Mutations in the FOXL2 gene have recently been shown to cause the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), a rare genetic disease (MIM 110100).1 In type I BPES eyelid abnormalities are associated with premature ovarian failure (POF), while in type II BPES only the eyelid malformation is observed.2 FOXL2 is the first human autosomal gene whose dominant mutations have been shown to be involved in POF. The eyelid malformation in both BPES types is inherited as a dominant trait and we have recently argued that ovarian failure in type II BPES is a recessive trait.3 FOXL2 is a single exon gene of 2.7 kb. The predicted protein of 376 amino acids belongs to the large family of forkhead/winged helix transcription factors, containing a characteristic 100 amino acid DNA binding forkhead domain. Many members are known to be involved in vertebrate embryogenesis4 and some have been implicated in inherited developmental human disorders.5 Apart from the forkhead domain, the FOXL2 protein also contains a polyalanine (poly-Ala) tract whose role has not yet been elucidated. Recurrent mutations leading to its expansion cause type II BPES and account for 30% of the deleterious alterations detected in the open reading frame (ORF).6,7 These alleles have been considered as hypomorphic (residual activity) in the context of the ovary.1,6 Northern blot analysis and RNA in situ hybridisation have shown that FOXL2 is expressed in developing mouse eyelids and in adult ovarian follicular cells.1 Here we have performed a comparative sequence analysis of FOXL2 in order to study the evolution of the FOXL2 coding region. We have estimated the synonymous (Ks) and non-synonymous (Ka) substitution rates in the ORF of several species, human, goat, mouse and pufferfish. In addition, to determine the subcellular localisation of the FOXL2 protein and its …

Intragenomic conflicts arise when a genetic element favours its own transmission to the detriment of others. Conflicts over sex chromosome transmission are expected to have influenced genome structure, gene regulation, and speciation. In the mouse, the existence of an intragenomic conflict between X- and Y-linked multicopy genes has long been suggested but never demonstrated. The Y-encoded multicopy gene Sly has been shown to have a predominant role in the epigenetic repression of post meiotic sex chromatin (PMSC) and, as such, represses X and Y genes, among which are its X-linked homologs Slx and Slxl1. Here, we produced mice that are deficient for both Sly and Slx/Slxl1 and observed that Slx/Slxl1 has an opposite role to that of Sly, in that it stimulates XY gene expression in spermatids. Slx/Slxl1 deficiency rescues the sperm differentiation defects and near sterility caused by Sly deficiency and vice versa. Slx/Slxl1 deficiency also causes a sex ratio distortion towards the production of male offspring that is corrected by Sly deficiency. All in all, our data show that Slx/Slxl1 and Sly have antagonistic effects during sperm differentiation and are involved in a postmeiotic intragenomic conflict that causes segregation distortion and male sterility. This is undoubtedly what drove the massive gene amplification on the mouse X and Y chromosomes. It may also be at the basis of cases of F1 male hybrid sterility where the balance between Slx/Slxl1 and Sly copy number, and therefore expression, is disrupted. To the best of our knowledge, our work is the first demonstration of a competition occurring between X and Y related genes in mammals. It also provides a biological basis for the concept that intragenomic conflict is an important evolutionary force which impacts on gene expression, genome structure, and speciation. Both copies of a gene have normally an equal chance of being inherited; however, some genes can act “selfishly” to be transmitted to >50% of offspring: a phenomenon known as transmission distortion. Distorting genes on the X or Y chromosome leads to an excess of female/male offspring respectively. This then sets up a “genomic conflict” (arms race) between the sex chromosomes that can radically affect their gene content. Male mice that have lost part of their Y produce >50% female offspring and show over-activation of multiple genes on the X, providing strong circumstantial evidence for distortion. Here, we demonstrate the existence of a genomic conflict regulated by the genes Slx/Slxl1 and Sly, present in ∼50 to 100 copies on the X and Y chromosomes respectively. SLX/SLXL1 and SLY proteins have antagonistic effects on sex chromosome expression in developing sperm and skew the offspring sex-ratio in favor of females/males. Interestingly, while deficiency of either gene alone leads to severe fertility problems, fertility is improved when both genes are deficient. We believe that the conflict in which Slx/Slxl1 and Sly are involved led to the amplification of X and Y genes and may have played an important role in mouse speciation.

The past decade has seen a tremendous increase in interest and progress in the field of sperm epigenetics. Studies have shown that chromatin regulation during male germline development is multiple and complex, and that the spermatozoon possesses a unique epigenome. Its DNA methylation profile, DNA-associated proteins, nucleo-protamine distribution pattern and non-coding RNA set up a unique epigenetic landscape which is delivered, along with its haploid genome, to the oocyte upon fertilization, and therefore can contribute to embryogenesis and to the offspring health. An emerging body of compelling data demonstrates that environmental exposures and paternal lifestyle can change the sperm epigenome and, consequently, may affect both the embryonic developmental program and the health of future generations. This short review will attempt to provide an overview of what is currently known about sperm epigenome and the existence of transgenerational epigenetic inheritance of paternally acquired traits that may contribute to the offspring phenotype

Mutations in the forkhead transcription factor gene FOXL2 are involved in ovarian failure, which occurs in human BPES syndrome. This syndrome presents a sexually dimorphic expression, specific to the ovary in several vertebrates. We cloned the open reading frame of chicken FOXL2 (cFoxL2) and studied cFoxL2 expression in developing gonads and during adulthood to examine the role of FOXL2 in ovarian differentiation and function in birds. The spatial and temporal dynamics of cFoxL2 and aromatase expression were analyzed in parallel by using real‐time quantitative reverse transcriptase‐polymerase chain reaction and immunohistochemistry in attempt to investigate the possible role of cFoxL2 in the regulation of aromatase. The expression patterns of cFoxL2 and aromatase transcripts were highly correlated during the sex‐differentiation period (4.7–12.7 days of incubation). Aromatase and cFoxL2 proteins were colocalized in the medullar part of female gonads on embryonic day 14. Fourteen days after hatching, cFoxL2 protein was mainly detected in granulosa cells of developing follicles. In adult ovary follicular envelopes, apart from granulosa cells, cFoxL2 transcript and protein were detected at lower levels in theca cells where aromatase was present. A high level of cFoxL2 transcription was also observed in maturing and ovulated oocytes. Our results confirm that FoxL2 is an early regulator of ovarian development in birds and may be involved in aromatase transcription regulation. Developmental Dynamics 859–870, 2004.