Impact of mutation rate and selection at linked sites on DNA variation across the genomes of humans and other homininae

DNA diversity varies across the genome of many species. Variation in diversity across a genome might arise from regional variation in the mutation rate, variation in the intensity and mode of natural selection, and regional variation in the recombination rate. We show that both non-coding and non-synonymous diversity are positively correlated to a measure of the mutation rate and the recombination rate and negatively correlated to the density of conserved sequences in 50KB windows across the genomes of humans and non-human homininae. Interestingly, we find that while non-coding diversity is equally affected by these three genomic variables, non-synonymous diversity is mostly dominated by the density of conserved sequences. The positive correlation between diversity and our measure of the mutation rate seems to be largely a direct consequence of regions with higher mutation rates having more diversity. However, the positive correlation with recombination rate and the negative correlation with the density of conserved sequences suggests that selection at linked sites also affect levels of diversity. This is supported by the observation that the ratio of the number of non-synonymous to non-coding polymorphisms is negatively correlated to a measure of the effective population size across the genome. We show these patterns persist even when we restrict our analysis to GC-conservative mutations, demonstrating that the patterns are not driven by GC biased gene conversion. In conclusion, our comparative analyses describe how recombination rate, gene density, and mutation rate interact to produce the patterns of DNA diversity that we observe along the hominine genomes

Adaptive evolution is substantially impeded by Hill–Robertson interference in Drosophila

Hill–Robertson interference (HRi) is expected to reduce the efficiency of natural selection when two or more linked selected sites do not segregate freely, but no attempt has been done so far to quantify the overall impact of HRi on the rate of adaptive evolution for any given genome. In this work, we estimate how much HRi impedes the rate of adaptive evolution in the coding genome of Drosophila melanogaster. We compiled a data set of 6,141 autosomal protein-coding genes from Drosophila, from which polymorphism levels in D. melanogaster and divergence out to D. yakuba were estimated. The rate of adaptive evolution was calculated using a derivative of the McDonald–Kreitman test that controls for slightly deleterious mutations. We find that the rate of adaptive amino acid substitution at a given position of the genome is positively correlated to both the rate of recombination and the mutation rate, and negatively correlated to the gene density of the region. These correlations are robust to controlling for each other, for synonymous codon bias and for gene functions related to immune response and testes. We show that HRi diminishes the rate of adaptive evolution by approximately 27%. Interestingly, genes with low mutation rates embedded in gene poor regions lose approximately 17% of their adaptive substitutions whereas genes with high mutation rates embedded in gene rich regions lose approximately 60%. We conclude that HRi hampers the rate of adaptive evolution in Drosophila and that the variation in recombination, mutation, and gene density along the genome affects the HRi effect

Fluctuating selection models and Mcdonald-Kreitman type analyses

It is likely that the strength of selection acting upon a mutation varies through time due to changes in the environment. However, most population genetic theory assumes that the strength of selection remains constant. Here we investigate the consequences of fluctuating selection pressures on the quantification of adaptive evolution using McDonald-Kreitman (MK) style approaches. In agreement with previous work, we show that fluctuating selection can generate evidence of adaptive evolution even when the expected strength of selection on a mutation is zero. However, we also find that the mutations, which contribute to both polymorphism and divergence tend, on average, to be positively selected during their lifetime, under fluctuating selection models. This is because mutations that fluctuate, by chance, to positive selected values, tend to reach higher frequencies in the population than those that fluctuate towards negative values. Hence the evidence of positive adaptive evolution detected under a fluctuating selection model by MK type approaches is genuine since fixed mutations tend to be advantageous on average during their lifetime. Never-the-less we show that methods tend to underestimate the rate of adaptive evolution when selection fluctuates

Short-term genome stability of serial Clostridium difficile ribotype 027 isolates in an experimental gut model and recurrent human disease

Copyright: © 2013 Eyre et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedClostridium difficile whole genome sequencing has the potential to identify related isolates, even among otherwise indistinguishable strains, but interpretation depends on understanding genomic variation within isolates and individuals.Serial isolates from two scenarios were whole genome sequenced. Firstly, 62 isolates from 29 timepoints from three in vitro gut models, inoculated with a NAP1/027 strain. Secondly, 122 isolates from 44 patients (2–8 samples/patient) with mostly recurrent/on-going symptomatic NAP-1/027 C. difficile infection. Reference-based mapping was used to identify single nucleotide variants (SNVs).Across three gut model inductions, two with antibiotic treatment, total 137 days, only two new SNVs became established. Pre-existing minority SNVs became dominant in two models. Several SNVs were detected, only present in the minority of colonies at one/two timepoints. The median (inter-quartile range) [range] time between patients’ first and last samples was 60 (29.5–118.5) [0–561] days. Within-patient C. difficile evolution was 0.45 SNVs/called genome/year (95%CI 0.00–1.28) and within-host diversity was 0.28 SNVs/called genome (0.05–0.53). 26/28 gut model and patient SNVs were non-synonymous, affecting a range of gene targets.The consistency of whole genome sequencing data from gut model C. difficile isolates, and the high stability of genomic sequences in isolates from patients, supports the use of whole genome sequencing in detailed transmission investigations.Peer reviewe

Biochemisches Monitoring nach Meniskektomie

Fragestellung Die Schädigung des Kollagennetzwerks ist ein frühes Ereignis der Arthrose (OA). Wir untersuchten ein Kollagen Typ II -Neoepitop (CTX) in der Synovialflüssigkeit (SF) nach kompletter medialer Meniskektomie (ME). Methoden 32 NZW-Kaninchen hatten eine ME des rechten Kniegelenks. Kontrolle: 11 shamoperierte, 8 unoperierte Kaninchen. Die ME-Kaninchen wurden nach 2 (n = 8), 4 (n = 8) , 8 (n = 8) und 12 (n = 8) Wochen getötet, SF-lavagen beider Kniegelenke durchgeführt. Der ELISA misst ein Kollagen Typ II - Neoepitop, das nach Spaltung der C-telopeptide cross-linking Domaine entsteht. Makroskopisch: Grading beider Kniegelenke mit einem 9 Felder-Schema: Einzelflächen und Gesamtsummen von Tibia, Femur (jeweils medial und lateral) und Patella Histologisch: Grading mit H&E und Safranin O Schnitten (u.a. Proteoglykangehalt, Matrixstruktur, Zellularität, Tidemark und Osteophyten) Statistik: Wilcoxon - und Mann - Whitney U Test. Ergebnisse Makroskopisch: signifikante Veränderungen von medialer Tibia und Femur ab 2 Wochen nach ME, im Vergleich mit Gegenseite und mit nichtoperierten Kaninchen. Histologisch: beginnende OA zu allen Zeitpunkten. ME Knie: CTX Werte in der SF deutlich erhöht, zum kontralateralen Knie für 2, 4, 8 und 12 Wochen signifikant. Nichtoperierte Tiere: keine Unterschiede linkes vs. rechtes Knie, im Vergleich zur ME zu allen Zeitpunkten signifikant niedriger. Schlussfolgerungen Knorpelmarker sind Parameter der OA. Die Metalloproteinasen 1, 8 und 13 erzeugen ein Kollagen Typ II - Neoepitop, das zum Monitoring der arthrotischen Veränderungen geeignet erscheint

Calibration and Cross-Validation of Accelerometery for Estimating Movement Skills in Children Aged 8-12 Years

This study sought to calibrate triaxial accelerometery, worn on both wrists, waist and both ankles, during children’s physical activity (PA), with particular attention to object control motor skills performed at a fast and slow cadence, and to cross-validate the accelerometer cut-points derived from the calibration using an independent dataset. Twenty boys (10.1 ±1.5 years) undertook seven, five-minute bouts of activity lying supine, standing, running (4.5kmph−1) instep passing a football (fast and slow cadence), dribbling a football (fast and slow cadence), whilst wearing five GENEActiv accelerometers on their non-dominant and dominant wrists and ankles and waist. VO2 was assessed concurrently using indirect calorimetry. ROC curve analysis was used to generate cut-points representing sedentary, light and moderate PA. The cut-points were then cross-validated using independent data from 30 children (9.4 ± 1.4 years), who had undertaken similar activities whilst wearing accelerometers and being assessed for VO2. GENEActiv monitors were able to discriminate sedentary activity to an excellent level irrespective of wear location. For moderate PA, discrimination of activity was considered good for monitors placed on the dominant wrist, waist, non-dominant and dominant ankles but fair for the non-dominant wrist. Applying the cut-points to the cross-validation sample indicated that cut-points validated in the calibration were able to successfully discriminate sedentary behaviour and moderate PA to an excellent standard and light PA to a fair standard. Cut-points derived from this calibration demonstrate an excellent ability to discriminate children’s sedentary behaviour and moderate intensity PA comprising motor skill activity.N/

The effects of Morris water maze learning on the number, morphology and molecular composition of rat hippocampal dentate gyrus synapses

spatial long-term memory formation is dependent upon the hippocampus and associated brain structures in mammals. Memory storage is believed to involve changes in the way information is exchanged between neurons, and this is principally governed by their synaptic connections. Changes can occur in the functional properties of individual synapses, but evidence suggests that morphological changes may also occur. Research described in this thesis has used the Morris water maze, a behavioural paradigm that requires rodents to form long-term memories about a spatial environment, and this learning task involves the function of the hippocampus. Electron microscopy was used to investigate the ultrastructural morphology and composition of synapses in the hippocampal dentate gyrus in several groups of animals. Three time- points were investigated, 3, 9 and 24 hours after the start of training, which also corresponded to small, intermediate and large amounts of training, as well as two different types of control, naïve and swim-only. Animals investigated 3 hours after the start of training did not show significant long term memory for the task, whereas animals investigated 9 and 24 hours after the start of learning displayed long-term memory recall when measured by the quadrant analysis test (probe trial). Hippocampal dimensions and dentate granule cell densities were similar between all animal groups. No significant changes to synaptic ultrastructural morphology were evident in the 3 hour group. In the 9 hour group, significant increases in synapse density and synapse to neuron ratio were observed, with a simultaneous decrease in the synapse mean height and average area of PSD (post-synaptie density) per synapse. No significant changes were observed in the exercise-matched swim-only controls, suggesting that the changes were related to long-term memory formation. Morphological changes were not evident in the 24 hour group, despite long term memory recall, suggesting that the morphological changes following spatial learning in the Morris water maze are transient. The total amount of synaptic membrane was not significantly different between any of the groups, suggesting that although new, smaller synapses may be formed as a result of learning, changes also occur to existing synapses, which may result in their re-categorisation or even removal. Analysis of ionotropic glutamate receptors following training proved inconclusive, particularly for NMDA receptors, but did suggest that AMP A receptors are increased in the initial stages of learning, which may be a mechanism of short-term memory storage

Banning the bulb: institutional evolution and the phased ban of incandescent lighting in Germany

Much academic attention has been directed at analysing energy efficiency investments through the lens of ‘behavioural failure’. These studies have challenged the neoclassical framing of regulation which emphasises the efficiency benefits of price based policy, underpinned by the notion of rational individual self-mastery. The increasing use of a regulatory ban on electric lamps in many countries is one of the most recent and high profile flash points in this dialectic of ‘freedom-versus-the-state’ in the public policy discourse. This paper interrogates this debate through a study of electric lamp diffusion in Germany. It is argued that neoclassical theory and equilibrium analysis is inadequate as a tool for policy analysis as it takes the formation of market institutions, such as existing regulations, for granted. Further still, it may be prone to encourage idealistic debates around such grand narratives which may in practice simply serve those who benefit most from the status quo. Instead we argue for an evolutionary approach which we suggest offers a more pragmatic framing tool which focuses on the formation of market institutions in light of shifting social norms and political goals—in our case, progress towards energy efficiency and environmental goals

Evidence for a Triaxial Milky Way Dark Matter Halo from the Sagittarius Stellar Tidal Stream

Observations of the lengthy tidal streams produced by the destruction of the Sagittarius dwarf spheroidal (Sgr dSph) are capable of providing strong constraints on the shape of the Galactic gravitational potential. However, previous work, based on modeling different stream properties in axisymmetric Galactic models has yielded conflicting results: while the angular precession of the Sgr leading arm is most consistent with a spherical or slightly oblate halo, the radial velocities of stars in this arm are only reproduced by prolate halo models. We demonstrate that this apparent paradox can be resolved by instead adopting a triaxial potential. Our new Galactic halo model, which simultaneously fits all well-established phase space constraints from the Sgr stream, provides the first conclusive evidence for, and tentative measurement of, triaxiality in an individual dark matter halo. The Milky Way halo within ~ 60 kpc is best characterized by a minor/major axis ratio of the isovelocity contours c/a ~ 0.67, intermediate/major axis ratio b/a ~ 0.83, and triaxiality parameter T ~ 0.56. In this model, the minor axis of the dark halo is coincident with the Galactic X axis connecting the Sun and the Galactic Center to within ~ 15 degrees, while the major axis also lies in the Galactic plane, approximately along the Galactic Y axis.Comment: Accepted for publication in ApJ Letters. 3 figure