Pub Date : 2015-09-16DOI: 10.3934/genet.2015.3.219
M. Morey, A. Fernández‐Marmiesse, J. Cocho, M. Couce
Abstract Genetic epidemiology is the study of genetic factors and their influence on health and disease. Traditionally, these studies have been based on familial aggregation, segregation, or linkage analysis, mainly allowing the study of monogenic disorders. Advances in biotechnology have made techniques such as genome-wide association studies and next-generation sequencing possible, allowing more complex studies. In addition to the completion of large consortia projects, such as the Human Genome Project, ENCODE, and the 1000 Genome Project, these techniques make it possible to explain a higher proportion of the heritability in polygenic disorders compared to previous techniques. Here, we provide an overview of approaches to genetic epidemiology and how technological improvements have influenced experimentation in this area. These improvements have led genetic epidemiology to unprecedented advances, being excellent tools for understanding the genetic variability underlying complex phenotypes.
{"title":"Influence of technology in genetic epidemiology","authors":"M. Morey, A. Fernández‐Marmiesse, J. Cocho, M. Couce","doi":"10.3934/genet.2015.3.219","DOIUrl":"https://doi.org/10.3934/genet.2015.3.219","url":null,"abstract":"Abstract Genetic epidemiology is the study of genetic factors and their influence on health and disease. Traditionally, these studies have been based on familial aggregation, segregation, or linkage analysis, mainly allowing the study of monogenic disorders. Advances in biotechnology have made techniques such as genome-wide association studies and next-generation sequencing possible, allowing more complex studies. In addition to the completion of large consortia projects, such as the Human Genome Project, ENCODE, and the 1000 Genome Project, these techniques make it possible to explain a higher proportion of the heritability in polygenic disorders compared to previous techniques. Here, we provide an overview of approaches to genetic epidemiology and how technological improvements have influenced experimentation in this area. These improvements have led genetic epidemiology to unprecedented advances, being excellent tools for understanding the genetic variability underlying complex phenotypes.","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70248632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-11DOI: 10.3934/genet.2015.3.204
C. Ladeira, S. Viegas, M. Pádua, E. Carolino, M. Gomes, M. Brito
Abstract Antineoplastic drugs are hazardous chemical agents used mostly in the treatment of patients with cancer, however health professionals that handle and administer these drugs can become exposed and develop DNA damage. Comet assay is a standard method for assessing DNA damage in human biomonitoring and, combined with formamidopyrimidine DNA glycosylase (FPG) enzyme, it specifically detects DNA oxidative damage. The aim of this study was to investigate genotoxic effects in workers occupationally exposed to cytostatics (n = 46), as compared to a control group with no exposure (n = 46) at two Portuguese hospitals, by means of the alkaline comet assay. The potential of the OGG1 Ser326Cys polymorphism as a susceptibility biomarker was also investigated. Exposure was evaluated by investigating the contamination of surfaces and genotoxic assessment was done by alkaline comet assay in peripheral blood lymphocytes. OGG1 Ser326Cys (rs1052133) polymorphism was studied by Real Time PCR. As for exposure assessment, there were 121 (37%) positive samples out of a total of 327 samples analysed from both hospitals. No statistically significant differences (Mann-Whitney test, p > 0.05) were found between subjects with and without exposure, regarding DNA damage and oxidative DNA damage, nevertheless the exposed group exhibited higher values. Moreover, there was no consistent trend regarding the variation of both biomarkers as assessed by comet assay with OGG1 polymorphism. Our study was not statistically significant regarding occupational exposure to antineoplastic drugs and genetic damage assessed by comet assay. However, health professionals should be monitored for risk behaviour, in order to ensure that safety measures are applied and protection devices are used correctly.
{"title":"Relation between DNA damage measured by comet assay and OGG1 Ser326Cys polymorphism in antineoplastic drugs biomonitoring","authors":"C. Ladeira, S. Viegas, M. Pádua, E. Carolino, M. Gomes, M. Brito","doi":"10.3934/genet.2015.3.204","DOIUrl":"https://doi.org/10.3934/genet.2015.3.204","url":null,"abstract":"Abstract Antineoplastic drugs are hazardous chemical agents used mostly in the treatment of patients with cancer, however health professionals that handle and administer these drugs can become exposed and develop DNA damage. Comet assay is a standard method for assessing DNA damage in human biomonitoring and, combined with formamidopyrimidine DNA glycosylase (FPG) enzyme, it specifically detects DNA oxidative damage. The aim of this study was to investigate genotoxic effects in workers occupationally exposed to cytostatics (n = 46), as compared to a control group with no exposure (n = 46) at two Portuguese hospitals, by means of the alkaline comet assay. The potential of the OGG1 Ser326Cys polymorphism as a susceptibility biomarker was also investigated. Exposure was evaluated by investigating the contamination of surfaces and genotoxic assessment was done by alkaline comet assay in peripheral blood lymphocytes. OGG1 Ser326Cys (rs1052133) polymorphism was studied by Real Time PCR. As for exposure assessment, there were 121 (37%) positive samples out of a total of 327 samples analysed from both hospitals. No statistically significant differences (Mann-Whitney test, p > 0.05) were found between subjects with and without exposure, regarding DNA damage and oxidative DNA damage, nevertheless the exposed group exhibited higher values. Moreover, there was no consistent trend regarding the variation of both biomarkers as assessed by comet assay with OGG1 polymorphism. Our study was not statistically significant regarding occupational exposure to antineoplastic drugs and genetic damage assessed by comet assay. However, health professionals should be monitored for risk behaviour, in order to ensure that safety measures are applied and protection devices are used correctly.","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70248622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-07-29DOI: 10.3934/genet.2015.3.192
Kesheng Wang, Xuefeng Liu, Daniel Owusu, Yue Pan, C. Xie
Abstract Obesity and type 2 diabetes (T2D) are comorbidities with cancer which may be partially due to shared genetic variants. Genetic variants in the ankyrin repeat and sterile alpha motif domain containing (ANKS1B) gene may play a role in cancer, adiposity, body mass index (BMI), and body weight. However, few studies focused on the associations of ANKS1B with obesity and T2D. We examined genetic associations of 272 single nucleotide polymorphisms (SNPs) within the ANKS1B with the cancer (any diagnosed cancer omitting minor skin cancer), obesity and T2D using the Marshfield sample (716 individuals with cancers, 1442 individuals with obesity, and 878 individuals with T2D). The Health Aging and Body Composition (Health ABC) sample (305 obese and 1336 controls) was used for replication. Multiple logistic regression analysis was performed using the PLINK software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We identified 25 SNPs within the ANKS1B gene associated with cancer, 34 SNPs associated with obesity, and 12 SNPs associated with T2D (p < 0.05). The most significant SNPs associated with cancer, T2D, and obesity were rs2373013 (p = 2.21 × 10−4), rs10860548 (p = 1.92 × 10−3), and rs7139028 (p = 1.94 × 10−6), respectively. Interestingly, rs3759214 was identified for both cancer and T2D (p = 0.0161 and 0.044, respectively). Furthermore, seven SNPs were associated with both cancer and obesity (top SNP rs2372719 with p = 0.0161 and 0.0206, respectively); six SNPs were associated with both T2D and obesity (top SNP rs7139028 with p = 0.0231 and 1.94 × 10−6, respectively). In the Health ABC sample, 18 SNPs were associated with obesity, 5 of which were associated with cancer in the Marshfield sample. In addition, three SNPs (rs616804, rs7295102, and rs201421) were associated with obesity in meta-analysis using both samples. These findings provide evidence of common genetic variants in the ANKS1B gene influencing the risk of cancer, obesity, and T2D and will serve as a resource for replication in other populations.
{"title":"Polymorphisms in the ANKS1B gene are associated with cancer, obesity and type 2 diabetes","authors":"Kesheng Wang, Xuefeng Liu, Daniel Owusu, Yue Pan, C. Xie","doi":"10.3934/genet.2015.3.192","DOIUrl":"https://doi.org/10.3934/genet.2015.3.192","url":null,"abstract":"Abstract Obesity and type 2 diabetes (T2D) are comorbidities with cancer which may be partially due to shared genetic variants. Genetic variants in the ankyrin repeat and sterile alpha motif domain containing (ANKS1B) gene may play a role in cancer, adiposity, body mass index (BMI), and body weight. However, few studies focused on the associations of ANKS1B with obesity and T2D. We examined genetic associations of 272 single nucleotide polymorphisms (SNPs) within the ANKS1B with the cancer (any diagnosed cancer omitting minor skin cancer), obesity and T2D using the Marshfield sample (716 individuals with cancers, 1442 individuals with obesity, and 878 individuals with T2D). The Health Aging and Body Composition (Health ABC) sample (305 obese and 1336 controls) was used for replication. Multiple logistic regression analysis was performed using the PLINK software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We identified 25 SNPs within the ANKS1B gene associated with cancer, 34 SNPs associated with obesity, and 12 SNPs associated with T2D (p < 0.05). The most significant SNPs associated with cancer, T2D, and obesity were rs2373013 (p = 2.21 × 10−4), rs10860548 (p = 1.92 × 10−3), and rs7139028 (p = 1.94 × 10−6), respectively. Interestingly, rs3759214 was identified for both cancer and T2D (p = 0.0161 and 0.044, respectively). Furthermore, seven SNPs were associated with both cancer and obesity (top SNP rs2372719 with p = 0.0161 and 0.0206, respectively); six SNPs were associated with both T2D and obesity (top SNP rs7139028 with p = 0.0231 and 1.94 × 10−6, respectively). In the Health ABC sample, 18 SNPs were associated with obesity, 5 of which were associated with cancer in the Marshfield sample. In addition, three SNPs (rs616804, rs7295102, and rs201421) were associated with obesity in meta-analysis using both samples. These findings provide evidence of common genetic variants in the ANKS1B gene influencing the risk of cancer, obesity, and T2D and will serve as a resource for replication in other populations.","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70249079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-07-13DOI: 10.3934/genet.2015.3.173
Achal Rastogi, Xin Lin, Bérangère Lombard, D. Loew, L. Tirichine
Abstract Recent progress made on epigenetic studies revealed the conservation of epigenetic features in deep diverse branching species including Stramenopiles, plants and animals. This suggests their fundamental role in shaping species genomes across different evolutionary time scales. Diatoms are a highly successful and diverse group of phytoplankton with a fossil record of about 190 million years ago. They are distantly related from other super-groups of Eukaryotes and have retained some of the epigenetic features found in mammals and plants suggesting their ancient origin. Phaeodactylum tricornutum and Thalassiosira pseudonana, pennate and centric diatoms, respectively, emerged as model species to address questions on the evolution of epigenetic phenomena such as what has been lost, retained or has evolved in contemporary species. In the present work, we will discuss how the study of non-model or emerging model organisms, such as diatoms, helps understand the evolutionary history of epigenetic mechanisms with a particular focus on DNA methylation and histone modifications.
{"title":"Probing the evolutionary history of epigenetic mechanisms: what can we learn from marine diatoms","authors":"Achal Rastogi, Xin Lin, Bérangère Lombard, D. Loew, L. Tirichine","doi":"10.3934/genet.2015.3.173","DOIUrl":"https://doi.org/10.3934/genet.2015.3.173","url":null,"abstract":"Abstract Recent progress made on epigenetic studies revealed the conservation of epigenetic features in deep diverse branching species including Stramenopiles, plants and animals. This suggests their fundamental role in shaping species genomes across different evolutionary time scales. Diatoms are a highly successful and diverse group of phytoplankton with a fossil record of about 190 million years ago. They are distantly related from other super-groups of Eukaryotes and have retained some of the epigenetic features found in mammals and plants suggesting their ancient origin. Phaeodactylum tricornutum and Thalassiosira pseudonana, pennate and centric diatoms, respectively, emerged as model species to address questions on the evolution of epigenetic phenomena such as what has been lost, retained or has evolved in contemporary species. In the present work, we will discuss how the study of non-model or emerging model organisms, such as diatoms, helps understand the evolutionary history of epigenetic mechanisms with a particular focus on DNA methylation and histone modifications.","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70249065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-04-27DOI: 10.3934/genet.2015.2.163
R. Su, M. Adam, Linda A. Ramsdell, P. Fechner, M. Shnorhavorian
Abstract Genetic testing is judiciously applied to individuals with Disorders of Sex Development (DSD) and so it is necessary to identify those most likely to benefit from such testing. We hypothesized that the external masculinization score (EMS) is inversely associated with the likelihood of finding a pathogenic genetic variant. Patients with 46,XY DSD from a single institution evaluated from 1994–2014 were included. Results of advanced cytogenetic and gene sequencing tests were recorded. An EMS score (range 0–12) was assigned to each patient according to the team's initial external genitalia physical examination. During 1994–2011, 44 (40%) patients with 46,XY DSD were evaluated and underwent genetic testing beyond initial karyotype; 23% (10/44) had a genetic diagnosis made by gene sequencing or array. The median EMS score of those with an identified pathogenic variant was significantly different from those in whom no confirmed genetic cause was identified [median 3 (95% CI, 2–6) versus 6 (95% CI, 5–7), respectively (p = 0.02)], but limited to diagnoses of complete or partial androgen insensitivity (8/10) or 5α-reductase deficiency (2/10). In the modern cohort (2012–2014), the difference in median EMS in whom a genetic cause was or was not identified approached significance (p = 0.05, median 3 (95% CI, 0–7) versus 7 (95% CI, 6–9), respectively). When all patients from 1994–2014 are pooled, the EMS is significantly different amongst those with compared to those without a genetic cause (median EMS 3 vs. 6, p < 0.02). We conclude that an EMS of 3 or less may indicate a higher likelihood of identifying a genetic cause of 46,XY DSD and justify genetic screening, especially when androgen insensitivity is suspected.
{"title":"Can the external masculinization score predict the success of genetic testing in 46,XY DSD?","authors":"R. Su, M. Adam, Linda A. Ramsdell, P. Fechner, M. Shnorhavorian","doi":"10.3934/genet.2015.2.163","DOIUrl":"https://doi.org/10.3934/genet.2015.2.163","url":null,"abstract":"Abstract Genetic testing is judiciously applied to individuals with Disorders of Sex Development (DSD) and so it is necessary to identify those most likely to benefit from such testing. We hypothesized that the external masculinization score (EMS) is inversely associated with the likelihood of finding a pathogenic genetic variant. Patients with 46,XY DSD from a single institution evaluated from 1994–2014 were included. Results of advanced cytogenetic and gene sequencing tests were recorded. An EMS score (range 0–12) was assigned to each patient according to the team's initial external genitalia physical examination. During 1994–2011, 44 (40%) patients with 46,XY DSD were evaluated and underwent genetic testing beyond initial karyotype; 23% (10/44) had a genetic diagnosis made by gene sequencing or array. The median EMS score of those with an identified pathogenic variant was significantly different from those in whom no confirmed genetic cause was identified [median 3 (95% CI, 2–6) versus 6 (95% CI, 5–7), respectively (p = 0.02)], but limited to diagnoses of complete or partial androgen insensitivity (8/10) or 5α-reductase deficiency (2/10). In the modern cohort (2012–2014), the difference in median EMS in whom a genetic cause was or was not identified approached significance (p = 0.05, median 3 (95% CI, 0–7) versus 7 (95% CI, 6–9), respectively). When all patients from 1994–2014 are pooled, the EMS is significantly different amongst those with compared to those without a genetic cause (median EMS 3 vs. 6, p < 0.02). We conclude that an EMS of 3 or less may indicate a higher likelihood of identifying a genetic cause of 46,XY DSD and justify genetic screening, especially when androgen insensitivity is suspected.","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70249006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-04-06DOI: 10.3934/genet.2015.2.148
S. Branciamore, A. Rodin, Grigoriy Gogoshin, A. Riggs
Abstract In addition to genetic variation, epigenetic variation and transposons can greatly affect the evolutionary fitnesses landscape and gene expression. Previously we proposed a mathematical treatment of a general epigenetic variation model that we called Stochastic Epigenetic Modification (SEM) model. In this study we follow up with a special case, the Transposon Silencing Model (TSM), with, once again, emphasis on quantitative treatment. We have investigated the evolutionary effects of epigenetic changes due to transposon (T) insertions; in particular, we have considered a typical gene locus A and postulated that (i) the expression level of gene A depends on the epigenetic state (active or inactive) of a cis-located transposon element T, (ii) stochastic variability in the epigenetic silencing of T occurs only in a short window of opportunity during development, (iii) the epigenetic state is then stable during further development, and (iv) the epigenetic memory is fully reset at each generation. We develop the model using two complementary approaches: a standard analytical population genetics framework (diffusion equations) and Monte-Carlo simulations. Both approaches led to similar estimates for the probability of fixation and time of fixation of locus TA with initial frequency P in a randomly mating diploid population of effective size Ne . We have ascertained the effect that ρ, the probability of transposon modification during the developmental window, has on the population (species). One of our principal conclusions is that as ρ increases, the pattern of fixation of the combined TA locus goes from “neutral” to “dominant” to “over-dominant”. We observe that, under realistic values of ρ, epigenetic modifications can provide an efficient mechanism for more rapid fixation of transposons and cis-located gene alleles. The results obtained suggest that epigenetic silencing, even if strictly transient (being reset at each generation), can still have significant macro-evolutionary effects. Importantly, this conclusion also holds for the static fitness landscape. To the best of our knowledge, no previous analytical modeling has treated stochastic epigenetic changes during a window of opportunity.
{"title":"Epigenetics and Evolution: Transposons and the Stochastic Epigenetic Modification Model","authors":"S. Branciamore, A. Rodin, Grigoriy Gogoshin, A. Riggs","doi":"10.3934/genet.2015.2.148","DOIUrl":"https://doi.org/10.3934/genet.2015.2.148","url":null,"abstract":"Abstract In addition to genetic variation, epigenetic variation and transposons can greatly affect the evolutionary fitnesses landscape and gene expression. Previously we proposed a mathematical treatment of a general epigenetic variation model that we called Stochastic Epigenetic Modification (SEM) model. In this study we follow up with a special case, the Transposon Silencing Model (TSM), with, once again, emphasis on quantitative treatment. We have investigated the evolutionary effects of epigenetic changes due to transposon (T) insertions; in particular, we have considered a typical gene locus A and postulated that (i) the expression level of gene A depends on the epigenetic state (active or inactive) of a cis-located transposon element T, (ii) stochastic variability in the epigenetic silencing of T occurs only in a short window of opportunity during development, (iii) the epigenetic state is then stable during further development, and (iv) the epigenetic memory is fully reset at each generation. We develop the model using two complementary approaches: a standard analytical population genetics framework (diffusion equations) and Monte-Carlo simulations. Both approaches led to similar estimates for the probability of fixation and time of fixation of locus TA with initial frequency P in a randomly mating diploid population of effective size Ne . We have ascertained the effect that ρ, the probability of transposon modification during the developmental window, has on the population (species). One of our principal conclusions is that as ρ increases, the pattern of fixation of the combined TA locus goes from “neutral” to “dominant” to “over-dominant”. We observe that, under realistic values of ρ, epigenetic modifications can provide an efficient mechanism for more rapid fixation of transposons and cis-located gene alleles. The results obtained suggest that epigenetic silencing, even if strictly transient (being reset at each generation), can still have significant macro-evolutionary effects. Importantly, this conclusion also holds for the static fitness landscape. To the best of our knowledge, no previous analytical modeling has treated stochastic epigenetic changes during a window of opportunity.","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70248984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-03-23DOI: 10.3934/genet.2015.2.127
R. Risso, S. Einaudi, C. Crespi, Angela M. Caldarera, F. Verna, E. Merlini, R. Lala
Abstract The choice of sex in newborns with genital ambiguity is challenging. Information concerning the satisfaction of subjects with disorders of sex development from childhood to adulthood is required in order to address sex attribution policies. This study focuses on the methods that enable clinicians to investigate the alignment of phenotypes with gender identity and quality of life in people with disorders of this kind. These methods are presented as tools for studying a cohort of ten subjects with 45,X/46,XY mosaicism examined between 1985 and 2014 in the Department of Pediatric Endocrinology, Regina Margherita Children's Hospital, Turin: five children and five young adults, four reared as females and six as males. Clinical outcome was assessed by means of a clinical scoring system considering height, genital appearance, gonads and pubertal development. The Gender Identity Questionnaire for Children and the World Health Organization Quality of Life assessment were adopted. The four male children strongly identified with their assigned sex: male attribution was satisfactory until pubertal age. In young adults the clinical scores ranged between 55–65% for both genders. In the young male, the reduced sexual activity and the poor body image perception strongly affected his quality of life. The clinical scores of the two young female adults (60% for both) were not balanced with their quality of life scores (87.5% and 68.75% respectively): individual traits and social-familial context should be investigated in order to explain these differences. Clinical and psychosocial assessment in people with disorders of sex development is mandatory in order to plan care procedures; a detailed analysis requires adequate tools. Clinical scoring system, Gender Identity Questionnaire for Children and World Health Organization Quality of Life assessment can be used to investigate the alignment of physical phenotype with gender identity and quality of life.
{"title":"Sex attribution, gender identity and quality of life in disorders of sex development due to 45,X/46,XY mosaicism: methods for clinical and psychosocial assessment","authors":"R. Risso, S. Einaudi, C. Crespi, Angela M. Caldarera, F. Verna, E. Merlini, R. Lala","doi":"10.3934/genet.2015.2.127","DOIUrl":"https://doi.org/10.3934/genet.2015.2.127","url":null,"abstract":"Abstract The choice of sex in newborns with genital ambiguity is challenging. Information concerning the satisfaction of subjects with disorders of sex development from childhood to adulthood is required in order to address sex attribution policies. This study focuses on the methods that enable clinicians to investigate the alignment of phenotypes with gender identity and quality of life in people with disorders of this kind. These methods are presented as tools for studying a cohort of ten subjects with 45,X/46,XY mosaicism examined between 1985 and 2014 in the Department of Pediatric Endocrinology, Regina Margherita Children's Hospital, Turin: five children and five young adults, four reared as females and six as males. Clinical outcome was assessed by means of a clinical scoring system considering height, genital appearance, gonads and pubertal development. The Gender Identity Questionnaire for Children and the World Health Organization Quality of Life assessment were adopted. The four male children strongly identified with their assigned sex: male attribution was satisfactory until pubertal age. In young adults the clinical scores ranged between 55–65% for both genders. In the young male, the reduced sexual activity and the poor body image perception strongly affected his quality of life. The clinical scores of the two young female adults (60% for both) were not balanced with their quality of life scores (87.5% and 68.75% respectively): individual traits and social-familial context should be investigated in order to explain these differences. Clinical and psychosocial assessment in people with disorders of sex development is mandatory in order to plan care procedures; a detailed analysis requires adequate tools. Clinical scoring system, Gender Identity Questionnaire for Children and World Health Organization Quality of Life assessment can be used to investigate the alignment of physical phenotype with gender identity and quality of life.","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70248925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-03-01DOI: 10.3934/genet.2015.2.110
S. Waters, P. Waters
Abstract In females, X chromosome inactivation (XCI) ensures transcriptional silencing of one of the two Xs (either in a random or imprinted fashion) in somatic cells. Comparing this silencing between species has offered insight into different mechanisms of X inactivation, providing clues into the evolution of this epigenetic process in mammals. Long-noncoding RNAs have emerged as a common theme in XCI of therian mammals (eutherian and marsupial). Eutherian X inactivation is regulated by the noncoding RNA product of XIST, within a cis-acting master control region called the X inactivation center (XIC). Marsupials XCI is XIST independent. Instead, XCI is controlled by the long-noncoding RNA Rsx, which appears to be a functional analog of the eutherian XIST gene, insofar that its transcript coats the inactive X and represses activity of genes in cis. In this review we discuss XCI in eutherians, and contrast imprinted X inactivation in mouse and marsupials. We provide particular focus on the evolution of genomic elements that confer the unique epigenetic features that characterize the inactive X chromosome.
{"title":"Imprinted X chromosome inactivation: evolution of mechanisms in distantly related mammals","authors":"S. Waters, P. Waters","doi":"10.3934/genet.2015.2.110","DOIUrl":"https://doi.org/10.3934/genet.2015.2.110","url":null,"abstract":"Abstract In females, X chromosome inactivation (XCI) ensures transcriptional silencing of one of the two Xs (either in a random or imprinted fashion) in somatic cells. Comparing this silencing between species has offered insight into different mechanisms of X inactivation, providing clues into the evolution of this epigenetic process in mammals. Long-noncoding RNAs have emerged as a common theme in XCI of therian mammals (eutherian and marsupial). Eutherian X inactivation is regulated by the noncoding RNA product of XIST, within a cis-acting master control region called the X inactivation center (XIC). Marsupials XCI is XIST independent. Instead, XCI is controlled by the long-noncoding RNA Rsx, which appears to be a functional analog of the eutherian XIST gene, insofar that its transcript coats the inactive X and represses activity of genes in cis. In this review we discuss XCI in eutherians, and contrast imprinted X inactivation in mouse and marsupials. We provide particular focus on the evolution of genomic elements that confer the unique epigenetic features that characterize the inactive X chromosome.","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70248919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-02-26DOI: 10.3934/genet.2015.2.104
N. Nokoff, S. Travers, N. Meeks
Abstract Androgen insensitivity syndrome (AIS) is caused by mutations in the gene encoding the androgen receptor (AR). The incidence of AIS is estimated to be 1 in 99,000. Complete androgen insensitivity syndrome (CAIS) is characterized by a 46,XY karyotype with external genitalia that appear typically female and results from mutations that render the androgen receptor non-functional. Partial androgen insensitivity syndrome (PAIS) results from partial loss of function mutations in AR. Rarely, PAIS results from somatic mosaicism for an AR mutation and not from a hypomorphic variant. We present two cases of PAIS due to somatic mosaicism, one caused by a novel nonsense mutation and one caused by a missense mutation previously reported in CAIS. Two patients with atypical genitalia presented to our multidisciplinary clinic for disorders of sex development and sequencing of AR was performed as part of the diagnostic evaluation. In case one, AR sequencing revealed mosaicism for a nonsense mutation, c.1331T > A; p.Leu444Ter. This mutation has not previously been reported, but is presumed to be pathogenic. In case two, AR sequencing revealed a mosaic missense mutation, c.2279 C > A; p.Ser760Tyr, which has previously been reported in CAIS but not in PAIS. Similar phenotypes may result from AR mutations that are present in a mosaic state with full loss of function or hypomorphic mutations that partially impair the function of the protein in either all tissues or in a mosaic state.
{"title":"Two cases of androgen insensitivity due to somatic mosaicism","authors":"N. Nokoff, S. Travers, N. Meeks","doi":"10.3934/genet.2015.2.104","DOIUrl":"https://doi.org/10.3934/genet.2015.2.104","url":null,"abstract":"Abstract Androgen insensitivity syndrome (AIS) is caused by mutations in the gene encoding the androgen receptor (AR). The incidence of AIS is estimated to be 1 in 99,000. Complete androgen insensitivity syndrome (CAIS) is characterized by a 46,XY karyotype with external genitalia that appear typically female and results from mutations that render the androgen receptor non-functional. Partial androgen insensitivity syndrome (PAIS) results from partial loss of function mutations in AR. Rarely, PAIS results from somatic mosaicism for an AR mutation and not from a hypomorphic variant. We present two cases of PAIS due to somatic mosaicism, one caused by a novel nonsense mutation and one caused by a missense mutation previously reported in CAIS. Two patients with atypical genitalia presented to our multidisciplinary clinic for disorders of sex development and sequencing of AR was performed as part of the diagnostic evaluation. In case one, AR sequencing revealed mosaicism for a nonsense mutation, c.1331T > A; p.Leu444Ter. This mutation has not previously been reported, but is presumed to be pathogenic. In case two, AR sequencing revealed a mosaic missense mutation, c.2279 C > A; p.Ser760Tyr, which has previously been reported in CAIS but not in PAIS. Similar phenotypes may result from AR mutations that are present in a mosaic state with full loss of function or hypomorphic mutations that partially impair the function of the protein in either all tissues or in a mosaic state.","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70248338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
1 Cell Cycle and Development Laboratory, Research Division, Peter MacCallum Cancer Centre, 7 St Andrew’s place, East Melbourne, Melbourne, Victoria, 3002, Australia 2 Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, 7 St Andrew’s place, East Melbourne, Melbourne, Victoria, 3002, Australia 3 Department of Anatomy and Neuroscience, University of Melbourne, 1-100 Grattan street, Parkville, Melbourne, Victoria, 3010, Australia 4 Department of Biochemistry and Molecular Biology, University of Melbourne, 1-100 Grattan street, Parkville, Melbourne, Victoria, 3010, Australia
{"title":"Drosophila models of cancer","authors":"H. Richardson","doi":"10.3934/genet.2015.1.97","DOIUrl":"https://doi.org/10.3934/genet.2015.1.97","url":null,"abstract":"1 Cell Cycle and Development Laboratory, Research Division, Peter MacCallum Cancer Centre, 7 St Andrew’s place, East Melbourne, Melbourne, Victoria, 3002, Australia 2 Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, 7 St Andrew’s place, East Melbourne, Melbourne, Victoria, 3002, Australia 3 Department of Anatomy and Neuroscience, University of Melbourne, 1-100 Grattan street, Parkville, Melbourne, Victoria, 3010, Australia 4 Department of Biochemistry and Molecular Biology, University of Melbourne, 1-100 Grattan street, Parkville, Melbourne, Victoria, 3010, Australia","PeriodicalId":43477,"journal":{"name":"AIMS Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70248322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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