Selective sweeps versus introgression - population genetic dynamics of the murine leukemia virus receptor Xpr1 in wild populations of the house mouse (Mus musculus)

Background: The interaction between viruses and their receptors in the host can be expected to lead to an evolutionary arms race resulting in cycles of rapid adaptations. We focus here on the receptor gene Xpr1 (xenotropic and polytropic retrovirus receptor 1) for murine leukemia viruses (MLVs). In a previous screen for selective sweeps in mouse populations we discovered that a population from Germany was almost monomorphic for Xpr1 haplotypes, while a population from France was polymorphic. Results: Here we analyze Xpr1 sequences and haplotypes from a broad sample of wild mouse populations of two subspecies, M. m. domesticus and M. m. musculus, to trace the origins of this distinctive polymorphism pattern. We show that the high polymorphism in the population in France is caused by a relatively recent invasion of a haplotype from a population in Iran, rather than a selective sweep in Germany. The invading haplotype codes for a novel receptor variant, which has itself undergone a recent selective sweep in the Iranian population. Conclusions: Our data support a scenario in which Xpr1 is frequently subject to positive selection, possibly as a response to resistance development against recurrently emerging infectious viruses. During such an infection cycle, receptor variants that may convey viral resistance can be captured from another population and quickly introgress into populations actively dealing with the infectious virus. © 2015 Hasenkamp et al

Functional characterization of adaptively relevant genes in the house mouse (Mus musculus L.)

One of the main themes in evolutionary biology is the characterization of the molecular basis of adaptation. A prerequisite for adaptation is the presence of heritable variation in the form of functionally distinct alleles which have differential effects on the lifetime reproductive success of an organism. That is why a lot of effort has been made in recent years to identify genes that are under positive selection and thus involved in adaptive processes in natural populations of different species. Through comprehensive genetic screens a large number of such candidate genes have been identified. However, knowledge about the allelic variation, its molecular function and phenotypic effects remains still rare. In this study, I took advantage of data about candidate genes for selective sweeps from previous hitchhiking mapping studies in four European wild mouse (Mus musculus L.) populations and of the extensive knowledge about mice through years of lab mouse research. Two candidate genes, namely Xpr1 and Dmrt1, with a generally well characterized function were analyzed to gain information about potential functional alleles, their variation and extent of the selective sweep across different populations and possible functional effects of the different alleles. Xpr1 is a cell-surface receptor which is especially known for its function in infection of cells by polytropic and xenotropic murine leukemia viruses (X/P-MLVs), which can cause leukemia and lymphomas in mice. The transcription factor Dmrt1 is a highly conserved member of the sex determination cascade in vertebrates and required for normal gonadal differentiation in mice. For both genes, I focused on coding sequence variation as potential target of positive selection in 11 wild mouse populations and several outgroups. Analyzed M. m. domesticus populations came from France, Germany and Iran, while the M. m. musulus populations came from Czech Republic and Kazakhstan. Additionally, microsatellites in a region of 200 kb around both loci were analyzed to survey the extent of the originally identified selective sweeps across populations. For the analysis of potential functional effects of the identified alleles, information about the general function of the genes was used. The two genes showed coding sequence variation among the populations. For Xpr1, 14 different alleles were identified which occurred as haplotypes. Two of these alleles were associated to a signature of positive selection and an introgression of one of these haplotypes from Iran to Southern France was observed. Furthermore, evidence for balancing selection on two haplotypes in three other populations was found. Analysis of potential functional effects of the receptor alleles focused in associations between these alleles and variation in transcribed P-MLVs in captive mice. However, no association could be found and no infectious virions were detected. Together with finding from previous studies, the here obtained results suggest that Xpr1 variation in wild mouse populations is shaped by ongoing adaptive evolution, but that to current knowledge other factors than disease induction by XPR1-dependent MLVs might drive this process. For Dmrt1, one amino acid exchange between Asparagine (N) and Serine (S) was observed, while data from other studies suggested that no differential expression or alternative splicing occurred. N seemed to be the derived allele and generated a potential N-linked glycosylation site. It was also found to be potentially under positive selection in five populations from France. The functional analysis focused on potential differences in target gene regulation due to the different Dmrt1 alleles. In a comparative microarray-based analysis across early postnatal stages I found that differential transcription of Dmrt1 target genes was increased between the different alleles when Dmrt1 was present. This result together with the population genetic data suggests that there is possibly a functional difference between the N and S allele that could be the target of positive selection, though more analyses will be necessary to gain insights into the potential beneficial nature of the N allele.Table of contents List of figures.......................................................................................................... III List of tables............................................................................................................V Danksagung..........................................................................................................VII Zusammenfassung.................................................................................................IX Summary................................................................................................................XI Declaration...........................................................................................................XIII General introduction................................................................................................ 1 A brief introduction to molecular evolution ........................................................... 1 Identification and analysis of adaptively relevant genes....................................... 4 The wild mouse (Mus musculus L.) as a model system ....................................... 9 Scope of the thesis ............................................................................................ 12 Chapter 1 - Natural variation in the cell-surface receptor Xpr1 in wild populations of the house mouse .............................................................................................. 15 Chapter 2 - Characterization of functional allelic variation in Dmrt1 in wild populations of the house mouse ....................................................................... 33 Bibliography .......................................................................................................... 57 Eidesstattliche Erklärung....................................................................................... 69 Appendix............................................................................................................... 71 S1 (General):..................................................................................................... 71 S2 (Chapter 1): .................................................................................................. 72 S3 (Chapter 2): ................................................................................................ 10

Design and test of a MEMS strain-sensing device for monitoring artificial knee implants

This paper describes the development of a polyimide-based MEMS strain-sensing device. Finite element analysis was used to investigate an artificial knee implant and assist on device design and to optimize sensing characteristics. The sensing element of the device was fabricated using polyimide micromachining with embedded thin-metallic wires and placed into a knee prosthesis. The device was evaluated experimentally in a mechanical knee simulator using static and dynamic axial load conditions similar to those encountered in vivo. Results indicates the sensor is capable of measuring the strain associated to the total axial forces in the range of approximately 4 times body weight with a good sensitivity and accuracy for events happening within 1 s time windo

Neurobiological substrates of cognitive rigidity and autonomic inflexibility in generalized anxiety disorder

Generalized anxiety disorder (GAD) is characterized by difficulties in inhibiting both perseverative thoughts (worry and rumination) and autonomic arousal. We investigated the neurobiological substrates of such abnormal inhibitory processes, hypothesizing aberrant functional coupling within ‘default mode’ (DMN) and autonomic brain networks. Functional imaging and heart rate variability (HRV) data were acquired from GAD patients and controls during performance of three tracking tasks interspersed with a perseverative cognition (PC) induction. After detection of infrequent target stimuli, activity within putative DMN hubs was suppressed, consistent with a redirection of attentional resources from internal to external focus. This magnitude of activity change was attenuated in patients and individuals with higher trait PC, but was predicted by individual differences in HRV. Following the induction of PC in controls, this pattern of neural reactivity became closer to that of GAD patients. Results support, at a neural level, the association between cognitive inflexibility and autonomic rigidity

Clinical implications and dynamics of clonal hematopoiesis in anti-CD19 CAR T-cell treated patients

Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CH(pos) and CH(neg) patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CH(pos) patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome

Planck 2015 results. XIII. Cosmological parameters

We present results based on full-mission Planck observations of temperature and polarization anisotropies of the CMB. These data are consistent with the six-parameter inflationary LCDM cosmology. From the Planck temperature and lensing data, for this cosmology we find a Hubble constant, H0= (67.8 +/- 0.9) km/s/Mpc, a matter density parameter Omega_m = 0.308 +/- 0.012 and a scalar spectral index with n_s = 0.968 +/- 0.006. (We quote 68% errors on measured parameters and 95% limits on other parameters.) Combined with Planck temperature and lensing data, Planck LFI polarization measurements lead to a reionization optical depth of tau = 0.066 +/- 0.016. Combining Planck with other astrophysical data we find N_ eff = 3.15 +/- 0.23 for the effective number of relativistic degrees of freedom and the sum of neutrino masses is constrained to < 0.23 eV. Spatial curvature is found to be |Omega_K| < 0.005. For LCDM we find a limit on the tensor-to-scalar ratio of r <0.11 consistent with the B-mode constraints from an analysis of BICEP2, Keck Array, and Planck (BKP) data. Adding the BKP data leads to a tighter constraint of r < 0.09. We find no evidence for isocurvature perturbations or cosmic defects. The equation of state of dark energy is constrained to w = -1.006 +/- 0.045. Standard big bang nucleosynthesis predictions for the Planck LCDM cosmology are in excellent agreement with observations. We investigate annihilating dark matter and deviations from standard recombination, finding no evidence for new physics. The Planck results for base LCDM are in agreement with BAO data and with the JLA SNe sample. However the amplitude of the fluctuations is found to be higher than inferred from rich cluster counts and weak gravitational lensing. Apart from these tensions, the base LCDM cosmology provides an excellent description of the Planck CMB observations and many other astrophysical data sets