Epistasis and Entropy

Epistasis is a key concept in the theory of adaptation. Indicators of epistasis are of interest for large system where systematic fitness measurements may not be possible. Some recent approaches depend on information theory. We show that considering shared entropy for pairs of loci can be misleading. The reason is that shared entropy does not imply epistasis for the pair. This observation holds true also in the absence of higher order epistasis. We discuss a refined approach for identifying pairwise interactions using entropy

The Changing Geometry of a Fitness Landscape Along an Adaptive Walk

It has recently been noted that the relative prevalence of the various kinds of epistasis varies along an adaptive walk. This has been explained as a result of mean regression in NK model fitness landscapes. Here we show that this phenomenon occurs quite generally in fitness landscapes. We propose a simple and general explanation for this phenomemon, confirming the role of mean regression. We provide support for this explanation with simulations, and discuss the empirical relevance of our findings.Comment: 29 pages, 7 figure

Immune cell composition and cytokine expression in the pregnant and non-pregnant uterus

The success of implantation and further development of the embryo is heavily dependent on the endometrial immune cell composition and its ability to communicate with fetal semi-allogeneic trophoblast cells. Although our understanding of the immune cell population in the uterus has improved, its precise role in normal reproduction and reproductive disorders is still not fully resolved. Here, we examined immune cells and signal molecules derived from the endometrium around the time of implantation, in postmenopause, and in early pregnancy. In study I, we analyzed cytokine and chemokine characteristics in menstrual blood from healthy nulliparous women with regular menstrual cycles, both before and after luteal phase endometrial scratching. The menstrual blood cytokine profile showed little interindividual variation and differed distinctly from peripheral blood. Endometrial scratching did not affect the cytokine profile in menstrual blood. Study II examined the dynamics of endometrial MAIT cells in various reproductive states, including pre- and postmenopausal endometrium and in first trimester decidua. We also evaluated the impact of genetic and environmental factors on the endometrial MAIT cell population by comparing the size of the MAIT cell compartment in menstrual and peripheral blood from monozygotic twins. Additionally, we examined the tissue-residency of endometrial MAIT cells by using transplanted uteri as a model. Finally, we assessed the ability of MAIT cells to react against N. gonorrhoeae, a pathogen known to infect the female genital tract and pose a growing threat of antibiotic resistance. We found that the frequency of endometrial MAIT cells remained stable throughout the different reproductive stages of the endometrium, and that they exhibited both a more activated state and a tissue-resident phenotype compared to their peripheral counterparts. However, in the transplanted uteri, only MAIT cells positive for the recipients HLA were present within the uterus, suggesting that endometrial MAIT cells are transiently tissue-resident and replenished over time from the circulation. Last, we demonstrated that MAIT cells are functional and respond to N. gonorrhoeae. In study III, we investigated the immune cell characteristics in vaginal blood from women with first trimester pregnancy bleeding and associated findings with pregnancy outcome (miscarriage/ not miscarriage). Saliva and serum proteome was analyzed and correlated to vaginal immune cell phenotype and outcome of pregnancy. We found that vaginal blood contained all main immune cell lineages, and that a higher frequency of tissue-resident CD49a+ NK cells in vaginal blood was associated with pregnancy loss. The frequency of vaginal blood tissue-resident NK cells correlated with levels of several maternal serum proteins. In summary, this thesis provides valuable new insights into reproductive physiology and sheds light on various aspects of the uterine immune system. The findings from this research can be used for future comparisons with reproductive pathological states that may involve altered cytokine and immune cell composition

Using remote sensing to explore the spectral and spatial characteristics of wetland vegetation.

Wetlands play an important role as ecotones between terrestrial and aquatic habitats and, as a result, represent an environment of high biodiversity and important hydrological function. Ecological understanding in these environments is hampered by difficult terrain and the dynamic and heterogeneous nature of the vegetation. Remote sensing can provide large amounts of contemporaneous data quickly, objectively and over large areas. This study utilises remote sensing data in conjunction with field data and habitat maps derived from traditional ecological surveys to investigate the use of remote sensing as a tool to aid the ecological understanding and monitoring of wetland environments. This study investigated three main objectives; the first two involved the use of field spectrometry from six habitat types in a freshwater wetland in the north of Scotland. Multivariate analyses demonstrated the possibility of distinguishing between these habitat types using field spectra alone. Detailed vegetation datasets were also collected and the relationship between these and variation in the associated spectra was investigated. Significant relationships were established between ordination axes and spectral bands in the green and NIR regions of the spectrum. Results also demonstrated the potential for remote sensing data to characterise the nature of habitat boundaries. The third objective involved the use of airborne imagery to classify remote sensing data into ecologically meaningful classes. Classification accuracies of over 70% were obtained. Work over the last decade has seen a bridging of the relationship between remote sensing and ecology although it is widely acknowledged that our ecological understanding of the remote sensing-vegetation relationship is still limited at many scales and in many ecosystems, not least the wetland environment. This study provides a much needed basis to research in this cross-disciplinary field and identifies further areas that would benefit from future work

Introduction: Forensic Fail

Background: About 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results. Aim: The purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours. Methods: A total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray. Results: Pathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022). SDHx/VHL/ EPAS1 associated cases had higher norepinephrine output (P = 0.03) and lower epinephrine output (P<0.001) compared to RET/NF1/H-RAS cases. Conclusion: Somatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients

Geometry of fitness landscapes: Peaks, shapes and universal positive epistasis

Darwinian evolution is driven by random mutations, genetic recombination (gene shuffling) and selection that favors genotypes with high fitness. For systems where each genotype can be represented as a bitstring of length $L$, an overview of possible evolutionary trajectories is provided by the $L$-cube graph with nodes labeled by genotypes and edges directed toward the genotype with higher fitness. Peaks (sinks in the graphs) are important since a population can get stranded at a suboptimal peak. The fitness landscape is defined by the fitness values of all genotypes in the system. Some notion of curvature is necessary for a more complete analysis of the landscapes, including the effect of recombination. The shape approach uses triangulations (shapes) induced by fitness landscapes. The main topic for this work is the interplay between peak patterns and shapes. Because of constraints on the shapes for $L=3$ imposed by peaks, there are in total 25 possible combinations of peak patterns and shapes. Similar constraints exist for higher $L$. Specifically, we show that the constraints induced by the staircase triangulation can be formulated as a condition of {\emph{universal positive epistasis}}, an order relation on the fitness effects of arbitrary sets of mutations that respects the inclusion relation between the corresponding genetic backgrounds. We apply the concept to a large protein fitness landscape for an immunoglobulin-binding protein expressed in Streptococcal bacteria.Comment: 20 pages, 6 figure