33 research outputs found
Fetal alcohol spectrum disorders: genetic and epigenetic mechanisms
Fetal alcohol spectrum disorders (FASD) are a consequence of prenatal alcohol exposure. The etiology of the complex FASD phenotype with growth deficit, birth defects and neurodevelopmental impairments is under extensive research. Both genetic and environmental factors contribute to the wide phenotype: chromosomal rearrangements, risk and protective alleles, environmentalâinduced epigenetic alterations as well as geneâenvironment interactions are all involved. Understanding the molecular mechanisms of prenatal alcohol exposure can provide tools for prevention or intervention of the alcoholâinduced developmental disorders in the future. By revealing the alcoholâinduced genetic and epigenetic alterations which associate with the variable FASD phenotypes, it is possible to identify biomarkers for the disorder. This would enable early diagnoses and personalized support for development of the affected child.Peer reviewe
LukihÀiriön alttiusgeenit ja mekanismit hermoston kehityksessÀ
Developmental dyslexia is a specific reading disability, which is characterised by unexpected difficulty in reading, spelling and writing despite adequate intelligence, education and social environment. It is the most common childhood learning disorder affecting 5-10 % of the population and thus constitutes the largest portion of all learning disorders. It is a persistent developmental failure although it can be improved by compensation. According to the most common theory, the deficit is in phonological processing, which is needed in reading when the words have to be divided into phonemes, or distinct sound elements. This occurs in the lowest level of the hierarchy of the language system and disturbs processes in higher levels, such as understanding the meaning of words.
Dyslexia is a complex genetic disorder and previous studies have found nine locations in the genome that associate with it. Altogether four susceptibility genes have been found and this study describes the discovery of the first two of them, DYX1C1 and ROBO1. The first clues were obtained from two Finnish dyslexic families that have chromosomal translocations which disrupt these genes. Genetic analyses supported their role in dyslexia: DYX1C1 associates with dyslexia in the Finnish population and ROBO1 was linked to dyslexia in a large Finnish pedigree. In addition a genome-wide scan in Finnish dyslexic families was performed. This supported the previously detected dyslexia locus on chromosome 2 and revealed a new locus on chromosome 7.
Dyslexia is a neurological disorder and the neurobiological function of the susceptibility genes DYX1C1 and ROBO1 are consistent with this. ROBO1 is an axon guidance receptor gene, which is involved in axon guidance across the midline in Drosophila and axonal pathfinding between the two hemispheres via the corpus callosum, as well as neuronal migration in the brain of mice. The translocation and decreased ROBO1 expression in dyslexic individuals indicate that two functional copies of ROBO1 gene are required in reading. DYX1C1 was a new gene without a previously known function. Inhibition of Dyx1c1 expression showed that it is needed in normal brain development in rats. Without Dyx1c1 protein, the neurons in the developing brain will not migrate to their final position in the cortex.
These two dyslexia susceptibility genes DYX1C1 and ROBO1 revealed two distinct neurodevelopmental mechanisms of dyslexia, axonal pathfinding and neuronal migration. This study describes the discovery of the genes and our research to clarify their role in developmental dyslexia.LukihÀiriö eli dysleksia on yleisin oppimishÀiriö. Se mÀÀritellÀÀn vaikeutena oppia lukemaan, tavaamaan ja kirjoittamaan normaalista ÀlykkyydestÀ, koulutuksesta tai sosiaalisesta ympÀristöstÀ huolimatta. YleisimmÀn teorian mukaan lukihÀiriön syy piilee kielellisen jÀrjestelmÀn alimmalla tasolla, missÀ sanat pilkotaan ÀÀnteiksi eli foneemeiksi. TÀmÀ hÀiriö jÀrjestelmÀn alimmalla tasolla vaikeuttaa ylempien tasojen toimintaa kuten sanojen ymmÀrtÀmistÀ. Jonkin asteinen lukihÀiriö hÀiritsee jopa joka kymmenennen ihmisen elÀmÀÀ. LievimmillÀÀn hÀiriö hankaloittaa arkea kirjoitusvirheinÀ ja vÀÀrinkÀsityksinÀ, mutta pahimmillaan se voi johtaa sosiaalisiin ja koulutuksellisiin ongelmiin sekÀ syrjÀytymiseen yhteiskunnasta.
LukihÀiriö on neurologinen hÀiriö, johon liitetÀÀn usein myös hÀiriöt kuulossa, nÀössÀ tai motoriikassa. AivokuvantamismenetelmillÀ on huomattu eroja lukihÀiriöisen ja normaalin lukijan aivojen aktiivisuusalueilla sekÀ aivojen rakenteissa. Geneettisten tutkimusten perusteella kyseessÀ on monitekijÀinen hÀiriö, jolle altistavat geenien lisÀksi ympÀristötekijÀt. Tutkimuksissa se on yhdistetty yhdeksÀÀn paikkaan kromosomistossa ja tÀhÀn mennessÀ nÀiltÀ alueilta on löytynyt neljÀ alttiusgeeniÀ, joista kahden ensimmÀisen, DYX1C1:n ja ROBO1:n löytymisestÀ kerrotaan tÀssÀ työssÀ. Alttiusgeenien DYX1C1:n ja ROBO1:n tehtÀvÀt tukevat lukihÀiriön neurobiologista taustaa. ROBO1 on ennestÀÀn tunnettu aksoninohjausreseptorigeeni, jolla on merkittÀvÀ tehtÀvÀ hermoston kehityksessÀ: aivopuoliskoja yhdistÀvÀn aivokurkiaisen muodostumisessa sekÀ aivosolujen migraatiossa. Geenin katkeaminen lukihÀiriöisellÀ ihmisellÀ sekÀ alentunut ROBO1 proteiinin tuotto suuressa lukihÀiriöperheessÀ osoittivat ettÀ kaksi toiminnallista ROBO1-geeniÀ tarvitaan normaaliin lukutaitoon. DYX1C1 on uusi ja tehtÀvÀltÀÀn tuntematon geeni. Tutkimustemme mukaan se on tarpeen rotan normaalissa aivojen kehityksessÀ ja ilman sitÀ hermosolujen vaellus omalle paikalleen aivokuoreen estyy. Tulosten perusteella lukihÀiriössÀ voisi olla kyse hienoisesta muutoksesta DYX1C1-geenin ilmenemisen sÀÀtelyssÀ jossakin aivojen kehityksen vaiheista.
Tutkimuksemme tavoitteena oli selvittÀÀ lukihÀiriön biologista taustaa ja löytÀmÀmme alttiusgeenit tarjoavat ikkunan aivoihin: tietoa lukutaitoon vaikuttavista neurobiologisista tapahtumista sekÀ aivojen kehityksestÀ. Työn tarkoitus oli myös helpottaa lukihÀiriöstÀ kÀrsivien elÀmÀÀ, edistÀÀ sen varhaista diagnosointia ja mahdollistaa nÀin tarvittava tuki sekÀ harjoitus. Tutkimusten mukaan lukutaitoa on pystytty parantamaan harjoittelun avulla. Aivojen hermoyhteyksien muotoutuvuus kuitenkin vÀhenee iÀn myötÀ, joten harjoitus tulisi aloittaa mahdollisimman varhain
Early prenatal alcohol exposure alters imprinted gene expression in placenta and embryo in a mouse model
Prenatal alcohol exposure (PAE) can harm the embryonic development and cause life-long consequences in offspring's health. To clarify the molecular mechanisms of PAE we have used a mouse model of early alcohol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first eight days of gestation (GD 0.5-8.5). Owing to the detected postnatal growth-restricted phenotype in the offspring of this mouse model and both prenatal and postnatal growth restriction in alcohol-exposed humans, we focused on imprinted genes Insulin-like growth factor 2 (Igf2), H19, Small Nuclear Ribonucleoprotein Polypeptide N (Snrpn) and Paternally expressed gene 3 (Peg3), which all are known to be involved in embryonic and placental growth and development. We studied the effects of alcohol on DNA methylation level at the Igf2/H19 imprinting control region (ICR), Igf2 differentially methylated region 1, Snrpn ICR and Peg3 ICR in 9.5 embryonic days old (E9.5) embryos and placentas by using MassARRAY EpiTYPER. To determine alcohol-induced alterations globally, we also examined methylation in long interspersed nuclear elements (Line-1) in E9.5 placentas. We did not observe any significant alcohol-induced changes in DNA methylation levels. We explored effects of PAE on gene expression of E9.5 embryos as well as E9.5 and E16.5 placentas by using quantitative PCR. The expression of growth promoter gene Igf2 was decreased in the alcohol-exposed E9.5 and E16.5 placentas. The expression of negative growth controller H19 was significantly increased in the alcohol exposed E9.5 embryos compared to controls, and conversely, a trend of decreased expression in alcohol-exposed E9.5 and E16.5 placentas were observed. Furthermore, increased Snrpn expression in alcohol-exposed E9.5 embryos was also detected. Our study indicates that albeit no alterations in the DNA methylation levels of studied sequences were detected by EpiTYPER, early PAE can affect the expression of imprinted genes in both developing embryo and placenta.Peer reviewe
18q12.3-q21.1 microdeletion detected in the prenatally alcohol-exposed dizygotic twin with discordant fetal alcohol syndrome phenotype
Abstract Background A pair of dizygotic twins discordantly affected by heavy prenatal alcohol exposure (PAE) was reported previously by Riikonen, suggesting the role of genetic risk or protective factors in the etiology of alcohol-induced developmental disorders. Now, we have re-examined these 25-year-old twins and explored genetic origin of the phenotypic discordancy reminiscent with fetal alcohol syndrome (FAS). Furthermore, we explored alterations in DNA methylation profile of imprinting control region at growth-related insulin-like growth factor 2 (IGF2)/H19 locus in twins' white blood cells (WBC), which have been associated earlier with alcohol-induced genotype-specific changes in placental tissue. Methods Microarray-based comparative genomic hybridization (aCGH) was used to detect potential submicroscopic chromosomal abnormalities, and developmental as well as phenotypic information about twins were collected. Traditional bisulfite sequencing was used for DNA methylation analysis. Results Microarray-based comparative genomic hybridization revealed a microdeletion 18q12.3-q21.1. in affected twin, residing in a known 18q deletion syndrome region. This syndrome has been associated with growth restriction, developmental delay or intellectual deficiency, and abnormal facial features in previous studies, and thus likely explains the phenotypic discordancy between the twins. We did not observe association between WBCs? DNA methylation profile and PAE, but interestingly, a trend of decreased DNA methylation at the imprinting control region was seen in the twin with prenatal growth retardation at birth. Conclusions The microdeletion emphasizes the importance of adequate chromosomal testing in examining the etiology of complex alcohol-induced developmental disorders. Furthermore, the genotype-specific decreased DNA methylation at the IGF2/H19 locus cannot be considered as a biological mark for PAE in adult WBCs.Peer reviewe
Early gestational ethanol exposure in mice : Effects on brain structure, energy metabolism and adiposity in adult offspring
We examined whether an early-life event ethanol exposure in the initial stages of pregnancy affected offspring brain structure, energy metabolism, and body composition in later life. Consumption of 10% (v/v) ethanol by inbred C57BL/6J female mice from 0.5 to 8.5 days post coitum was used to model alcohol exposure during the first 3-4 weeks of gestation in humans, when pregnancy is not typically recognized. At adolescence (postnatal day [P] 28) and adulthood (P64), the brains of male offspring were scanned ex vivo using ultra-high field (16.4 T) magnetic resonance imaging and diffusion tensor imaging. Energy metabolism and body composition were measured in adulthood by indirect calorimetry and dual energy X-ray absorptiometry (DXA), respectively. Ethanol exposure had no substantial impact on white matter organization in the anterior commissure, corpus callosum, hippocampal commissure, internal capsule, optic tract, or thalamus. Whole brain volume and the volumes of the neocortex, cerebellum, and caudate putamen were also unaffected. Subtle, but non-significant, effects were observed on the hippocampus and the hypothalamus in adult ethanol-exposed male offspring. Ethanol exposure was additionally associated with a trend toward decreased oxygen consumption, carbon dioxide production, and reduced daily energy expenditure, as well as significantly increased adiposity, albeit with normal body weight and food intake, in adult male offspring. In summary, ethanol exposure restricted to early gestation had subtle long-term effects on the structure of specific brain regions in male offspring. The sensitivity of the hippocampus to ethanol-induced damage is reminiscent of that reported by other studies despite differences in the level, timing, and duration of exposure and likely contributes to the cognitive impairment that characteristically results from prenatal ethanol exposure. The hypothalamus plays an important role in regulating metabolism and energy homeostasis. Our finding of altered daily energy expenditure and adiposity in adult ethanol-exposed males is consistent with the idea that central nervous system abnormalities also underpin some of the metabolic phenotypes associated with ethanol exposure in pregnancy. (C) 2018 Elsevier Inc. All rights reserved.Peer reviewe
Maternal Ethanol Consumption Alters the Epigenotype and the Phenotype of Offspring in a Mouse Model
Peer reviewe
Chromatin modifier developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders
Peer reviewe
Early Maternal Alcohol Consumption Alters Hippocampal DNA Methylation, Gene Expression and Volume in a Mouse Model
The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.Peer reviewe
In vitro fertilization does not increase the incidence of de novo copy number alterations in fetal and placental lineages
Although chromosomal instability (CIN) is a common phenomenon in cleavage-stage embryogenesis following in vitro fertilization (IVF)1,2,3, its rate in naturally conceived human embryos is unknown. CIN leads to mosaic embryos that contain a combination of genetically normal and abnormal cells, and is significantly higher in in vitro-produced preimplantation embryos as compared to in vivo-conceived preimplantation embryos4. Even though embryos with CIN-derived complex aneuploidies may arrest between the cleavage and blastocyst stages of embryogenesis5,6, a high number of embryos containing abnormal cells can pass this strong selection barrier7,8. However, neither the prevalence nor extent of CIN during prenatal development and at birth, following IVF treatment, is well understood. Here we profiled the genomic landscape of fetal and placental tissues postpartum from both IVF and naturally conceived children, to investigate the prevalence and persistence of large genetic aberrations that probably arose from IVF-related CIN. We demonstrate that CIN is not preserved at later stages of prenatal development, and that de novo numerical aberrations or large structural DNA imbalances occur at similar rates in IVF and naturally conceived live-born neonates. Our findings affirm that human IVF treatment has no detrimental effect on the chromosomal constitution of fetal and placental lineages