Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe.

The aim of this study is to quantify the prevalence and types of rare chromosome abnormalities (RCAs) in Europe for 2000-2006 inclusive, and to describe prenatal diagnosis rates and pregnancy outcome. Data held by the European Surveillance of Congenital Anomalies database were analysed on all the cases from 16 population-based registries in 11 European countries diagnosed prenatally or before 1 year of age, and delivered between 2000 and 2006. Cases were all unbalanced chromosome abnormalities and included live births, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. There were 10,323 cases with a chromosome abnormality, giving a total birth prevalence rate of 43.8/10,000 births. Of these, 7335 cases had trisomy 21,18 or 13, giving individual prevalence rates of 23.0, 5.9 and 2.3/10,000 births, respectively (53, 13 and 5% of all reported chromosome errors, respectively). In all, 473 cases (5%) had a sex chromosome trisomy, and 778 (8%) had 45,X, giving prevalence rates of 2.0 and 3.3/10,000 births, respectively. There were 1,737 RCA cases (17%), giving a prevalence of 7.4/10,000 births. These included triploidy, other trisomies, marker chromosomes, unbalanced translocations, deletions and duplications. There was a wide variation between the registers in both the overall prenatal diagnosis rate of RCA, an average of 65% (range 5-92%) and the prevalence of RCA (range 2.4-12.9/10,000 births). In all, 49% were liveborn. The data provide the prevalence of families currently requiring specialised genetic counselling services in the perinatal period for these conditions and, for some, long-term care.

Multiple paternity and its consequences in the white campion " Silene latifolia "

Summary Several studies have demonstrated that the number of pollen donors siring seeds of individual fruits is frequently greater than one and, consequently, that plants have multiple mates. Multiple paternity can have important consequences at the population level. It influences the genetic variability of a population, the reproductive success of males and the fitness of females and future generations. It also influences male-male interactions for fertilization and it is fundamental in providing opportunity of female choice. I investigated the occurrence and the importance of multiple paternity within fruits in natural populations of the dioecious Silene latifolia using microsatellite DNA markers, especially developed for this study. I found that multiple paternity occurs in all populations investigated in the European range of the species, varying from one to nine sires per fruit with a mean of three, suggesting that multiple paternity is highly prevalent in natural populations. In the presence of multiple paternity I investigated if there was a female genotype influence on siring success of the males. I used the same pollen mixture from two males and applied it to three replicate females of different relatedness (two full sisters and one unrelated). I found female genotype influence in one of the two populations investigated, which might reflect different population history. Since these results suggested some degree of female choice, we investigated whether the occurrence of multiple paternity and post-pollination selection could provide opportunity for inbreeding avoidance. First, I measured inbreeding depression at different life-cycle stages for offspring obtained by single-donor crosses with brothers or unrelated males replicated on distinct flowers on the same female plant. To address inbreeding avoidance, I determined paternity in crosses using mixed pollen loads of the two males. I found significant inbreeding depression in the studied population, even under benign experimental conditions, and although the unrelated male did not sire significantly more offspring, there was an effect of genetic dissimilarity on paternity. This suggests that paternity is affected by relatedness among mates, but maybe additionally affected by other factors such as pollen competitive ability or male-female interactions. Using inbred and outbred crosses, I further investigated sex ratio bias inheritance in this species, and found that sex ratio bias of the parental generation was significantly correlated to pollen germination success of the F2 generation, which suggests that sex ratio bias in this species results from the specific X/Y combination and not only on Y performance. An effect of X and Y is consistent with sex chromosome meiotic drive. In conclusion, I found multiple paternity to be widespread in the study species and that females of similar genotype produce similar paternity shares. I found that inbreeding depression is substantial, therefore receiving pollen from several donors might lead to fewer inbred offspring, I also found an effect of genetic dissimilarity on paternity shares, which indicates that there is some ability to discriminate against related pollen, although this seems not to be the only determinant of paternity outcome. Finally I found sex ratio bias to be dependent on both X and Y chromosomes as predicted by sex chromosome meiotic drive. Résumé Plusieurs études ont démontré qu'il n'était pas rare que les graines contenues dans un même fruit soient issues de la fécondation par plusieurs pollens provenant de mâles différents, ce qui sous-entend que les plantes peuvent avoir plusieurs partenaires sexuels. La paternité multiple peut avoir d'importantes conséquences au niveau populationnel dans la mesure où elle peut influencer le degré de variabilité génétique de la population, le succès reproducteur des mâles, la fitness des femelles et des futures générations. La paternité multiple peut également avoir un impact sur les interactions mâle-mâle lors de la fertilisation et peut être considérée comme fondamentale vis-à-vis de la femelle, qui y trouve alors une opportunité de choisir son ou ses partenaires. Dans le cadre de ce travail de thèse j'ai cherché à déterminer si la paternité multiple était un phénomène observable et important dans les populations naturelles de l'espèce dioïque, Silene latifolia. Pour ce faire, j'ai utilisé des marqueurs microsatellites, spécialement développés pour cette étude. J'ai observé des phénomènes de paternité multiple dans toutes les populations de l'étude, réparties dans l'aire de distribution européenne de l'espèce. Le nombre de pères par fruit varie de un à neuf, avec un nombre moyen de trois, ce qui signifie que la paternité multiple est très répandue dans les populations naturelles. En raison de ces résultats, je me suis demandée si le génotype de la femelle influence le succès de paternité des mâles. J'ai alors réalisé des pollinisations manuelles sur la base d'un mélange de pollens issus de deux mâles, que j'ai appliqué sur trois femelles (réplicats) présentant différents degrés d'apparentement (deux soeurs. et une femelle étrangère). Il ressort de cette expérience que le génotype de la femelle peut influencer la paternité dans l'une des deux populations étudiées, ce qui pourrait refléter des différences en terme d'histoire des populations. Dans la mesure où ces résultats suggèrent un certain degré de choix chez la femelle, j'ai cherché à savoir si la paternité multiple et la sélection post-pollinisation pouvaient être des moyens d'éviter les croisements consanguins. Dans un premier temps, j'ai évalué la dépression de consanguinité à différentes étapes du cycle de vie chez des descendants issus de croisements à un seul donneur, celui-ci étant alternativement un frère ou un étranger, répliqués sur plusieurs fleurs d'une même plante femelle. Afin d'estimer l'évitement de croisements consanguins, j'ai effectué des croisements dont le pollen était un mélange des deux mâles (frère et étranger), puis j'ai déterminé la paternité dans les fruits obtenus. J'ai pu mettre en évidence un effet de dépression de consanguinité- significatif dans les populations étudiées, même dans des conditions expérimentales moins rudes qu'à l'extérieur. Bien que le mâle étranger n'ait pas engendré un nombre significativement plus important de graines, il y avait un effet de dissimilarité génétique sur la paternité. Ceci suggère que la paternité est affectée par le degré d'apparentement entre les partenaires, mais qu'elle peut aussi être affectée par d'autres facteurs tels que la compétitivité du pollen ou encore par les interactions mâles-femelles. L'utilisation de croisements consanguins et hybrides m'a également permis d'étudier l'héritabilité du biais de sex ratio chez cette espèce. Il s'est avéré que le biais de sex ratio de la génération parentale était significativement corrélé au succès de germination du pollen de la génération F2, ce qui signifie que, chez cette espèce, le biais de sex ratio résulte d'une combinaison spécifique de X/Y et non uniquement de la performance de Y. Un effet de X et Y est compatible avec l'hypothèse de distorsion de ségrégation méiotique des chromosomes sexuels. En conclusion, il ressort de mes résultats que la paternité multiple est un phénomène largement répandu chez S. latifolia et la paternité accomplie par un mâle est plus similaire entre soeurs qu'avec une femelle étrangère J'ai également mis en évidence que la dépression de consanguinité a un impact considérable; aussi, recevoir du pollen de plusieurs donneurs différents pourrait permettre à la femelle de produire moins de descendants consanguins. J'ai aussi trouvé un effet de la dissimilarité génétique sur le partage de paternité, ce qui indique que la discrimination contre le pollen d'apparentés est possible, bien que cela ne semble pas être le seul facteur déterminant dans le résultat de la paternité. Enfin, j'ai trouvé que le biais de sex ratio est dépendant des deux chromosomes X et Y, conformément à la théorie de distorsion de ségrégation méiotique des chromosomes sexuels.

Social chromosome variants differentially affect queen determination and the survival of workers in the fire ant Solenopsis invicta.

Intraspecific variation in social organization is common, yet the underlying causes are rarely known. An exception is the fire ant Solenopsis invicta in which the existence of two distinct forms of social colony organization is under the control of the two variants of a pair of social chromosomes, SB and Sb. Colonies containing exclusively SB/SB workers accept only one single queen and she must be SB/SB. By contrast, when colonies contain more than 10% of SB/Sb workers, they accept several queens but only SB/Sb queens. The variants of the social chromosome are associated with several additional important phenotypic differences, including the size, fecundity and dispersal strategies of queens, aggressiveness of workers, and sperm count in males. However, little is known about whether social chromosome variants affect fitness in other life stages. Here, we perform experiments to determine whether differential selection occurs during development and in adult workers. We find evidence that the Sb variant of the social chromosome increases the likelihood of female brood to develop into queens and that adult SB/Sb workers, the workers that cull SB/SB queens, are overrepresented in comparison to SB/SB workers. This demonstrates that supergenes such as the social chromosome can have complex effects on phenotypes at various stages of development.

A cross-sectional survey of attitudes to HIV risk and rapid HIV testing among clients of sex workers in Switzerland.

OBJECTIVES: To assess attitudes to HIV risk and acceptability of rapid HIV testing among clients of street-based female sex workers (FSW) in Lausanne, Switzerland, where HIV prevalence in the general population is 0.4%. METHODS: The authors conducted a cross-sectional study in the red light district of Lausanne for five nights in September of 2008, 2009 and 2010. Clients of FSW were invited to complete a questionnaire in the street assessing demographic characteristics, attitudes to HIV risk and HIV testing history. All clients interviewed were then offered anonymous finger stick rapid HIV testing in a van parked on-site. RESULTS: The authors interviewed 112, 127 and 79 clients in 2008, 2009 and 2010, respectively. All were men, average age 32-37 years old; 40-60% were in a stable relationship. History of unprotected sex was higher with non-commercial partners (33-50%) than with FSW (6-11%); 29-46% of clients had never undergone an HIV test. Anonymous rapid HIV testing was accepted by 45-50% of clients. Out of 109 HIV tests conducted during the three study periods, none was reactive. CONCLUSIONS: On-site HIV counselling and testing is acceptable among clients of FSW in this urban setting. These individuals represent an unquantified population, a proportion of which has an incomplete understanding of HIV risk in the face of high-risk behaviour, with implications for potential onward transmission to non-commercial sexual partners.

Rapid evolution of cancer/testis genes on the X chromosome.

BACKGROUND: Cancer/testis (CT) genes are normally expressed only in germ cells, but can be activated in the cancer state. This unusual property, together with the finding that many CT proteins elicit an antigenic response in cancer patients, has established a role for this class of genes as targets in immunotherapy regimes. Many families of CT genes have been identified in the human genome, but their biological function for the most part remains unclear. While it has been shown that some CT genes are under diversifying selection, this question has not been addressed before for the class as a whole. RESULTS: To shed more light on this interesting group of genes, we exploited the generation of a draft chimpanzee (Pan troglodytes) genomic sequence to examine CT genes in an organism that is closely related to human, and generated a high-quality, manually curated set of human:chimpanzee CT gene alignments. We find that the chimpanzee genome contains homologues to most of the human CT families, and that the genes are located on the same chromosome and at a similar copy number to those in human. Comparison of putative human:chimpanzee orthologues indicates that CT genes located on chromosome X are diverging faster and are undergoing stronger diversifying selection than those on the autosomes or than a set of control genes on either chromosome X or autosomes. CONCLUSION: Given their high level of diversifying selection, we suggest that CT genes are primarily responsible for the observed rapid evolution of protein-coding genes on the X chromosome.

Microsatellites can be misleading: an empirical and simulation study.

It has been long recognized that highly polymorphic genetic markers can lead to underestimation of divergence between populations when migration is low. Microsatellite loci, which are characterized by extremely high mutation rates, are particularly likely to be affected. Here, we report genetic differentiation estimates in a contact zone between two chromosome races of the common shrew (Sorex araneus), based on 10 autosomal microsatellites, a newly developed Y-chromosome microsatellite, and mitochondrial DNA. These results are compared to previous data on proteins and karyotypes. Estimates of genetic differentiation based on F- and R-statistics are much lower for autosomal microsatellites than for all other genetic markers. We show by simulations that this discrepancy stems mainly from the high mutation rate of microsatellite markers for F-statistics and from deviations from a single-step mutation model for R-statistics. The sex-linked genetic markers show that all gene exchange between races is mediated by females. The absence of male-mediated gene flow most likely results from male hybrid sterility.

Inflammatory markers and blood pressure: sex differences and the effect of fat mass in the CoLaus Study.

Several studies have reported high levels of inflammatory biomarkers in hypertension, but data coming from the general population are sparse, and sex differences have been little explored. The CoLaus Study is a cross-sectional examination survey in a random sample of 6067 Caucasians aged 35-75 years in Lausanne, Switzerland. Blood pressure (BP) was assessed using a validated oscillometric device. Anthropometric parameters were also measured, including body composition, using electrical bioimpedance. Crude serum levels of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and ultrasensitive C-reactive protein (hsCRP) were positively and IL-1β (IL-1β) negatively (P<0.001 for all values), associated with BP. For IL-6, IL-1β and TNF-α, the association disappeared in multivariable analysis, largely explained by differences in age and body mass index, in particular fat mass. On the contrary, hsCRP remained independently and positively associated with systolic (β (95% confidence interval): 1.15 (0.64; 1.65); P<0.001) and diastolic (0.75 (0.42; 1.08); P<0.001) BP. Relationships of hsCRP, IL-6 and TNF-α with BP tended to be stronger in women than in men, partly related to the difference in fat mass, yet the interaction between sex and IL-6 persisted after correction for all tested confounders. In the general population, the associations between inflammatory biomarkers and rising levels of BP are mainly driven by age and fat mass. The stronger associations in women suggest that sex differences might exist in the complex interplay between BP and inflammation.

Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer.

BACKGROUND: The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. METHODS: We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). RESULTS: Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (OR(per allele)=1.22, 95% CI=1.01-1.47, p(trend)=0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (OR(per allele)=1.20, 95% CI=0.99-1.45, p(trend)=0.06). PGR rs1042838 was also marginally associated with risk (OR(per allele)=1.25, 95% CI=0.96-1.61, p(trend)=0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. CONCLUSION: Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.

Temperature-induced sex reversal is not responsible for sex-ratio distortions in grayling Thymallus thymallus or brown trout Salmo trutta.

On the basis of the experiments carried out over various years, it was concluded that (1) grayling Thymallus thymallus and brown trout Salmo trutta are resistant to temperature-induced sex reversal at ecologically relevant temperatures, (2) environmental sex reversal is unlikely to cause the persistent sex ratio distortion observed in at least one of the study populations and (3) sex-specific tolerance of temperature-related stress may be the cause of distorted sex ratios in populations of T. thymallus or S. trutta.

Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.

Subtelomeric deletion of chromosome 10p15.3: clinical findings and molecular cytogenetic characterization.

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.3 deletion have been reported to date; however, only limited clinical information is available for these probands and the deleted region has not been molecularly mapped. Comprehensive clinical history was obtained for 12 of the 19 individuals described in this study. Common features among these 12 individuals include: cognitive/behavioral/developmental differences (11/11), speech delay/language disorder (10/10), motor delay (10/10), craniofacial dysmorphism (9/12), hypotonia (7/11), brain anomalies (4/6) and seizures (3/7). Parental studies were performed for nine of the 19 individuals; the 10p15.3 deletion was de novo in seven of the probands, not maternally inherited in one proband and inherited from an apparently affected mother in one proband. Molecular mapping of the 19 individuals reported in this study has identified two genes, ZMYND11 (OMIM 608668) and DIP2C (OMIM 611380; UCSC Genome Browser), mapping within 10p15.3 which are most commonly deleted. Although no single gene has been identified which is deleted in all 19 individuals studied, the deleted region in all but one individual includes ZMYND11 and the deleted region in all but one other individual includes DIP2C. There is not a clearly identifiable phenotypic difference between these two individuals and the size of the deleted region does not generally predict clinical features. Little is currently known about these genes complicating a direct genotype/phenotype correlation at this time. These data however, suggest that ZMYND11 and/or DIP2C haploinsufficiency contributes to the clinical features associated with 10p15 deletions in probands described in this study.

Persistent unequal sex ratio in a population of grayling (salmonidae) and possible role of temperature increase.

In some fishes, water chemistry or temperature affects sex determination or creates sex-specific selection pressures. The resulting population sex ratios are hard to predict from laboratory studies if the environmental triggers interact with other factors, whereas in field studies, singular observations of unusual sex ratios may be particularly prone to selective reporting. Long-term monitoring largely avoids these problems. We studied a population of grayling (Thymallus thymallus) in Lake Thun, Switzerland, that has been monitored since 1948. Samples of spawning fish have been caught about 3 times/week around spawning season, and water temperature at the spawning site has been continuously recorded since 1970. We used scale samples collected in different years to determine the average age of spawners (for life-stage specific analyses) and to identify the cohort born in 2003 (an extraordinarily warm year). Recent tissue samples were genotyped on microsatellite markers to test for genetic bottlenecks in the past and to estimate the genetically effective population size (N(e) ). Operational sex ratios changed from approximately 65% males before 1993 to approximately 85% males from 1993 to 2011. Sex ratios correlated with the water temperatures the fish experienced in their first year of life. Sex ratios were best explained by the average temperature juvenile fish experienced during their first summer. Grayling abundance is declining, but we found no evidence of a strong genetic bottleneck that would explain the apparent lack of evolutionary response to the unequal sex ratio. Results of other studies show no evidence of endocrine disruptors in the study area. Our findings suggest temperature affects population sex ratio and thereby contributes to population decline. Persistencia de Proporción de Sexos Desigual en una Población de Tímalos (Salmonidae) y el Posible Papel del Incremento de la Temperatura.

Sex- and melanism-specific variations in the oxidative status of adult tawny owls in response to manipulated reproductive effort.

Oxidative stress, determined by the balance between the production of damaging reactive oxygen species (ROS) and antioxidant defences, is hypothesized to play an important role in shaping the cost of reproduction and life history trade-offs. To test this hypothesis, we manipulated reproductive effort in 94 breeding pairs of tawny owls (Strix aluco) to investigate the sex- and melanism-specific effects on markers of oxidative stress in red blood cells (RBCs). This colour polymorphic bird species shows sex-specific division of labour and melanism-specific history strategies. Brood sizes at hatching were experimentally enlarged or reduced to increase or decrease reproductive effort, respectively. We obtained an integrative measure of the oxidative balance by measuring ROS production by RBCs, intracellular antioxidant glutathione levels and membrane resistance to ROS. We found that light melanic males (the sex undertaking offspring food provisioning) produced more ROS than darker conspecifics, but only when rearing an enlarged brood. In both sexes, light melanic individuals had also a larger pool of intracellular antioxidant glutathione than darker owls under relaxed reproductive conditions (i.e. reduced brood), but not when investing substantial effort in current reproduction (enlarged brood). Finally, resistance to oxidative stress was differently affected by the brood size manipulation experiment in males and females independently of their plumage coloration. Altogether, our results support the hypothesis that reproductive effort can alter the oxidative balance in a sex- and colour-specific way. This further emphasizes the close link between melanin-based coloration and life history strategies.

Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance.

BackgroundBipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain.AimsWe sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL.MethodTo detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 5775) and cognitive performance (n = 342) among healthy individuals.ResultsIntegrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P = 5.85×10(-5)). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.54×10(-8)). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals.ConclusionsOur findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.