Sibpair studies implicate chromosome 18 in essential hypertension

Interest in chromosome 18 in essential hypertension comes from comparative mapping of rat blood pressure quantitative trait loci (QTL), familial orthostatic hypotensive syndrome studies, and essential hypertension pedigree linkage analyses indicating that a locus or loci on human chromosome 18 may play a role in hypertension development. To further investigate involvement of chromosome 18 in human essential hypertension, the present study utilized a linkage scan approach to genotype twelve microsatellite markers spanning human chromosome 18 in 177 Australian Caucasian hypertensive (HT) sibling pairs. Linkage analysis showed significant excess allele sharing of the D18S61 marker when analyzed with SPLINK (P=0.00012), ANALYZE (Sibpair) (P=0.0081), and also with MAPMAKER SIBS (P=0.0001). Similarly, the D18S59 marker also showed evidence for excess allele sharing when analyzed with SPLINK (P=0.016), ANALYZE (Sibpair) (P=0.0095), and with MAPMAKER SIBS (P = 0.014). The adenylate cyclase activating polypeptide 1 gene (ADCYAP1) is involved in vasodilation and has been co-localized to the D18S59 marker. Results testing a microsatellite marker in the 3′ untranslated region of ADCYAP1 in age and gender matched HT and normotensive (NT) individuals showed possible association with hypertension (P = 0.038; Monte Carlo P = 0.02), but not with obesity. The present study shows a chromosome 18 role in essential hypertension and indicates that the genomic region near the ADCYAP1 gene or perhaps the gene itself may be implicated. Further investigation is required to conclusively determine the extent to which ADCYAP1 polymorphisms are involved in essential hypertension. © 2003 Wiley-Liss, Inc.

Low formalin concentrations induce fine-tuned responses that are sex and age-dependent : a developmental study

The formalin test is increasingly applied as a model of inflammatory pain using high formalin concentrations (5–15%). However, little is known about the effects of low formalin concentrations on related behavioural responses. To examine this, rat pups were subjected to various concentrations of formalin at four developmental stages: 7, 13, 22, and 82 days of age. At postnatal day (PND) 7, sex differences in flinching but not licking responses were observed with 0.5% formalin evoking higher flinching in males than in females. A dose response was evident in that 0.5% formalin also produced higher licking responses compared to 0.3% or 0.4% formalin. At PND 13, a concentration of 0.8% formalin evoked a biphasic response. At PND 22, a concentration of 1.1% evoked higher flinching and licking responses during the late phase (10–30 min) in both males and females. During the early phase (0–5 min), 1.1% evoked higher licking responses compared to 0.9% or 1% formalin. 1.1% formalin produced a biphasic response that was not evident with 0.9 or 1%. At PND 82, rats displayed a biphasic pattern in response to three formalin concentrations (1.25%, 1.75% and 2.25%) with the presence of an interphase for both 1.75% and 2.25% but not for 1.25%. These data suggest that low formalin concentrations induce fine-tuned responses that are not apparent with the high formalin concentration commonly used in the formalin test. These data also show that the developing nociceptive system is very sensitive to subtle changes in formalin concentrations.

Sex and the virtual suburbs : the pornosphere and community standards

This chapter looks at the management and zoning of online sexual culture–the web sites which make up the pornosphere (McNair 2013). It explores the concept of ‘community standards’, which has been a central part of the management of sexually explicit materials in the offline world, and asks what it might mean to talk about ‘community standards’ on the Internet. And finally, it uses the concept of virtual-community standards to revisit the question of managing access to sexually explicit materials on the Internet.

Sex hormone regulation of innate immunity in the female reproductive tract : the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens

The immune system in the female reproductive tract (FRT) does not mount an attack against HIV or other sexually transmitted infections (STI) with a single endogenously produced microbicide or with a single arm of the immune system. Instead, the body deploys dozens of innate antimicrobials to the secretions of the female reproductive tract. Working together, these antimicrobials along with mucosal antibodies attack many different viral, bacterial and fungal targets. Within the FRT, the unique challenges of protection against sexually transmitted pathogens coupled with the need to sustain the development of an allogeneic fetus have evolved in such a way that sex hormones precisely regulate immune function to accomplish both tasks. The studies presented in this review demonstrate that estradiol and progesterone secreted during the menstrual cycle act both directly and indirectly on epithelial cells and other immune cells in the reproductive tract to modify immune function in a way that is unique to specific sites throughout the FRT. As presented in this review, studies from our laboratory and others demonstrate that the innate immune response is under hormonal control, varies with the stage of the menstrual cycle, and as such is suppressed at mid-cycle to optimize conditions for successful fertilization and pregnancy. In doing so, a window of STI vulnerability is created during which potential pathogens including HIV enter the reproductive tract to infect host targets.

The X-chromosome and susceptibility to ankylosing spondylitis

Objective. Ankylosing spondylitis (AS) affects 0.25-1.0% of the population, and its etiology is incompletely understood. Susceptibility to this highly familial disease (λ(s) = 58) is primarily genetically determined. There is a significant sex bias in AS, and there are differences in recurrence risk to the offspring of affected mothers and fathers, suggesting that there may be an X-linked recessive effect. We undertook an X- chromosome linkage study to determine any contribution of the X-chromosome to AS susceptibility. Methods. A linkage study of the X-chromosome using 234 affected sibling pairs was performed to investigate this hypothesis. Results. No linkage of the X-chromosome with susceptibility to AS was found. Model- free multipoint linkage analysis strongly excluded any significant genetic contribution (λ ≥1.5) to AS susceptibility encoded on the X-chromosome (logarithm of odds [LOD] <-2.0). Smaller genetic effects (A ≥1.3) were also found to be unlikely (LOD <-1.0). Conclusion. The sex bias in AS is not explained by X-chromosome-encoded genetic effects. The disease model best explaining the sex bias in occurrence and transmission of AS is a polygenic model with a higher susceptibility threshold in females.

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

Genome-wide study of familial juvenile hyperuricaemic (gouty) nephropathy (FJHN) indicates a new locus, FJHN3, linked to chromosome 2p22.1-p21

Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1β) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1β mutations are found in only ~45% of FJHN probands, indicating the involvement of other genetic loci in ~55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1β and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a ~5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a ~5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.

Dosage Compensation And Sex Determination In Drosophila - Mechanism Of Measurement Of The X/A Ratio

We propose a molecular mechanism for the intra-cellular measurement of the ratio of the number of X chromosomes to the number of sets of autosomes, a process central to both sex determination and dosage compensation in Drosophila melanogaster. In addition to the two loci, da and Sxl, which have been shown by Cline (Genetics, 90, 683, 1978)and others to be involved in these processes, we postulate two other loci, one autosomal (ω) and the other, X-linked (π). The product of the autosomal locus da stimulates ω and initiates synthesis of a limited quantity of repressor. Sxl and π ,both of which are X-linked, compete for this repressor as well as for RNA polymerase. It is assumed that Sxl has lower affinity than π for repressor as well as polymerase and that the binding of polymerase to one of these sites modulates the binding affinity of the other site for the enzyme. It can be shown that as a result of these postulated interactions transcription from the Sxl site is proportional to the X/A ratio such that the levels of Sxl+ product are low in males, high in females and intermediate in the intersexes. If, as proposed by Cline, the Sxl- product is an inhibitor of X chromosome activity, this would result in dosage compensation. The model leads to the conclusion that high levels of Sxl+ product promote a female phenotype and low levels, a male phenotype. One interesting consequence of the assumptions on which the model is based is that the level of Sxl+ product in the cell, when examined as a function of increasing repressor concentration, first goes up and then decreases, yielding a bell-shaped curve. This feature of the model provides an explanation for some of the remarkable interactions among mutants at the Sxl, da and mle loci and leads to several predictions. The proposed mechanism may also have relevance to certain other problems, such as size regulation during development, which seem to involve measurement of ratios at the cellular level.

A model for mammalian male determination based on a passive Y chromosome

A model is suggested for mammalian male determination based on interactions postulated to occur among an autosomal repressor gene, an X-linked male-determining gene termed Tdx, and multiple copies of certain DNA sequences on the Y chromosome that do not code for any protein. The repressor, synthesised in limited amounts, has higher affinity for the Y-linked sequences than for Tdx and its affinity for Tdx is greater than that of RNA polymerase. In XY cells the Y effectively binds all available repressor, permitting transcription of Tdx to occur. In XX cells, since competition from the Y-linked high-affinity sequences is absent, the repressor binds to Tdx and prevents transcription. As a result of this competition between Tdx and the Y-linked high-affinity sites for limiting concentrations of the autosomal repressor, the product of the Tdx gene (TDX) is synthesized in the male but not in the female. It is suggested that in determination of the male sex, the role of the Y chromosome is to serve as a sink for the Tdx repressor. The proposed interactions provide a plausible explanation for the genetic properties of several anomalies of sexual development in mouse, man, and other mammals. The model suggests that the postulated multiple, highaffinity sequences on the Y chromosome of the mouse are included among the DNA sequences referred to as the Sxr-Bkm sequences.

Effects of 17α-ethinyl estradiol on the mating system of the sand goby (Pomatoschistus minutus)

In aquatic environments, endocrine disrupting chemicals (EDCs) that interfere with the endocrinology of males and females form a threat to the maintenance of populations. EDCs are a diverse group of natural and manmade chemicals that already at very low concentrations (at nanogram levels) can have severe effects on reproduction by individuals, e.g. complete sex reversal, feminisation of males, impaired reproduction even resulting in near extinction of populations. With regard to fish, despite the extensive literature on physiological effects of EDCs, very little is known about potential population-level effects. In this thesis, I examined how 17α-ethinyl estradiol (EE2), a synthetic estrogen used in oral contraceptive pills, affects the reproductive behaviour of a marine fish, the sand goby (Pomatoschistus minutus). The aims were fourfold. First, I investigated how exposure to EE2 affects courtship and parental care of sand goby males. Secondly, I looked at effects on the mating system and sexual selection. In the third study, I observed the effects of exposure in a social context where exposed males had to compete with non-exposed males for resources and mates. Finally, I studied the effects of exposure on male-male competition and male aggressive behaviour. This work revealed that EE2 exposure impairs the ability of males to acquire and defend a nest, as well as diminishes the attractiveness of males to females by decreasing their courtship and aggressive behaviour. These effects are harmful for a male whose reproductive success is determined by the ability to compete for limited resources and to attract mates. Furthermore, this thesis showed that selection on male size was relaxed after EE2 exposure and male size had a smaller effect on mating success. These effects can be of a profound nature as they interfere with sexual selection, and may in the long run lead to the loss of traits maintained through sexual selection. The thesis shows that an exposure to environmentally relevant levels of EE2 clearly reduces the chances of individuals to reproduce successfully. Furthermore, it strongly suggests that several types of biomarkers should be used to detect and assess the effects of EDC exposure because severe behavioural effects can sometimes be seen before effects are detectable at the molecular or morphometric level. Behavioural assays should be considered an important complementary tool for the standard ecotoxicological assays because observed behavioural changes have direct and negative effects on fitness, while the connection between changes in molecular expression and fitness may be less obvious.

Consanguinity, twinning and secondary sex ratio in the population of Karnataka, South India

Consanguineous marriages are strongly favoured in the state of Karnataka. Of 65492 marriages studied 33·07% were consanguineous, equivalent to a coefficient of inbreeding (F) of 0·0298. The twinning rate was low, 6·9 per thousand, whereas the secondary sex ratio, 0·5221, was higher than in comparable major human populations. Consanguinity exerted no significant effect on either parameter. The results also indicate that consanguinity is not associated with excess antenatal losses and suggest the possibility of enhanced selection against mutations at X chromosome loci.

Comparative Analyses of Age- and Sex-Specific Patterns of Vocal Behaviour in Four Species of Old World Monkeys

Sound recordings and behavioural data were collected from four primate species of two genera (Macaca, Presbytis). Comparative analyses of structural and behavioural aspects of vocal communication revealed a high degree of intrageneric similarity but striking intergeneric differences. In the two macaque species (Macaca silenus, Macaca radiata), males and females shared the major part of the repertoire. In contrast, in the two langurs (Presbytis johnii, Presbytis entellus), many calls were exclusive to adult males. Striking differences between both species groups occurred with respect to age-specific patterns of vocal behaviour. The diversity of vocal behaviour was assessed from the number of different calls used and the proportion of each call in relation to total vocal output for a given age/sex class. In Macaca, diversity decreases with the age of the vocalizer, whereas in Presbytis the age of the vocalizer and the diversity of vocal behaviour are positively correlated. A comparison of the data of the two genera does not suggest any causal relationship between group composition (e.g. multi-male vs. one-male group) and communication system. Within each genus, interspecific differences in vocal behaviour can be explained by differences in social behaviour (e.g. group cohesion, intergroup relation, mating behaviour) and functional disparities. Possible factors responsible for the pronounced intergeneric differences in vocal behaviour between Macaca and Presbytis are discussed.

Synergistic interaction between particular X-chromosome deletions andSex-lethal causes female lethality inDrosophila melanogaster

We studied the effect on female viability of trans-heterozygous combinations of X-chromosome deficiencies and Sxt-(fl), a null allele of Sex-lethal. Twentyfive deficiencies, which together covered 80% of the X chromosome, were tested. Seven of these trans-heterozygous combinations caused significant levels of female lethality. Two of the seven interacting deficiencies include the previously known sex determination genes sans fille and sisterless-a. Four of the remaining uncover X-chromosomal regions that were not hitherto known to contain sex determination genes. These newly identified regions are defined by deficiencies Df(1)RA2 (7D10; 8A4-5), Df(1)KA14 (7F1-2; 8C6), Df(1)C52 (8E; 9C-D) and Df(1)N19 (17A1; 18A2). These four deficiencies were characterized further to determine whether it was the maternal or zygotic dosage that was primarily responsible for the observed lethality of female embryos, daughterless and extra macrochaetae, two known regulators of Sxl, influence the interaction of these deficiencies with Sxl.

Organization and function of the phage Lambda chromosome

The process of prophage integration by phage λ and the function and structure of the chromosomal elements required for λ integration have been studied with the use of λ deletion mutants. Since att^φ, the substrate of the integration enzymes, is not essential for λ growth, and since att^φ resides in a portion of the λ chromosome which is not necessary for vegetative growth, viable λ deletion mutants were isolated and examined to dissect the structure of att^φ.

Deletion mutants were selected from wild type populations by treating the phage under conditions where phage are inactivated at a rate dependent on the DNA content of the particles. A number of deletion mutants were obtained in this way, and many of these mutants proved to have defects in integration. These defects were defined by analyzing the properties of Int-promoted recombination in these att mutants.

The types of mutants found and their properties indicated that att^φ has three components: a cross-over point which is bordered on either side by recognition elements whose sequence is specifically required for normal integration. The interactions of the recognition elements in Int-promoted recombination between att mutants was examined and proved to be quite complex. In general, however, it appears that the λ integration system can function with a diverse array of mutant att sites.

The structure of att^φ was examined by comparing the genetic properties of various att mutants with their location in the λ chromosome. To map these mutants, the techniques of heteroduplex DNA formation and electron microscopy were employed. It was found that integration cross-overs occur at only one point in att^φ and that the recognition sequences that direct the integration enzymes to their site of action are quite small, less than 2000 nucleotides each. Furthermore, no base pair homology was detected between att^φ and its bacterial analog, att^B. This result clearly demonstrates that λ integration can occur between chromosomes which have little, if any, homology. In this respect, λ integration is unique as a system of recombination since most forms of generalized recombination require extensive base pair homology.

An additional study on the genetic and physical distances in the left arm of the λ genome was described. Here, a large number of conditional lethal nonsense mutants were isolated and mapped, and a genetic map of the entire left arm, comprising a total of 18 genes, was constructed. Four of these genes were discovered in this study. A series of λdg transducing phages was mapped by heteroduplex electron microscopy and the relationship between physical and genetic distances in the left arm was determined. The results indicate that recombination frequency in the left arm is an accurate reflection of physical distances, and moreover, there do not appear to be any undiscovered genes in this segment of the genome.

The effects of size-selective fisheries on the stock dynamics of and sperm limitation in sex-changing fish

Fisheries models have traditionally focused on patterns of growth, fecundity, and survival of fish. However, reproductive rates are the outcome of a variety of interconnected factors such as life-history strategies, mating patterns, population sex ratio, social interactions, and individual fecundity and fertility. Behaviorally appropriate models are necessary to understand stock dynamics and predict the success of management strategies. Protogynous sex-changing fish present a challenge for management because size-selective fisheries can drastically reduce reproductive rates. We present a general framework using an individual-based simulation model to determine the effect of life-history pattern, sperm production, mating system, and management strategy on stock dynamics. We apply this general approach to the specific question of how size-selective fisheries that remove mainly males will impact the stock dynamics of a protogynous population with fixed sex change compared to an otherwise identical dioecious population. In this dioecious population, we kept all aspects of the stock constant except for the pattern of sex determination (i.e. whether the species changes sex or is dioecious). Protogynous stocks with fixed sex change are predicted to be very sensitive to the size-selective fishing pattern. If all male size classes are fished, protogynous populations are predicted to crash even at relatively low fishing mortality. When some male size classes escape fishing, we predict that the mean population size of sex-changing stocks will decrease proportionally less than the mean population size of dioecious species experiencing the same fishing mortality. For protogynous species, spawning-per-recruit measures that ignore fertilization rates are not good indicators of the impact of fishing on the population. Decreased mating aggregation size is predicted to lead to an increased effect of sperm limitation at constant fishing mortality and effort. Marine protected areas have the potential to mitigate some effects of fishing on sperm limitation in sex-changing populations.