Distinct patterns of mitochondrial genome diversity in bonobos (Pan paniscus) and humans

<p>Abstract</p> <p>Background</p> <p>We have analyzed the complete mitochondrial genomes of 22 <it>Pan paniscus </it>(bonobo, pygmy chimpanzee) individuals to assess the detailed mitochondrial DNA (mtDNA) phylogeny of this close relative of <it>Homo sapiens</it>.</p> <p>Results</p> <p>We identified three major clades among bonobos that separated approximately 540,000 years ago, as suggested by Bayesian analysis. Incidentally, we discovered that the current reference sequence for bonobo likely is a hybrid of the mitochondrial genomes of two distant individuals. When comparing spectra of polymorphic mtDNA sites in bonobos and humans, we observed two major differences: (i) Of all 31 bonobo mtDNA homoplasies, i.e. nucleotide changes that occurred independently on separate branches of the phylogenetic tree, 13 were not homoplasic in humans. This indicates that at least a part of the unstable sites of the mitochondrial genome is species-specific and difficult to be explained on the basis of a mutational hotspot concept. (ii) A comparison of the ratios of non-synonymous to synonymous changes (<it>d</it>_<it>N</it><it>/d</it>_<it>S</it>) among polymorphic positions in bonobos and in 4902 <it>Homo sapiens </it>mitochondrial genomes revealed a remarkable difference in the strength of purifying selection in the mitochondrial genes of the F₀F₁-ATPase complex. While in bonobos this complex showed a similar low value as complexes I and IV, human haplogroups displayed 2.2 to 7.6 times increased <it>d</it>_<it>N</it><it>/d</it>_{<it>S </it>}ratios when compared to bonobos.</p> <p>Conclusions</p> <p>Some variants of mitochondrially encoded subunits of the ATPase complex in humans very likely decrease the efficiency of energy conversion leading to production of extra heat. Thus, we hypothesize that the species-specific release of evolutionary constraints for the mitochondrial genes of the proton-translocating ATPase is a consequence of altered heat homeostasis in modern humans.</p

Digital Collages and Aesthetic-Communicative Networking: Insights into a Workshop of the NFKB Research Cluster Interaction and Participation

Dieser Beitrag dokumentiert Eindrücke, Beobachtungen und Ergebnisse aus einem Online-Workshop des Forschungsclusters «Interaktion und Partizipation in der Kulturellen Bildung», der die Vorstellung von Themen, Arbeitsweisen und Prinzipien des Forschungsclusters zum Ziel hatte. Dabei lag es nahe, die Auseinandersetzung selbst interaktiv und partizipativ sowie entlang der Thematik der rahmenden Tagung zu konzipieren. Ein Grossteil der Kommunikation wird hierfür parallel zur Videokonferenz auf ein digitales Whiteboard verlagert, auf dem alle Teilnehmenden individuell und gemeinsam agieren können. Als Material liegen zentrale Fragmente aus einem Text des Clusters bereit, in dem die Begriffe Interaktion und Partizipation in einem gemeinsamen Selbstversuch und geleitet vom Prinzip der Collage verhandelt werden. Dieses Textprinzip wird zum Handlungsprinzip des Workshops: Die Teilnehmenden werden dem Versuch ausgesetzt, in kleinen Gruppen auf dem digitalen Whiteboard sowohl mit dem bereitgestellten als auch mit eigenem Material selbst Collagen zu erstellen. In dem experimentellen Format des Workshops konturiert sich performativ ein ästhetisch-digitaler Möglichkeits- und Erfahrungsraum, in dem die individuellen Positionen und Perspektiven aller Beteiligten über Text, Bild und Sprache interaktiv in vernetzende Artikulationsformen treten. In den entstandenen Collagen kommen Aspekte von Ästhetik, Digitalität und Macht in eindrücklicher Weise zum Tragen.This contribution documents – especially visually – impressions, observations and results from an online workshop «Interaction and Participation in Cultural Education», which aimed to present topics, working methods and principles of the research cluster. It made sense to conceptualize the workshop itself in an interactive and participative manner, as well as along the theme of the framing conference. A large part of the communication is shifted to a digital whiteboard parallel to the video conference, on which all participants can act individually and together. Central fragments from a text of the cluster are available as material, in which the terms interaction and participation are negotiated in a joint self-experiment and guided by the principle of collage. The text principle becomes the operating principle of the workshop: The participants are exposed to the attempt to create collages themselves in small groups on the digital whiteboard using both the provided and their own material. In the experimental format of the workshop, an aesthetic-digital space of possibility and experience is contoured performatively, in which the individual positions and perspectives of all participants interactively enter into networked forms of articulation via text, image and language. In the resulting collages, aspects of aesthetics, digitality and power come into play in an impressive way

On the problem of supersonic gas flow in two-dimensional channel with the oscillating upper wall

In the present paper we solve the problem of supersonic gas flow in two-dimensional channel with the moving upper wall making oscillations according to the harmonic law. In order to get a numerical solution for gas dynamics equations we have implemented a difference scheme with space and time approximation of the first order and one with space approximation of the second order. Depending on a type of harmonic law and initial gas inflow conditions, the peculiarities of angle-shock wave propagation in moving curvilinear domains have been investigated. It has been determined that the increase of oscillation amplitude causes the increase of shock wave intensity. It has been shown that under particular oscillation amplitude the moving wall has practically no effect on the flow within the domain

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizure

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Large Phenotypic Variation of Individuals from a Family with a Novel <i>ASPM</i> Mutation Associated with Microcephaly, Epilepsy, and Behavioral and Cognitive Deficits

Here, we report a consanguineous family harboring a novel homozygous frame-shift mutation in ASPM leading to a truncation of the ASPM protein after amino acid position 1830. The phenotype of the patients was associated with microcephaly, epilepsy, and behavioral and cognitive deficits. Despite the obvious genetic similarity, the affected patients show a considerable phenotypic heterogeneity regarding the degree of mental retardation, presence of epilepsy and MRI findings. Interestingly, the degree of mental retardation and the presence of epilepsy correlates well with the severity of abnormalities detected in brain MRI. On the other hand, we detected no evidence for substantial nonsense-mediated ASPM transcript decay in blood samples. This indicates that other factors than ASPM expression levels are relevant for the variability of structural changes in brain morphology seen in patients with primary hereditary microcephaly caused by ASPM mutations

Loss of the Immunomodulatory Transcription Factor BATF2 in Humans Is Associated with a Neurological Phenotype

Epilepsy and mental retardation are known to be associated with pathogenic mutations in a broad range of genes that are expressed in the brain and have a role in neurodevelopment. Here, we report on a family with three affected individuals whose clinical symptoms closely resemble a neurodevelopmental disorder. Whole-exome sequencing identified a homozygous stop-gain mutation, p.Gln19*, in the BATF2 gene in the patients. The BATF2 transcription factor is predominantly expressed in macrophages and monocytes and has been reported to modulate AP-1 transcription factor-mediated pro-inflammatory responses. Transcriptome analysis showed altered base-level expression of interferon-stimulated genes in the patients’ blood, typical for type I interferonopathies. Peripheral blood mononuclear cells from all three patients demonstrated elevated responses to innate immune stimuli, which could be reproduced in CRISPR–Cas9-generated BATF2−/− human monocytic cell lines. BATF2 is, therefore, a novel disease-associated gene candidate for severe epilepsy and mental retardation related to dysregulation of immune responses, which underscores the relevance of neuroinflammation for epilepsy

POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts

Disorders of mitochondrial DNA (mtDNA) maintenance have emerged as an important cause of humangenetic disease, but demonstrating the functional consequences of de novo mutations remains a majorchallenge. We studied the rate of depletion and repopulation of mtDNA in human fibroblasts exposed toethidium bromide in patients with heterozygous POLG mutations, POLG2 and TK2 mutations. Ethidiumbromide induced mtDNA depletion occurred at the same rate in human fibroblasts from patients and healthycontrols. By contrast, the restoration of mtDNA levels was markedly delayed in fibroblasts from patients withcompound heterozygous POLG mutations. Specific POLG2 and TK2 mutations did not delay mtDNArepopulation rates. These observations are consistent with the hypothesis that mutations in POLG impairmtDNA repopulation within intact cells, and provide a potential method of demonstrating the functionalconsequences of putative pathogenic alleles causing a defect of mtDNA synthesis