Haplotype inference based on Hidden Markov Models in the QTL-MAS 2010 multi-generational dataset

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated an approach for efficient computation of genotype probabilities, and more generally probabilities of allele inheritance in inbred as well as outbred populations. That work also included an extension for haplotype inference, or phasing, using Hidden Markov Models. Computational phasing of multi-thousand marker datasets has not become common as of yet. In this communication, we further investigate the method presented earlier for such problems, in a multi-generational dataset simulated for QTL detection.</p> <p>Results</p> <p>When analyzing the dataset simulated for the 14th QTLMAS workshop, the phasing produced showed zero deviations compared to original simulated phase in the founder generation. In total, 99.93% of all markers were correctly phased. 97.68% of the individuals were correct in all markers over all 5 simulated chromosomes. Results were produced over a weekend on a small computational cluster. The specific algorithmic adaptations needed for the Markov model training approach in order to reach convergence are described.</p> <p>Conclusions</p> <p>Our method provides efficient, near-perfect haplotype inference allowing the determination of completely phased genomes in dense pedigrees. These developments are of special value for applications where marker alleles are not corresponding directly to QTL alleles, thus necessitating tracking of allele origin, and in complex multi-generational crosses. The cnF2freq codebase, which is in a current state of active development, is available under a BSD-style license.</p

Acute-Phase CD8 T cell responses that select for escape variants are needed to control live attenuated simian immunodeficiency virus

The overall CD8 T cell response to human/simian immunodeficiency virus (HIV/SIV) targets a collection of discrete epitope specificities. Some of these epitope-specific CD8 T cells emerge in the weeks and months following infection and rapidly select forsequence variants, whereas other CD8 T cell responses develop during the chronic infection phase and rarely select for sequence variants. In this study, we tested the hypothesis that acute-phase CD8 T cell responses that do not rapidly select for escapevariants are unable to control viral replication in vivo as well as those that do rapidly select for escape variants. We created a derivative of live attenuated SIV (SIVmac239Δnef) in which we ablated five epitopes that elicit early CD8 T cell responses and rapidly accumulate sequence variants in SIVmac239-infected Mauritian cynomolgus macaques (MCMs) that are homozygous for the M3 major histocompatibility complex (MHC) haplotype. This live attenuated SIV variant was called m3KOΔnef. Viremia was significantly higher in M3 homozygous MCMs infected withm3KOΔnef than in either MHC-mismatched MCMs infected with m3KOΔ nef or MCMs infected with SIVmac239Δnef. Three CD8 T cell responses, including two that do not rapidly select for escape variants, predominated during earlym3KOΔnef infection in the M3 homozygous MCMs, but these animals were unable to control viral replication. These re-sults provide evidence that acute-phase CD8 T cell responses that have the potential to rapidly select for escape variants in the early phase ofinfection are needed to establish viral control in vivo

Tornionjoen lohi-, meritaimen- ja vaellussiikakannat – yhteinen ruotsalais-suomalainen biologinen selvitys sopivien kalastussääntöjen arvioimiseksi vuodelle 2019

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Tornionjoen lohi-, meritaimen- ja vaellussiikakannat – yhteinen ruotsalais-suomalainen biologinen selvitys sopivien kalastussääntöjen arvioimiseksi vuodelle 2020

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The point of maximum curvature as a marker for physiological time series

We present a geometric analysis of the model of Stirling. In particular we analyze the curvature of a heart rate time series in response to a step like increment in the exercise intensity. We present solutions for the point of maximum curvature which can be used as a marker of physiological interest. This marker defines the point after which the heart rate no longer continues to rapidly rise and instead follows either a steady state or slow rise. These methods are then applied to find analytic solutions for a mono exponential model which is commonly used in the literature to model the response to a moderate exercise intensity. Numerical solutions are then found for the full model and parameter values presented in Stirling

Broad-Scale Recombination Patterns Underlying Proper Disjunction in Humans

Although recombination is essential to the successful completion of human meiosis, it remains unclear how tightly the process is regulated and over what scale. To assess the nature and stringency of constraints on human recombination, we examined crossover patterns in transmissions to viable, non-trisomic offspring, using dense genotyping data collected in a large set of pedigrees. Our analysis supports a requirement for one chiasma per chromosome rather than per arm to ensure proper disjunction, with additional chiasmata occurring in proportion to physical length. The requirement is not absolute, however, as chromosome 21 seems to be frequently transmitted properly in the absence of a chiasma in females, a finding that raises the possibility of a back-up mechanism aiding in its correct segregation. We also found a set of double crossovers in surprisingly close proximity, as expected from a second pathway that is not subject to crossover interference. These findings point to multiple mechanisms that shape the distribution of crossovers, influencing proper disjunction in humans

Strain-dependent host transcriptional responses to toxoplasma infection are largely conserved in mammalian and avian hosts

Toxoplasma gondii has a remarkable ability to infect an enormous variety of mammalian and avian species. Given this, it is surprising that three strains (Types I/II/III) account for the majority of isolates from Europe/North America. The selective pressures that have driven the emergence of these particular strains, however, remain enigmatic. We hypothesized that strain selection might be partially driven by adaptation of strains for mammalian versus avian hosts. To test this, we examine in vitro, strain-dependent host responses in fibroblasts of a representative avian host, the chicken (Gallus gallus). Using gene expression profiling of infected chicken embryonic fibroblasts and pathway analysis to assess host response, we show here that chicken cells respond with distinct transcriptional profiles upon infection with Type II versus III strains that are reminiscent of profiles observed in mammalian cells. To identify the parasite drivers of these differences, chicken fibroblasts were infected with individual F1 progeny of a Type II x III cross and host gene expression was assessed for each by microarray. QTL mapping of transcriptional differences suggested, and deletion strains confirmed, that, as in mammalian cells, the polymorphic rhoptry kinase ROP16 is the major driver of strain-specific responses. We originally hypothesized that comparing avian versus mammalian host response might reveal an inversion in parasite strain-dependent phenotypes; specifically, for polymorphic effectors like ROP16, we hypothesized that the allele with most activity in mammalian cells might be less active in avian cells. Instead, we found that activity of ROP16 alleles appears to be conserved across host species; moreover, additional parasite loci that were previously mapped for strain-specific effects on mammalian response showed similar strain-specific effects in chicken cells. These results indicate that if different hosts select for different parasite genotypes, the selection operates downstream of the signaling occurring during the beginning of the host's immune response. © 2011 Ong et al

Genetic Analysis of Genome-Scale Recombination Rate Evolution in House Mice

The rate of meiotic recombination varies markedly between species and among individuals. Classical genetic experiments demonstrated a heritable component to population variation in recombination rate, and specific sequence variants that contribute to recombination rate differences between individuals have recently been identified. Despite these advances, the genetic basis of species divergence in recombination rate remains unexplored. Using a cytological assay that allows direct in situ imaging of recombination events in spermatocytes, we report a large (∼30%) difference in global recombination rate between males of two closely related house mouse subspecies (Mus musculus musculus and M. m. castaneus). To characterize the genetic basis of this recombination rate divergence, we generated an F2 panel of inter-subspecific hybrid males (n = 276) from an intercross between wild-derived inbred strains CAST/EiJ (M. m. castaneus) and PWD/PhJ (M. m. musculus). We uncover considerable heritable variation for recombination rate among males from this mapping population. Much of the F2 variance for recombination rate and a substantial portion of the difference in recombination rate between the parental strains is explained by eight moderate- to large-effect quantitative trait loci, including two transgressive loci on the X chromosome. In contrast to the rapid evolution observed in males, female CAST/EiJ and PWD/PhJ animals show minimal divergence in recombination rate (∼5%). The existence of loci on the X chromosome suggests a genetic mechanism to explain this male-biased evolution. Our results provide an initial map of the genetic changes underlying subspecies differences in genome-scale recombination rate and underscore the power of the house mouse system for understanding the evolution of this trait

IL-6 and other biomarkers as predictors of severity in COVID-19

ObjectiveCytokine release syndrome is suggested to be the most important mechanism triggering acute respiratory distress syndrome and end organ damage in COVID-19. The severity of disease may be measured by different biomarkers.MethodsWe studied markers of inflammation and coagulation as recorded in 29 patients on admission to the hospital in order to identify markers of severe COVID-19 and need of ICU.ResultsPatients who were eventually admitted to ICU displayed significantly higher serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin. No statistical differences were found between the groups in median levels of lymphocytes, D-dimer or ferritin.ConclusionsIL-6 and CRP were the strongest predictors of severity in hospitalized patients with COVID-19.</p