Prédiction génétique des caractères complexes

L'objectif de cette thèse est le développement des approches statistiques pour la prédiction génétique de caractères complexes. Quatre approches adaptées à différentes situations génétiques, sont développées. En situation d'additivité, un modèle linéaire qui combine les données de transmission génétique avec des marqueurs SNP se révèle utile quand les SNP ne capturent pas l'ensemble des effets génétiques influençant le caractère. En situation des effets génétiques non-linéaires, une méthode de régression à noyaux (Nadaraya-Watson) produit des prédictions plus précises que celles données par la méthode standard (BLUP). Après cette comparaison entre méthodes paramétriques et non paramétriques, il est utile de les faire coopérer entre eux : une méthode d'agrégation statistique s'est révélée efficiente et robuste pour le mélange de prédicteurs. Enfin, un algorithme original de projections aléatoires de modèles linéaires permet de retrouver rapidement les paramètres du modèle, dans le cas où celui-ci est parcimonieux.The objective of this thesis is the development of statistical approaches for genetic prediction of complex traits. Four approaches are developed, adapted to different genetic contexts. Under additivity, a linear model combining transmission and SNP marker data is useful when the SNP do not capture all genetic effects influencing the trait. Under nonlinear genetic effects, a kernel regression method (Nadaraya-Watson) yields more precise predictions than the standard method (BLUP). After the comparison of parametric vs. Nonparametric methods, we propose to combine methods : a statistical aggregation method is efficient and robust to mix several predictors. Finally, an original algorithm of random projections of linear models allows rapid recovery of parsimonious model parameters

Detection of monoclonal protein by capillary zone electrophoresis can be challenged by iodinated contrast agent interference: a case report

The detection of monoclonal immunoglobulins is a key element in the diagnosis of monoclonal gammopathy. In clinical practice, screening and measurement of monoclonal proteins are commonly performed using capillary zone electrophoresis (CZE). Some exogenous substances, such as iodinated contrast agents, absorb incident UV light at the same wavelengths as the peptide bonds and may therefore interfere with the detection of proteins in CZE. We herein use the description of a case to illustrate that iodinated contrast agents can mask the presence of monoclonal immunoglobulins in CZE and we discuss the strategy needed to confirm this interference. Performing immunofixation, immunosubtraction, or a second CZE at a distance from the first blood sample is not only necessary to confirm the presence of an iodinated contrast media interference but also to ensure the absence of monoclonal proteins

Genetic prediction of complex traits: integrating infinitesimal and marked genetic effects

Genetic prediction for complex traits is usually based on models including individual (infinitesimal) or marker effects. Here, we concentrate on models including both the individual and the marker effects. In particular, we develop a ''Mendelian segregation'' model combining infinitesimal effects for base individuals and realized Mendelian sampling in descendants described by the available DNA data. The model is illustrated with an example and the analyses of a public simulated data file. Further, the potential contribution of such models is assessed by simulation. Accuracy, measured as the correlation between true (simulated) and predicted genetic values, was similar for all models compared under different genetic backgrounds. As expected, the segregation model is worthwhile when markers capture a low fraction of total genetic variance. (Résumé d'auteur

Characterization of Drosophila melanogaster JmjC+N histone demethylases

In this article, we characterize histone demethylase activity of the entire family of JmjC+N proteins of Drosophila melanogaster. Our results show that Lid (little imaginal discs), which is structurally homologous to JARID1, demethylates H3K4me3. However, contrary to what would be inferred from its demethylase activity, lid contributes to the establishment of transcriptionally competent chromatin states as: (i) is required for histone H3 acetylation; (ii) contributes to expression of the homoeotic gene Ultrabithorax (Ubx); and (iii) antagonizes heterochromatin-mediated gene silencing (PEV). These results, which are consistent with the identification of lid as a trithorax group (trxG) gene, are discussed in the context of current models for the contribution of H3K4me3 to the regulation of gene expression. Here, we also show that the two Drosophila JMJD2 homologues, dJMJD2(1)/CG15835 and dJMJD2(2)/CG33182, are capable of demethylating both H3K9me3 and H3K36me3. dJMJD2(1)/CG15835 regulates heterochromatin organization, as its over-expression induces spreading of HP1, out of heterochromatin, into euchromatin, without affecting the actual pattern of histone modifications of heterochromatin. dJMJD2(1)/CG15835 is excluded from heterochromatin and localizes to multiple euchromatic sites, where it regulates H3K36 methylation. These results indicate that dJMJD2(1)/CG15835 contributes to delimit hetero- and euchromatic territories through the regulation of H3K36 methylation in euchromatin. On the other hand, dJARID2/CG3654 shows no demethylase activity on H3K4me3, H3K9me3, H3K27me3, H3K36me3 and H4K20me3

Effects of Time of Day and Sleep Deprivation on Motorcycle-Driving Performance

The aim of this study was to investigate whether motorcycle handling capabilities – measured by means of the efficiency of emergency manoeuvres – were dependent on prior sleep deprivation and time of day. Twelve male participants voluntarily took part in four test sessions, starting at 6 a.m., 10 a.m., 2 p.m., and 6 p.m., following a night either with or without sleep. Each test session comprised temperature and sleepiness measurements, before three different types of motorcycling tests were initiated: (1) stability in straight ahead riding at low speed (in “slow motion” mode and in “brakes and clutch” mode), (2) emergency braking and (3) crash avoidance tasks performed at 20 kph and 40 kph. The results indicate that motorcycle control at low speed depends on time of day, with an improvement in performance throughout the day. Emergency braking performance is affected at both speeds by time of day, with poorer performance (longer total stopping distance, reaction time and braking distance) in the morning, and also by sleep deprivation, from measurements obtained at 40 kph (incorrect initial speed). Except for a tendency observed after the sleepless night to deviate from the initial speed, it seems that crash avoidance capabilities are quite unaffected by the two disturbance factors. Consequently, some motorcycle handling capabilities (stability at low speed and emergency braking) change in the same way as the diurnal fluctuation observed in body temperature and sleepiness, whereas for others (crash avoidance) the participants were able to maintain their initial performance level despite the high levels of sleepiness recorded after a sleepless night. Motorcycle riders have to be aware that their handling capabilities are limited in the early morning and/or after sleep deprivation. Both these situations can increase the risk of falls and of being involved in a road accident

Human GTPases associate with RNA polymerase II to mediate its nuclear import

Small GTPases share a biochemical mechanism and act as binary molecular switches. One important function of small GTPases in the cell is nucleocytoplasmic transport of both proteins and RNA. Here, we show the stable association of human GPN1 and GPN3, small GTPases related to Ran, with RNA polymerase II (RNAPII) isolated from either the cytoplasmic or nuclear fraction. GPN1 and GPN3 directly interact with RNAPII subunit 7 (RPB7)/RPB4 and the C-terminal domain (CTD) of RNAPII. Depletion of GPN1 or GPN3 using small interfering RNAs led to decreased RNAPII levels in the nucleus and an accumulation of this enzyme in the cytoplasm of human cells. Furthermore, isolation of a GPN1/GPN3/RNAPII complex from stable cell lines expressing a dominant negative GPN1 harboring mutations in the GTP-binding pocket demonstrated a role for these proteins in nuclear import of RNAPII. Thus, GPN1/GPN3 define a new family of small GTPases that are specialized for the transport of RNA polymerase II into the nucleus

Theoretical perspectives on the new era of central banking

International audienceThe role played by central banks in our economies has changed drastically since 2007, when they became key players in the stabilisation of financial and economic systems. In addition to gaining new competences, their policies strayed increasingly into the political realm and became more controversial. This new era of central banking has revived scholarly debates and vibrant future research perspectives on both dimensions of their independence: towards political and financial institutions. In this article, we review the theoretical debates between economists, political scientists, economic sociologists, and political philosophers on this issue

Fiscal Devaluation with Endogenous Markups: Productivity and Welfare

International audienceWe study fiscal devaluation (i.e., revenue‐neutral shift from payroll to consumption tax) in a two‐country model of international trade. We analyze how such a policy modifies competition between heterogeneous producers, endogenous markups, and the allocation of inputs. We show that fiscal devaluation increases (resp. decreases) consumption in the net importing (resp. net exporting) country, regardless of which country implements the policy. Numerical illustrations suggest that fiscal devaluation is a deflationary policy. In most cases, input resources are reallocated to less productive firms, partly because of the deformation of the profit structure along the distribution of productivity

Tax devaluation with endogenous margins

Several European countries have recently envisaged to implement fiscal policies thatconstitute alternatives to monetary devaluation in the context of a monetary union.Social value-added tax is one of these alternatives: it consists to shift fiscal revenuefrom payroll tax to value-added tax, with the objective to address simultaneously competitiveness and employment problems. We analyze the consequence of such a policy ina model of international trade with heterogeneous firmà laMelitz. We depart from theCES case for taking account of the way changes in the tax rates may mo dify competitionbetween producers, their margins, and the way these changes are refefected in prices. Wefirst show that social VAT is neutral for zero trade balances. Then, in a two-countrymodel, we show that, after the introduction of the social VAT, intensive and extensivemargins increase in the net importing country regardless of the country that implementsthe policy. Both margins decrease in the net exporting country. Considering non-CESutility functions, the effects of social VAT are attenuated (amplified) if love for varietyincreases (decreases) with quantitie