The effects of multiple features of alternatively spliced exons on the K(A)/K(S )ratio test

BACKGROUND: The evolution of alternatively spliced exons (ASEs) is of primary interest because these exons are suggested to be a major source of functional diversity of proteins. Many exon features have been suggested to affect the evolution of ASEs. However, previous studies have relied on the K(A)/K(S )ratio test without taking into consideration information sufficiency (i.e., exon length > 75 bp, cross-species divergence > 5%) of the studied exons, leading to potentially biased interpretations. Furthermore, which exon feature dominates the results of the K(A)/K(S )ratio test and whether multiple exon features have additive effects have remained unexplored. RESULTS: In this study, we collect two different datasets for analysis – the ASE dataset (which includes lineage-specific ASEs and conserved ASEs) and the ACE dataset (which includes only conserved ASEs). We first show that information sufficiency can significantly affect the interpretation of relationship between exons features and the K(A)/K(S )ratio test results. After discarding exons with insufficient information, we use a Boolean method to analyze the relationship between test results and four exon features (namely length, protein domain overlapping, inclusion level, and exonic splicing enhancer (ESE) frequency) for the ASE dataset. We demonstrate that length and protein domain overlapping are dominant factors, and they have similar impacts on test results of ASEs. In addition, despite the weak impacts of inclusion level and ESE motif frequency when considered individually, combination of these two factors still have minor additive effects on test results. However, the ACE dataset shows a slightly different result in that inclusion level has a marginally significant effect on test results. Lineage-specific ASEs may have contributed to the difference. Overall, in both ASEs and ACEs, protein domain overlapping is the most dominant exon feature while ESE frequency is the weakest one in affecting test results. CONCLUSION: The proposed method can easily find additive effects of individual or multiple factors on the K(A)/K(S )ratio test results of exons. Therefore, the system can analyze complex conditions in evolution where multiple features are involved. More factors can also be added into the system to extend the scope of evolutionary analysis of exons. In addition, our method may be useful when orthologous exons can not be found for the K(A)/K(S )ratio test

Widespread Over-Expression of the X Chromosome in Sterile F1 Hybrid Mice

The X chromosome often plays a central role in hybrid male sterility between species, but it is unclear if this reflects underlying regulatory incompatibilities. Here we combine phenotypic data with genome-wide expression data to directly associate aberrant expression patterns with hybrid male sterility between two species of mice. We used a reciprocal cross in which F1 males are sterile in one direction and fertile in the other direction, allowing us to associate expression differences with sterility rather than with other hybrid phenotypes. We found evidence of extensive over-expression of the X chromosome during spermatogenesis in sterile but not in fertile F1 hybrid males. Over-expression was most pronounced in genes that are normally expressed after meiosis, consistent with an X chromosome-wide disruption of expression during the later stages of spermatogenesis. This pattern was not a simple consequence of faster evolutionary divergence on the X chromosome, because X-linked expression was highly conserved between the two species. Thus, transcriptional regulation of the X chromosome during spermatogenesis appears particularly sensitive to evolutionary divergence between species. Overall, these data provide evidence for an underlying regulatory basis to reproductive isolation in house mice and underscore the importance of transcriptional regulation of the X chromosome to the evolution of hybrid male sterility

Reduced placental taurine transporter (TauT) activity in pregnancies complicated by pre-eclampsia and maternal obesity.

Taurine is an important nutrient in intrauterine life, being required for fetal organ development and cellular renewal of syncytiotrophoblast (STB), the nutrient transport epithelium of the placenta. As taurine is conditionally essential in human pregnancy, the fetal and placental demand for taurine is met by uptake from maternal blood into STB through the activity of TauT. Pre-eclampsia (PE) and maternal obesity are serious complications of pregnancy, associated with fetal growth restriction (FGR) and abnormal renewal of STB, and maternal obesity is a major risk factor for PE. Here we test the hypothesis that STB TauT activity is reduced in maternal obesity and PE compared to normal pregnancy. STB TauT activity, measured in fragments of placental tissue, was negatively related to maternal BMI over the range 18–46 kg/m(2) in both the first trimester (7–12 weeks gestation) and at term (p < 0.01; linear regression). Neither TauT activity nor expression in the first trimester differed to normal pregnancy at term. STB TauT activity was significantly lower in PE than normal pregnancy (p < 0.01). Neuropeptide Y (NPY), a protein kinase C (PKC) activator which is elevated in PE and obesity, reduced STB TauT activity by 20% (50 pM–50 nM: 2 h) (p < 0.03). Activation of PKC by phorbol 12-myristate-13-acetate (1 μM) reduced TauT activity by 18% (p < 0.05). As TauT activity is inhibited by phosphorylation, we propose that NPY activates PKC in the STB which phosphorylates TauT in PE and maternal obesity. Reduced TauT activity could contribute to dysregulated renewal of STB and FGR that are common to PE and maternal obesity

Maternal obesity is associated with a reduction in placental taurine transporter activity

BACKGROUND/OBJECTIVES: Maternal obesity increases the risk of poor pregnancy outcome including stillbirth, pre-eclampsia, fetal growth restriction and fetal overgrowth. These pregnancy complications are associated with dysfunctional syncytiotrophoblast, the transporting epithelium of the human placenta. Taurine, a β-amino acid with antioxidant and cytoprotective properties, has a role in syncytiotrophoblast development and function and is required for fetal growth and organ development. Taurine is conditionally essential in pregnancy and fetal tissues depend on uptake of taurine from maternal blood. We tested the hypothesis that taurine uptake into placental syncytiotrophoblast by the taurine transporter protein (TauT) is lower in obese women (body mass index (BMI)⩾30 kg m(−)(2)) than in women of ideal weight (BMI 18.5–24.9 kg m(−)(2)) and explored potential regulatory factors. SUBJECTS/METHODS: Placentas were collected from term (37–42-week gestation), uncomplicated, singleton pregnancies from women with BMI 19–49 kg m(−)(2). TauT activity was measured as the Na(+)-dependent uptake of (3)H-taurine into placental villous fragments. TauT expression in membrane-enriched placental samples was investigated by western blot. In vitro studies using placental villous explants examined whether leptin or IL-6, adipokines/cytokines that are elevated in maternal obesity, regulates TauT activity. RESULTS: Placental TauT activity was significantly lower in obese women (BMI⩾30) than women of ideal weight (P<0.03) and inversely related to maternal BMI (19–49 kg m(−)(2); P<0.05; n=61). There was no difference in TauT expression between placentas of ideal weight and obese class III (BMI⩾40) subjects. Long-term exposure (48 h) of placental villous explants to leptin or IL-6 did not affect TauT activity. CONCLUSIONS: Placental TauT activity at term is negatively related to maternal BMI. We propose that the reduction in placental TauT activity in maternal obesity could lower syncytiotrophoblast taurine concentration, compromise placental development and function, and reduce the driving force for taurine efflux to the fetus, thereby increasing the risk of poor pregnancy outcome

Consequences of maternal obesity on neonatal outcomes and cardio-metabolic health in infancy

Obesity is a growing global health problem and is well-recognized to be a major contributing factor for increased risk of several non-communicable diseases including cardiovascular disease, diabetes and cancer in both the developed and developing world. This development is multi-factorial, but an increasingly seden- tary lifestyle coupled with unhealthy dietary practices are key risk factors. Effective interventions for weight management would therefore not only be seen to reduce the epidemic of obesity, but also to lessen the risk for obesity-related morbidities. This article will briefly describe some factors that can cause obesity. Since men and women are different in their fat mass and distribution profile, and that ethnic groups are disproportionately affected by obesity, it is conceivable that disparities also exist in the occurrence of obesity and the consequential development of non-communicable diseases. Although the major adverse health outcomes due to obesity are mentioned, the influence and the role of sex, specifically women’s health, and ethnicity in the increased risk as well as development of obesity-induced health complications will also be discussed