Publications

Hox genes encode homeodomain-containing proteins that control embryonic development in multiple contexts. Up to 30 Hox genes, distributed among all four clusters, are expressed during mammalian kidney morphogenesis, but functional redundancy between them has made a detailed functional account difficult to achieve. We have investigated the role of the HoxD cluster through comparative molecular embryological analysis of a set of mouse strains carrying targeted genomic rearrangements such as deletions, duplications, and inversions. This analysis allowed us to uncover and genetically dissect the complex role of the HoxD cluster. Regulation of metanephric mesenchyme-ureteric bud interactions and maintenance of structural integrity of tubular epithelia are differentially controlled by some Hoxd genes during renal development, consistent with their specific expression profiles. We also provide evidence for a kidney-specific form of colinearity that underlies the differential expression of two distinct sets of genes located on both sides and overlapping at the Hoxd9 locus. These insights further our knowledge of the genetic control of kidney morphogenesis and may contribute to understanding certain congenital kidney malformations, including polycystic kidney disease and renal hypoplasia.

A comprehensive phylogenetic framework is indispensable for investigating the evolution of genomic features in mammals as a whole, and particularly in humans. Using the ENCODE sequence data, we estimated mammalian neutral evolutionary rates and selective pressures acting on conserved coding and noncoding elements. We show that neutral evolutionary rates can be explained by the generation time (GT) hypothesis. Accordingly, primates (especially humans), having longer GTs than other mammals, display slower rates of neutral evolution. The evolution of constrained elements, particularly of nonsynonymous sites, is in agreement with the expectations of the nearly neutral theory of molecular evolution. We show that rates of nonsynonymous substitutions (dN) depend on the population size of a species. The results are robust to the exclusion of hypermutable CpG prone sites. The average rate of evolution in conserved noncoding sequences (CNCs) is 1.7 times higher than in nonsynonymous sites. Despite this, CNCs evolve at similar or even lower rates than nonsynonymous sites in the majority of basal branches of the eutherian tree. This observation could be the result of an overall gradual or, alternatively, lineage-specific relaxation of CNCs. The latter hypothesis was supported by the finding that 3 of the 20 longest CNCs displayed significant relaxation of individual branches. This observation may explain why the evolution of CNCs fits the expectations of the nearly neutral theory less well than the evolution of nonsynonymous sites.

Practitioners of comparative genomics face huge analytical challenges as whole genome sequences and functional/expression data accumulate. Furthermore, the field would greatly benefit from a better integration of this wealth of data with evolutionary concepts.

Distance matrix methods constitute a major family of phylogenetic estimation methods, and the minimum evolution (ME) principle (aiming at recovering the phylogeny with shortest length) is one of the most commonly used optimality criteria for estimating phylogenetic trees. The major difficulty for its application is that the number of possible phylogenies grows exponentially with the number of taxa analyzed and the minimum evolution principle is known to belong to the NRho- hard class of problems.

We demonstrate that 3T3 fibroblast cells can exhibit periodic shape oscillations following a loss of cell-substrate adhesion. The oscillatory behavior can last many hours at a constant frequency, and can be switched off and on using chemical agents. We show that the oscillation frequency increases with increasing acto-myosin contractility. The oscillations also cease when extracellular calcium is depleted or when a blocker of calcium channels is introduced. We propose a theoretical description of the oscillations based on an instability of the cortical actin layer. The cortical actin layer is described using the hydrodynamic theory of active gels. We assume that calcium enters the cell via mechanically gated channels and that an increase of the calcium density increases the acto-myosin contractility in the cortical layer. The theory provides a stability diagram for the actin cortical layer showing an oscillatory instability and gives a good description of the oscillation period. We also discuss the connections between these oscillations and other oscillations observed after depolymerization of the microtubules and with the formation of blebs.

The hypothesis of isolation by distance (IBD) predicts that genetic differentiation between populations increases with geographic distance. However, gene flow is governed by numerous factors and the correlation between genetic differentiation and geographic distance is never simply linear. In this study, we analyze the interaction between the effects of geographic distance and of wild or domesticated status of the host plant on genetic differentiation in the bean beetle Acanthoscelides obvelatus. Geographic distance explained most of the among-population genetic differentiation. However, IBD varied depending on the kind of population pairs for which the correlation between genetic differentiation and geographic distance was examined. Whereas pairs of beetle populations associated with wild beans showed significant IBD (P < 10(-4)), no IBD was found when pairs of beetle populations on domesticated beans were examined (P= 0.2992). This latter result can be explained by long-distance migrations of beetles on domesticated plants resulting from human exchanges of bean seeds. Beetle populations associated with wild beans were also significantly more likely than those on domesticated plants to contain rare alleles. However, at the population level, beetles on cultivated beans were similar in allelic richness to those on wild beans. This similarity in allelic richness combined with differences in other aspects of the genetic diversity (i.e., IBD, allelic diversity) is compatible with strongly contrasting effects of migration and drift. This novel indirect effect of human actions on gene flow of a serious pest of a domesticated plant has important implications for the spread of new adaptations such as resistance to pesticides.

To demonstrate that a given change in the environment has contributed to the emergence of a given genotypic and phenotypic shift during the course of evolution, one should ask to what extent such shifts would have occurred without environmental change. Of course, such tests are rarely practical but phenotypic novelties can still be correlated to genomic shifts in response to environmental changes if enough information is available. We surveyed and re-evaluated the published data in order to estimate the role of environmental changes on the course of species and genomic evolution. Only a few published examples clearly demonstrate a causal link between a given environmental change and the fixation of a genomic variant resulting in functional modification (gain, loss or alteration of function). Many others suggested a link between a given phenotypic shift and a given environmental change but failed to identify the underlying genomic determinant(s) and/or the associated functional consequence(s). The proportion of genotypic and phenotypic variation that is fixed concomitantly with environmental changes is often considered adaptive and hence, the result of positive selection, even though alternative causes, such as genetic drift, are rarely investigated. Therefore, the second aim herein is to review evidence for the mechanisms leading to fixation.

The digestive tract is made of different subdivisions with various functions. During embryonic development, the developing intestine expresses combinations of Hox genes along its anterior to posterior axis, suggesting a role for these genes in this regionalization process. In particular, the transition from small to large intestine is labelled by the transcription of all Hoxd genes except Hoxd12 and Hoxd13, the latter two genes being transcribed only near the anus. Here, we describe two lines of mice that express Hoxd12 ectopically within this morphological transition. As a consequence, budding of the caecum is impeded, leading to complete agenesis in homozygous individuals. This effect is concurrent with a dramatic reduction of both Fgf10 and Pitx1 expression. Furthermore, the interactions between ;anterior' Hox genes and ectopic Hoxd12 suggest a model whereby anterior and posterior Hox products compete in controlling Fgf10 signalling, which is required for the growth of this organ in mice. These results illuminate components of the genetic cascade necessary for the emergence of this gut segment, crucial for many vertebrates.