to perform basic statistical analysis in a population-based genetic association case-control study. The steps described involve the (i) appropriate selection of measures ...of association and relevance of disease models; (ii) appropriate selection of tests of association; (iii) visualization and interpretation of results; (iv) consideration of appropriate methods to control for multiple testing; and (v) replication strategies. Assuming no previous experience with software such as PLINK, R or Haploview, we describe how to use these popular tools for handling single-nucleotide polymorphism data in order to carry out tests of association and visualize and interpret results. This protocol assumes that data quality assessment and control has been performed, as described in a previous protocol, so that samples and markers deemed to have the potential to introduce bias to the study have been identified and removed. Study design, marker selection and quality control of case-control studies have also been discussed in earlier protocols. The protocol should take ~1 h to complete.
High fidelity human mitochondrial DNA polymerase (Pol γ) contains two active sites, a DNA polymerization site (pol) and a 3′-5′ exonuclease site (exo) for proofreading. Although separated by 35 Å, ...coordination between the pol and exo sites is crucial to high fidelity replication. The biophysical mechanisms for this coordination are not completely understood. To understand the communication between the two active sites, we used a statistical-mechanical model of the protein ensemble to calculate the energetic landscape and local stability. We compared a series of structures of Pol γ, complexed with primer/template DNA, and either a nucleotide substrate or a series of nucleotide analogues, which are differentially incorporated and excised by pol and exo activity. Despite the nucleotide or its analogues being bound in the pol, Pol γ residue stability varied across the protein, particularly in the exo domain. This suggests that substrate presence in the pol can be “sensed” in the exo domain. Consistent with this hypothesis, in silico mutations made in one active site mutually perturbed the energetics of the other. To identify specific regions of the polymerase that contributed to this communication, we constructed an allosteric network connectivity map that further demonstrates specific pol–exo cooperativity. Thus, a cooperative network underlies energetic connectivity. We propose that Pol γ and other dual-function polymerases exploit an energetic coupling network that facilitates domain–domain communication to enhance discrimination between correct and incorrect nucleotides.
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