Foxl2 functions in sex determination and histogenesis throughout mouse ovary development

Background. Partial loss of function of the transcription factor FOXL2 leads to premature ovarian failure in women. In animal models, Foxl2 is required for maintenance, and possibly induction, of female sex determination independently of other critical genes, e.g., Rspo1. Here we report expression profiling of mouse ovaries that lack Foxl2 alone or in combination with Wnt4 or Kit/c-Kit. Results. Following Foxl2 loss, early testis genes (including Inhbb, Dhh, and Sox9) and several novel ovarian genes were consistently dysregulated during embryonic development. In the absence of Foxl2, expression changes affecting a large fraction of pathways were opposite those observed in Wnt4-null ovaries, reinforcing the notion that these genes have complementary actions in ovary development. Loss of one copy of Foxl2 revealed strong gene dosage sensitivity, with molecular anomalies that were milder but resembled ovaries lacking both Foxl2 alleles. Furthermore, a Foxl2 transgene disrupted embryonic testis differentiation and increased the levels of key female markers. Conclusion. The results, including a comprehensive principal component analysis, 1) support the proposal of dose-dependent Foxl2 function and anti-testis action throughout ovary differentiation; and 2) identify candidate genes for roles in sex determination independent of FOXL2 (e.g., the transcription factors IRX3 and ZBTB7C) and in the generation of the ovarian reserve downstream of FOXL2 (e.g., the cadherin-domain protein CLSTN2 and the sphingomyelin synthase SGMS2). The gene inventory is a first step toward the identification of the full range of pathways with partly autonomous roles in ovary development, and thus provides a framework to analyze the genetic bases of female fertility

Heritability of Cardiovascular and Personality Traits in 6,148 Sardinians

In family studies, phenotypic similarities between relatives yield information on the overall contribution of genes to trait variation. Large samples are important for these family studies, especially when comparing heritability between subgroups such as young and old, or males and females. We recruited a cohort of 6,148 participants, aged 14–102 y, from four clustered towns in Sardinia. The cohort includes 34,469 relative pairs. To extract genetic information, we implemented software for variance components heritability analysis, designed to handle large pedigrees, analyze multiple traits simultaneously, and model heterogeneity. Here, we report heritability analyses for 98 quantitative traits, focusing on facets of personality and cardiovascular function. We also summarize results of bivariate analyses for all pairs of traits and of heterogeneity analyses for each trait. We found a significant genetic component for every trait. On average, genetic effects explained 40% of the variance for 38 blood tests, 51% for five anthropometric measures, 25% for 20 measures of cardiovascular function, and 19% for 35 personality traits. Four traits showed significant evidence for an X-linked component. Bivariate analyses suggested overlapping genetic determinants for many traits, including multiple personality facets and several traits related to the metabolic syndrome; but we found no evidence for shared genetic determinants that might underlie the reported association of some personality traits and cardiovascular risk factors. Models allowing for heterogeneity suggested that, in this cohort, the genetic variance was typically larger in females and in younger individuals, but interesting exceptions were observed. For example, narrow heritability of blood pressure was approximately 26% in individuals more than 42 y old, but only approximately 8% in younger individuals. Despite the heterogeneity in effect sizes, the same loci appear to contribute to variance in young and old, and in males and females. In summary, we find significant evidence for heritability of many medically important traits, including cardiovascular function and personality. Evidence for heterogeneity by age and sex suggests that models allowing for these differences will be important in mapping quantitative traits

Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells

The discovery that the SRY gene induces male sex in humans and other mammals led to speculation about a possible equivalent for female sex. However, only partial effects have been reported for candidate genes experimentally tested so far. Here we demonstrate that inactivation of two ovarian somatic factors, Wnt4 and Foxl2, produces testis differentiation in XX mice, resulting in the formation of testis tubules and spermatogonia. These genes are thus required to initiate or maintain all major aspects of female sex determination in mammals. The two genes are independently expressed and show complementary roles in ovary morphogenesis. In addition, forced expression of Foxl2 impairs testis tubule differentiation in XY transgenic mice, and germ cell-depleted XX mice lacking Foxl2 and harboring a Kit mutation undergo partial female-to-male sex reversal. The results are all consistent with an anti-testis role for Foxl2. The data suggest that the relative autonomy of the action of Foxl2, Wnt4 and additional ovarian factor(s) in the mouse should facilitate the dissection of their respective contributions to female sex determination

Clustering of Genetic Correlations

<p>The 98 quantative traits are classified into clusters inferred from genetic correlations between any two traits, with an “average” distance measure used in the clustering algorithm. Classes of traits are color-coded as personality (red), serum composition (blue), cardiovascular (black), and anthropometric (green). Overlap of the apparent genetic contribution to variance is indicated on the ordinate, with larger overlaps towards the bottom. Eighteen values exceed 50% overlap (see text).</p