Claude Bazin

Stress and transposable elements: co‐evolution or useful parasites?

The activity of transposable elements can be induced by environmental and population factors and in particular by stresses in various organisms. A consequence of the increase in transposable element mobility is the creation of new genetic variability that can be useful in the face of stressful conditions. In this review, results supporting this hypothesis are presented and discussed. The main question is how stress induces the activity of transposable elements. We discuss hypotheses based upon the existence of promoters or fixation sites of transcription activators in the untranslated regions of transposable elements, similar to those found in regulatory regions of host defence genes.

Relationships Between Transposable Elements Based Upon the Integrase-Transposase Domains: Is There a Common Ancestor?

The integrase domain of RNA-mediated elements (class I) and the transposase domain of DNA-mediated transposable elements (class II) were compared. A number of elements contain the DDE signature, which plays an important role in their integration. The possible relationships betweenmariner-Tc1 andIS elements, retrotransposons, and retroviruses were analyzed from an alignment of this region. Themariner-Tc1 superfamily, and LTR retrotransposons and retroviruses were found to be monophyletic groups. However, theIS elements of bacteria were found in several groups. These results were used to propose an evolutionary history that suggests a common ancestor for some integrases and transposases.

Do the integrases of LTR-retrotransposons and class II element transposases have a common ancestor?

The integrases of retrotransposons (class I) and retroviruses and the transposases of bacterial type elements (class II) were compared. The DDE signature that is crucial for the integration of these elements is present in most of them, except for the non-LTR retrotransposons and members of the hAT and P super-families. Alignment of this region was used to infer the relationships between class II elements, retrotransposons, and retroviruses. The mariner-Tc1 and the Pogo-Fot1 super-families were found to be closely related and probably monophyletic, as were LTR retrotransposons and retroviruses. The IS elements of bacteria were clustered in several families, some of them being closely related to the transposase of the mariner-Tc1 super-family or to the LTR retrotransposon and retrovirus integrases. These results plus that of Xiong and Eickbush (1990) were used to develop an evolutionary history suggesting a common ancestral origin(s) for the integrases and transposases containing the DDE signature. The position of the telomeric elements (Het-A and TART) was assessed by comparing their gag and reverse transcriptase domains (when present) to those of group II introns and non-LTR retrotransposons. This preliminary analysis suggests that telomeric elements may be derived from non-LTR retrotransposons.

Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase

FOXL2 is a transcription factor that is essential for ovarian function and maintenance, the germline mutations of which are responsible for the Blepharophimosis Ptosis Epicanthus-inversus Syndrome (BPES), often associated with premature ovarian failure. Recent evidence has linked FOXL2 downregulation or somatic mutation (p.Cys134Trp) to cancer, although underlying molecular mechanisms remain unclear. Using a functional genomic approach, we find that FOXL2 modulates cell-cycle regulators in a way which tends to induce G1 arrest. Indeed, FOXL2 upregulation promotes cell accumulation in G1 phase and protects cells from oxidative damage, notably by promoting oxidized DNA repair and by increasing the amounts of anti-oxidant agent glutathione. In agreement with clinical observations, we find that FOXL2-mutated versions leading to BPES along with ovarian dysfunction mostly fail to transactivate cell-cycle and DNA repair targets, whereas mutations leading to isolated craniofacial defects (and normal ovarian function) activate them correctly. Interestingly, these assays revealed a mild promoter-specific hypomorphy of the tumor-associated mutation (p.Cys134Trp). Finally, the SIRT1 deacetylase suppresses FOXL2 activity on targets linked to cell-cycle and DNA repair in a dose-dependent manner. Accordingly, we find that SIRT1 inhibition by nicotinamide limits proliferation, notably by increasing endogenous FOXL2 amount/activity. The body of evidence presented here supports the idea that FOXL2 plays a key role in granulosa cell homeostasis, the failure of which is central to ovarian ageing and tumorigenesis. As granulosa cell tumors respond poorly to conventional chemotherapy, our findings on the deacetylase inhibitor nicotinamide provide an interesting option for targeted therapy.

Genetic basis of sperm and testis length differences and epistatic effect on hybrid inviability and sperm motility between Drosophila simulans and D. sechellia.

Results are reported from a genetic study of hybrid inviability and three ‘fertilization traits’ (sperm motility and length, and testis size) that affect hybrid sterility between the sibling species Drosophila simulans and D. sechellia. The main findings are as follows, (i) For sperm length there was a dominant effect of the D. simulans genome over that of D. sechellia, and the Y chromosome of D. sechellia in the background of D. simulans reduced the sperm length. (ii) In contrast, testis length, in spite of its generally high correlation with sperm length, showed an additive effect. (iii) We found a strong asymmetric incompatibility between the D. sechellia X chromosome and D. simulans autosomes: D. sechellia X chromosome with D. simulans autosomes, but not the reverse, showed a significant reduction in testis length as well as in hybrid inviability compared to the parental species. (iv) Between the two autosomes, chromosome 3 had a greater effect on these traits than chromosome 2, and there was additionally an epistatic effect between these chromosomes with respect to their parental vs. recombinant status: recombinant chromosomes 2 and 3, together, had lower viability than any other combination. (v) The testis size in the backcross generation was greater than the parental species, suggesting that some modifier genes are being released from their species-specific genetic control. (vi) The species-specific homogeneity of the genome was important for all three traits—offspring viability, hybrid male fertility and testis length. These results are discussed with respect to the role of sexual selection and genetic divergence during speciation.

Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems

Mutations of FOXL2 are responsible for the Blepharophimosis-Ptotsis-Epicantus-inversus Syndrome (BPES), involving complex eyelid malformations often associated with premature ovarian failure (POF). Loss-of-function mutations are expected to lead to BPES associated with POF, whereas hypomorphic mutations would lead to BPES without ovarian dysfunction. However, multiple exceptions to the genotype-phenotype correlation have been described and missense mutations in the forkhead domain can lead to either type of BPES. This renders almost impossible the prediction of a POF condition from a given genotype. Moreover, no clear-cut correlation between nuclear and/or cytoplasmic aggregation or cytoplasmic retention of mutant FOXL2 forms and the BPES type has been established thus far. Here, we dissect the molecular and functional effects of 10 FOXL2 mutants, known to induce BPES associated with POF or not. We found a correlation between the transcriptional activity of FOXL2 variants on two different reporter promoters and the type of BPES. We used this functional classification framework to explore the behavior of 18 missense mutations leading to BPES of unknown type. The reporters used enabled us to assess the risk of POF associated with these mutations. Moreover, we document a previously overlooked correlation between subcellular mislocalization and aggregation of mutant FOXL2 and the type of BPES, known or predicted using our reporter assays. Thus, intranuclear aggregation and cytoplasmic mislocalization of mutant FOXL2 may be considered as loose predictors of ovarian dysfunction. The functional classification tool described here is a first step towards circumventing the lack of a clear-cut genotype-phenotype correlation in BPES.

Is the evolution of transposable elements modular

The evolution of transposable element structures can be analyzed in populations and species and by comparing the functional domains in the main classes of elements. We begin with a synthesis of what we know about the evolution of the mariner elements in the Drosophilidae family in terms of populations and species. We suggest that internal deletion does not occur at random, but appears to frequently occur between short internal repeats. We compared the functional domains of the DNA and/or amino acid sequences to detect similarities between the main classes of elements. This included the gag, reverse transcriptase, and envelope genes of retrotransposons and retroviruses, and the integrases of retrotransposons and retroviruses, and transposases of class II elements. We find that each domain can have its own evolutionary history. Thus, the evolution of transposable elements can be seen to be modular.

The evolutionary genetics of thehobo transposable element in theDrosophila melanogaster complex

Hobo elements are a family of transposable elements found inDrosophila melanogaster and its three sibling species:D. simulans, D. mauritiana andD. sechellia. Studies inD. melanogaster have shown thathobo may be mobilized, and that the genetic effects of such mobilizations included the general features of hybrid dysgenesis: mutations, chromosomal rearrangements and gonadal dysgenis in F1 individuals. At the evolutionary level somehobo-hybridizing sequences have also been found in the other members of themelanogaster subgroup and in many members of the relatedmontium subgroup. Surveys of older collected strains ofD. melanogaster suggest that completehobo elements were absent prior to 50 years ago and that they have recently been introduced into this species by horizontal transfer. In this paper we review our findings and those of others, in order to precisely describe the geographical distribution and the evolutionary history ofhobo in theD. melanogaster complex. Studies of the DNA sequences reveal a different level of divergence between the groupD. melanogaster, D. simulans andD. mauritiana and the fourth speciesD. sechellia. The hypothesis of multiple transfers in the recent past into theD. melanogaster complex from a common outside source is discussed.

PHYLOGENETIC ANALYSIS OF MOS1-LIKE TRANSPOSABLE ELEMENTS IN THE DROSOPHILIDAE

Abstract. We have performed a phylogenetic analysis of 59 mariner elements in 14 Drosophilidae species that are related to the active Drosophila mauritiana Mos1 element. This includes 38 previously described sequences and 21 new sequences amplified by PCR from 10 species. Most of the elements detected are nonfunctional due to several frameshifts and deletions. They have been subdivided into four groups according to specific signatures in the nucleotidic and amino acid sequences. The mean nucleotide diversity is 4.8 ± 0.1% and reflects mainly the divergence of inactive elements over different periods. Although this probably gives rise to occasional homoplasies between distantly related taxa, the elements of each species remain grouped together. Horizontal transfer, reported previously between D. mauritiana and Zaprionus tuberculatus, can be extended to Z. verruca, while the Mos1-like element of Z. indianus belongs to another group. Interpretation of the phylogeny leads to a comparison of the influence of common ancestral sequences and putative horizontal transfers.

A scenario for the hobo transposable element invasion, deduced from the structure of natural populations of Drosophila melanogaster using tandem TPE repeats.

Temporal surveys of hobo transposable elements in natural populations reveal a historical pattern suggesting a recent world-wide invasion of D. melanogaster by these transposons, perhaps following a recent horizontal transfer. To clarify the dynamics of hobo elements in natural populations, and thus to provide further data for our understanding of the hobo invasion, TPE tandem repeats, observed in the polymorphic S region of the element, were used as molecular markers. The number of TPE repeats was studied in 101 current populations from around the world, and in 63 strains collected in the past. This revealed a geographical distribution which seems to have been stable since the beginning of the 1960s. This distribution is compatible with a number of hypotheses for the dynamics of hobo elements. We propose a scenario based on an invasion in two stages: first, a complete invasion by elements with three TPE repeats, followed by the beginning of a new invasion involving hobo elements with five or seven repeats.