Functional impact and evolution of a novel human polymorphic inversion that disrupts a gene and creates a fusion transcript

Since the discovery of chromosomal inversions almost 100 years ago, how they are maintained in natural populations has been a highly debated issue. One of the hypotheses is that inversion breakpoints could affect genes and modify gene expression levels, although evidence of this came only from laboratory mutants. In humans, a few inversions have been shown to associate with expression differences, but in all cases the molecular causes have remained elusive. Here, we have carried out a complete characterization of a new human polymorphic inversion and determined that it is specific to East Asian populations. In addition, we demonstrate that it disrupts the ZNF257 gene and, through the translocation of the first exon and regulatory sequences, creates a previously nonexistent fusion transcript, which together are associated to expression changes in several other genes. Finally, we investigate the potential evolutionary and phenotypic consequences of the inversion, and suggest that it is probably deleterious. This is therefore the first example of a natural polymorphic inversion that has position effects and creates a new chimeric gene, contributing to answer an old question in evolutionary biology

Coe Genes Are Expressed in Differentiating Neurons in the Central Nervous System of Protostomes

Genes of the coe (collier/olfactory/early B-cell factor) family encode Helix-Loop-Helix transcription factors that are widely conserved in metazoans and involved in many developmental processes, neurogenesis in particular. Whereas their functions during vertebrate neural tube formation have been well documented, very little is known about their expression and role during central nervous system (CNS) development in protostomes. Here we characterized the CNS expression of coe genes in the insect Drosophila melanogaster and the polychaete annelid Platynereis dumerilii, which belong to different subgroups of protostomes and show strikingly different modes of development. In the Drosophila ventral nerve cord, we found that the Collier-expressing cells form a subpopulation of interneurons with diverse molecular identities and neurotransmitter phenotypes. We also demonstrate that collier is required for the proper differentiation of some interneurons belonging to the Eve-Lateral cluster. In Platynereis dumerilii, we cloned a single coe gene, Pdu-coe, and found that it is exclusively expressed in post mitotic neural cells. Using an original technique of in silico 3D registration, we show that Pdu-coe is co-expressed with many different neuronal markers and therefore that, like in Drosophila, its expression defines a heterogeneous population of neurons with diverse molecular identities. Our detailed characterization and comparison of coe gene expression in the CNS of two distantly-related protostomes suggest conserved roles of coe genes in neuronal differentiation in this clade. As similar roles have also been observed in vertebrates, this function was probably already established in the last common ancestor of all bilaterians

Effects of testosterone replacement on HDL subfractions and apolipoprotein A-I containing lipoproteins

OBJECTIVES: Gonadal steroids are important regulators of lipoprotein metabolism. The aims of this study were to determine the effects of a minimum effective dose of testosterone replacement on high density lipoprotein (HDL) subfractions and apolipoprotein (apo) A-I containing particles (lipoprotein (Lp)A-I) and LpA-I:A-II) in hypogonadal men with primary testicular failure and to investigate the underlying mechanisms of these changes. MEASUREMENTS: Eleven Chinese hypogonadal men were started on testosterone enanthate 250 mg intramuscularly at 4-weekly intervals. HDL was subfractionated by density gradient ultracentrifugation and LpA-I was analysed by electro- immunodiffusion after 3, 6 and 12 weeks of treatment. Plasma cholesteryl ester transfer protein (CETP) activity and lipolytic enzymes activities in post-heparin plasma were measured to determine the mechanisms underlying testosterone-induced changes in HDL. RESULTS: The dosage of testosterone enanthate used in the present study resulted in suboptimal trough testosterone levels. No changes were seen in plasma total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL-C,) apo B and apo(a) after 12 weeks. There was a drop in HDL3-C compared to baseline (0.82 ± 0.17 mmol/1 vs. 0.93 ± 0.13, P< 0.01) whereas a small but significant increase was seen in HDL2-C (0.21 ± 0.13 mmol/vs. 0.11 ± 0.09, P<0.05). Plasma apo A-I decreased after treatment (1.34 ± 0.25 g/l vs. 1.50 ± 0.29, P<0.01), due to a reduction in LpA-I:A-II particles (0.86 ± 0.18 g/l vs. 0.99 ± 0.24, P<0.01). No changes were observed in the levels of LpA-I particles. No significant changes were seen in plasma CETP and lipoprotein lipase activities after testosterone replacement but there was a transient increase in hepatic lipase (HL) activity at weeks 3 and 6. The decrease in HDL correlated with the increase in HL activity (r= 0.62, P< 0.05). CONCLUSIONS: Testosterone replacement in the form of parenteral testosterone ester given 4-weekly, although unphysiological, was not associated with unfavourable changes in lipid profiles. The reduction in HDL was mainly in HDL3-C and in LpA-I:A-II particles and not in the more anti-atherogenic HDL2 and LpA-I particles. The changes in HDL subclasses were mainly mediated through the effect of testosterone on hepatic lipase activity.link_to_subscribed_fulltex

Iodine insufficiency and neonatal hyperthyrotropinaemia in Hong Kong

Objectives: 23% of the neonatal hypothyroidism in Hong Kong is transient. The present study aims to evaluate iodine excretion in healthy pregnant women in Hong Kong and to determine whether iodine insufficiency may occur in the local population to account for the type of neonatal thyroid dysfunction seen in our screening programme. Subjects: Pilot screening of urinary iodine excretion was determined in 253 healthy pregnant women between 32 and 36 weeks gestation. Fetal and maternal thyroid function in relation to urinary iodine excretion was evaluated in another 55 pregnant women who had given birth to infants with cord blood TSH ≤16 mlU/l (95th percentile of the cord blood TSH screening programme) and the results were compared to a control group of 160 healthy women whose infants had cord blood TSH < 16 mlU/l. Results: Using a cut-off value of 0.79 μmol/l, a level as defined by WHO as iodine deficiency, we found that 35.8% of the pregnant women had urinary iodine concentrations below this cut off value. We demonstrated that the existence of borderline iodine supply affected the maternal and fetal thyroid function as evidenced by (i) a negative correlation between maternal TSH and urinary iodine concentration, (ii) higher cord blood TSH in those infants whose mothers had a low urinary iodine concentration as compared to those in whose mothers it was normal, (iii) women who had given birth to infants with cord blood TSH ≤16 mlU/l had lower urinary iodine concentrations and serum fT4 levels as compared to mothers who had given birth to infants with normal cord TSH levels, and their offspring also had higher cord blood thyroglobulin levels. Conclusion: Although Hong Kong is not a goitrous area, borderline iodine deficiency exists, iodization of salt in our community could obviate the necessity for iodine supplements in pregnant women and other at risk groups.link_to_subscribed_fulltex

Changes in serum lipoprotein(a) and lipids during treatment of hyperthyroidism

Because of suggestions that thyroid hormones modulate serum lipoprotein(a) [Lp(a)] concentration, we evaluated prospectively the serial changes of serum Lp(a), measured as apolipoprotein(a) [apo(a)], and other lipoproteins in 40 subjects with hyperthyroidism treated with radioactive iodine (RAI) therapy. Hyperthyroid patients had lower (P <0.001) concentrations of apo(a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apo B, but higher apo A-I concentrations compared with age-matched controls [geometric mean (range)]; apo(a) 81 (17- 614) vs 187 (17-1808 IU/L): TC 4.07 ± 0.8 vs 5.22 ± 1.00 mmol/L (mean ± SD); LDL-C 2.47 ± 0.89 vs 3.40 ± 0.88 mmol/L; HDL-C 1.05 ± 0.33 vs 1.24 ± 0.34 mmol/L; apo B 0.66 ± 0.23 vs 1.13 ± 0.34 g/L, and apo A-I 2.07 ± 0.42 vs 1.46 ± 0.28 g/L, respectively. Euthyroidism was associated with normalization of serum TC, LDL-C, and apo B within 1 month of treatment. However, apo(a) required 4 months to normalize, and HDL-C and apo A-I were still abnormal 6 months after RAI. Serum apo(a), TC, LDL-C, and apo B were negatively correlated with serum thyroxine (T4), free thyroxine index, and triiodothyronine (T3) and positively correlated with thyrotropin during the transitional period from hyperthyroidism to euthyroidism. Parallel changes of these lipoproteins and thyroid hormones were also observed after treatment of hyperthyroidism. In conclusion, thyroid hormones do modulate lipoproteins, particularly Lp(a). The delay in normalization of apo(a) but not LDL suggests an effect on apo(a) production rather than on LDL removal.published_or_final_versio

Plasma levels of immunoreactive melatonin, estradiol, progesterone, follicle stimulating hormone, and β-human chorionic gonadotropin during pregnancy and shortly after parturition in humans

Plasma concentrations of immunoreactive melatonin, estradiol, progesterone,follicle stimulating hormone (FSH), and β-human chorionic gonadotropin (βhCG) were studied between 1000 and 1230 h in 105 Chinese females during six periods of normal pregnancy and 1-5 min after normal delivery. We have also examined the midday levels of immunoreactive melatonin in the cord blood of fetuses and plasma collected 1-5 min after and 24 h after delivery from their mothers. Concentrations of hormone immunoreactivities were determined by radioimmunoassay, and distinct fluctuations of all hormones were recorded during pregnancy. In the pregnant females, there were significant negative correlations between melatonin and estradiol, melatonin and progesterone, βhCG and progesterone, and βhCG and estradiol, and positive correlations between melatonin and FSH and progesterone and estradiol. Furthermore, plasma melatonin levels in the cord blood demonstrated no sex difference and were significantly lower than and correlated positively with the levels in their mothers. Our results suggest that sex steroids may inhibit and FSH may potentiate circulating melatonin levels in gravid women; changes in the levels of melatonin during pregnancy may affect the in utero development of the human embryo; and circulating melatonin in the mother may be the major source of blood melatonin in the fetus before parturition.link_to_subscribed_fulltex

Serum apolipoprotein(a) correlates with growth hormone levels in Chinese patients with acromegaly

Untreated acromegaly is associated with an increased cardiovascular morbidity and mortality. The contribution of altered lipid metabolism remains unclear. We investigated the relationship between serum apolipoprotein(a) (apo(a)) and growth hormone (GH) levels in 15 patients with acromegaly before and during treatment with octreotide, a long-acting somatostatin analogue, 288-600 μg/day s.c., for 6 months. Before treatment serum apo(a) was significantly elevated in acromegalic patients (geometric mean being 323 U/l vs. 142 U/l in controls (n = 92; P < 0.01)). Octreotide treatment resulted in significant reductions in serum apo(a) concentration (F = 7.22; P < 0.01; geometric mean being 232 U/l and 248 U/l at 3 months and 6 months respectively) and apo(a) concentrations on treatment were not significantly different from control values. There were significant reductions in serum GH (F = 7.30; P < 0.01), insulin growth factor 1 (IGF1) (F = 31.4, P < 0.001) and insulin (F = 4.57; P < 0.05) concentrations. Plasma glycosylated haemoglobin levels were unchanged. Apo(a) levels correlated with serum GH (r = 0.450; P < 0.01) but showed no correlation with basal insulin concentrations. Serum HDL cholesterol increased on treatment (F = 4.29; P < 0.05). Triglycerides were reduced only in the 12 patients without diabetes mellitus (P = 4.75; P < 0.05). No significant change in LDL cholesterol occurred. Our findings suggest that apo(a) may constitute another cardiovascular risk factor in untreated acromegaly and that GH may be involved in the regulation of circulating apo(a) concentration.link_to_subscribed_fulltex