اشترك بالحزمة الذهبية واحصل على وصول غير محدود شمرا أكاديميا
تسجيل مستخدم جديدLack of evidence for a substantial rate of templated mutagenesis in B cell diversification
40
0
0.0
(
0
)
اسأل ChatGPT حول البحث
ﻻ يوجد ملخص باللغة العربية
B cell receptor sequences diversify through mutations introduced by purpose-built cellular machinery. A recent paper has concluded that a templated mutagenesis process is a major contributor to somatic hypermutation, and therefore immunoglobulin diversification, in mice and humans. In this proposed process, mutations in the immunoglobulin locus are introduced by copying short segments from other immunoglobulin genes. If true, this would overturn decades of research on B cell diversification, and would require a complete re-write of computational methods to analyze B cell data for these species. In this paper, we re-evaluate the templated mutagenesis hypothesis. By applying the original inferential method using potential donor templates absent from B cell genomes, we obtain estimates of the methodss false positive rates. We find false positive rates of templated mutagenesis in murine and human immunoglobulin loci that are similar to or even higher than the original rate inferences, and by considering the bases used in substitution we find evidence that if templated mutagenesis occurs, it is at a low rate. We also show that the statistically significant results in the original paper can easily result from a slight misspecification of the null model.
قيم البحث
اقرأ أيضاً
We suggest a possible correlation between the ionization events caused by the background neutron radiation and the experimental data on mutations with damage in the DNA repair mechanism, coming from the Long Term Evolution Experiment in E. Coli populations.
We test the hypothesis that interconnections across financial institutions can be explained by a diversification motive. This idea stems from the empirical evidence of the existence of long-term exposures that cannot be explained by a liquidity motiv
e (maturity or currency mismatch). We model endogenous interconnections of heterogenous financial institutions facing regulatory constraints using a maximization of their expected utility. Both theoretical and simulation-based results are compared to a stylized genuine financial network. The diversification motive appears to plausibly explain interconnections among key players. Using our model, the impact of regulation on interconnections between banks -currently discussed at the Basel Committee on Banking Supervision- is analyzed.
An accurate assessment of the risk of extreme environmental events is of great importance for populations, authorities and the banking/insurance/reinsurance industry. Koch (2017) introduced a notion of spatial risk measure and a corresponding set of
axioms which are well suited to analyze the risk due to events having a spatial extent, precisely such as environmental phenomena. The axiom of asymptotic spatial homogeneity is of particular interest since it allows one to quantify the rate of spatial diversification when the region under consideration becomes large. In this paper, we first investigate the general concepts of spatial risk measures and corresponding axioms further and thoroughly explain the usefulness of this theory for both actuarial science and practice. Second, in the case of a general cost field, we give sufficient conditions such that spatial risk measures associated with expectation, variance, Value-at-Risk as well as expected shortfall and induced by this cost field satisfy the axioms of asymptotic spatial homogeneity of order $0$, $-2$, $-1$ and $-1$, respectively. Last but not least, in the case where the cost field is a function of a max-stable random field, we provide conditions on both the function and the max-stable field ensuring the latter properties. Max-stable random fields are relevant when assessing the risk of extreme events since they appear as a natural extension of multivariate extreme-value theory to the level of random fields. Overall, this paper improves our understanding of spatial risk measures as well as of their properties with respect to the space variable and generalizes many results obtained in Koch (2017).
The antibody repertoire of each individual is continuously updated by the evolutionary process of B cell receptor mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput seq
uencing. Here, we develop modern statistical molecular evolution methods for the analysis of B cell sequence data, and then apply them to a very deep short-read data set of B cell receptors. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on B cell receptors using a novel method that side-steps the difficulties encountered by previous work in differentiating between selection and motif-driven mutation; this is done through stochastic mapping and empirical Bayes estimators that compare the evolution of in-frame and out-of-frame rearrangements. We use this new method to derive a per-residue map of selection, which provides a more nuanced view of the constraints on framework and variable regions.
Most theories of evolutionary diversification are based on equilibrium assumptions: they are either based on optimality arguments involving static fitness landscapes, or they assume that populations first evolve to an equilibrium state before diversi
fication occurs, as exemplified by the concept of evolutionary branching points in adaptive dynamics theory. Recent results indicate that adaptive dynamics may often not converge to equilibrium points and instead generate complicated trajectories if evolution takes place in high-dimensional phenotype spaces. Even though some analytical results on diversification in complex phenotype spaces are available, to study this problem in general we need to reconstruct individual-based models from the adaptive dynamics generating the non-equilibrium dynamics. Here we first provide a method to construct individual-based models such that they faithfully reproduce the given adaptive dynamics attractor without diversification. We then show that a propensity to diversify can by introduced by adding Gaussian competition terms that generate frequency dependence while still preserving the same adaptive dynamics. For sufficiently strong competition, the disruptive selection generated by frequency-dependence overcomes the directional evolution along the selection gradient and leads to diversification in phenotypic directions that are orthogonal to the selection gradient.
سجل دخول لتتمكن من نشر تعليقات
التعليقات
جاري جلب التعليقات
سجل دخول لتتمكن من متابعة معايير البحث التي قمت باختيارها
