RESUMEN
Human prefrontal cortex (PFC) is associated with broad individual variabilities in functions linked to personality, social behaviors, and cognitive functions. The phenotype variabilities associated with brain functions can be caused by genetic or epigenetic factors. The interactions between these factors in human subjects is, as of yet, poorly understood. The heterogeneity of cerebral tissue, consisting of neuronal and nonneuronal cells, complicates the comparative analysis of gene activities in brain specimens. To approach the underlying neurogenomic determinants, we performed a deep analysis of open chromatin-associated histone methylation in PFC neurons sorted from multiple human individuals in conjunction with whole-genome and transcriptome sequencing. Integrative analyses produced novel unannotated neuronal genes and revealed individual-specific chromatin "blueprints" of neurons that, in part, relate to genetic background. Surprisingly, we observed gender-dependent epigenetic signals, implying that gender may contribute to the chromatin variabilities in neurons. Finally, we found epigenetic, allele-specific activation of the testis-specific gene nucleoporin 210 like (NUP210L) in brain in some individuals, which we link to a genetic variant occurring in <3% of the human population. Recently, the NUP210L locus has been associated with intelligence and mathematics ability. Our findings highlight the significance of epigenetic-genetic footprinting for exploring neurologic function in a subject-specific manner.-Gusev, F. E., Reshetov, D. A., Mitchell, A. C., Andreeva, T. V., Dincer, A., Grigorenko, A. P., Fedonin, G., Halene, T., Aliseychik, M., Goltsov, A. Y., Solovyev, V., Brizgalov, L., Filippova, E., Weng, Z., Akbarian, S., Rogaev, E. I. Epigenetic-genetic chromatin footprinting identifies novel and subject-specific genes active in prefrontal cortex neurons.
Asunto(s)
Cromatina/metabolismo , Cognición/fisiología , Epigénesis Genética/fisiología , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Sitios Genéticos/fisiología , Histonas/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Metilación , Persona de Mediana Edad , Neuronas/citología , Proteínas de Complejo Poro Nuclear/biosíntesis , Corteza Prefrontal/citología , EmbarazoRESUMEN
A strain of obligately anaerobic, spore-forming, Gram-positive rods was isolated from child faeces and characterized both phenotypically and genotypically. Phylogenetic analysis based on 16S rRNA gene and whole genome sequencing revealed the strain to represent a member of the family Ruminococcaceae distant from described species and genera. The strain was moderately saccharolytic with mannose as the preferred substrate and produced lactic acid, acetic acid and H2 as the end products. The major cellular long-chain fatty acids were C16â:â0 and C16â:â0 aldehyde. The genomic DNA G+C content was 52.3 mol%. On the basis of chemotaxonomic and genomic properties it was concluded that the strain represents a novel species in a new genus within the family Ruminococcaceae, for which the name Hydrogeniiclostidium mannosilyticum gen. nov., sp. nov. is proposed. The type strain of Hydrogeniiclostidium mannosilyticum is ASD2818T (=VKM B-3268T=JCM 33295T).
Asunto(s)
Clostridiales/clasificación , Heces/microbiología , Filogenia , Técnicas de Tipificación Bacteriana , Composición de Base , Preescolar , Clostridiales/aislamiento & purificación , ADN Bacteriano/genética , Ácidos Grasos/química , Humanos , Masculino , ARN Ribosómico 16S/genética , Federación de Rusia , Análisis de Secuencia de ADNRESUMEN
OBJECTIVES: The aim of this study was to establish maternal contribution to false positive noninvasive prenatal DNA screening (NIPS) results and develop the method to distinguish maternal and fetal origin of high-risk monosomy X NIPS calls including mosaic maternal cases. METHOD: A total of 906 women carrying singleton pregnancies have been recruited. Maternal plasma DNA semiconductor massive parallel sequencing was performed to detect common aneuploidies. For the case of high monosomy X risk call, analysis method to distinguish fetal and maternal monosomy X has been additionally applied. RESULTS: According to NIPS results, 18 patients had a high risk of fetal monosomy X. In 11 (61%) cases, fetal aneuploidy was confirmed by karyotyping. Other 7 cases were false positives. In 3 out of 7 cases, additional analysis based on in silico size selection was allowed to assume maternal monosomy X. In these cases, fluorescence in situ hybridization analysis confirmed mosaic monosomy X in maternal blood cells. CONCLUSION: The prevalence of mosaic monosomy X karyotype is 0.3% (3/906)-10 times higher than published before. Additional in silico size-selection and data analysis increases PPV for monosomy X from 61% to 73% for studied population.
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Pruebas de Detección del Suero Materno/métodos , Mosaicismo , Síndrome de Turner/diagnóstico , Adulto , Simulación por Computador , Reacciones Falso Positivas , Femenino , Humanos , Embarazo , Análisis de Secuencia de ADNRESUMEN
The effective implementation of whole-exome sequencing- and whole-genome sequencing-based diagnostics in the management of children affected with genetic diseases and the rapid decrease in the cost of next-generation sequencing (NGS) enables the expansion of this method to newborn genetic screening programs. Such NGS-based screening greatly increases the number of diseases that can be detected compared to conventional newborn screening, as the latter is aimed at early detection of a limited number of inborn diseases. Moreover, genetic testing provides new possibilities for family members of the proband, as many variants responsible for adult-onset conditions are inherited from the parents. However, the idea of NGS-based screening in healthy children raises issues of medical and ethical integrity as well as technical questions, including interpretation of the observed variants. Pilot studies have shown that both parents and medical professionals have moved forward and are enthused about these new possibilities. However, either the number of participants or the number of genes studied in previous investigations thus far has been limited to a few hundred, restricting the scope of potential findings. Our current study (NCT05325749) includes 7,000 apparently healthy infants born at our center between February 2021 and May 2023, who were screened for pathogenic variants in 2,350 genes. Clinically significant variants associated with early-onset diseases that can be treated, prevented, or where symptoms can be alleviated with timely introduced symptomatic therapy, were observed in 0.9% of phenotypically normal infants, 2.1% of the screened newborns were found to carry variants associated with reduced penetrance or monogenic diseases of adult-onset and/or variable expressivity, and 0.3% had chromosomal abnormalities. Here, we report our results and address questions regarding the interpretation of variants in newborns who were presumed to be healthy.
RESUMEN
Accurate unambiguous identification of ancient or historical specimens can potentially be achieved by DNA analysis. The controversy surrounding the fate of the last Russian Emperor, Nicholas II, and his family has persisted, in part, because the bodies of 2 children, Prince Alexei and 1 of his sisters, have not been found. A grave discovered in 1991 contained remains putatively identified as those of the Russian Royal family. However, not all family members were represented. Here, we report the results of genomic analyses of new specimens, the human remains of 2 burned skeletons exhumed from a grave discovered in July 2007, and the results of a comprehensive genomic analysis of remains from the 1991 discovery. Additionally, approximately 117 years old archival blood specimens from Nicholas II were obtained and genotyped, which provided critical material for the specific determination of individual identities and kinship identifications. Results of genotypic analyses of damaged historical specimens were evaluated alongside samples from descendants of both paternal and maternal lineages of the European Royal families, and the results conclusively demonstrate that the recently found remains belong to children of Nicholas II: Prince Alexei and his sister. The results of our studies provide unequivocal evidence that the remains of Nicholas II and his entire family, including all 5 children, have been identified. We demonstrate that convergent analysis of complete mitochondrial genome sequences combined with nuclear DNA profiles is an efficient and conclusive method for individual and kinship identification of specimens obtained from old historic relics.
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Personajes , Antropología Forense/métodos , Genoma Humano , Europa (Continente) , Familia , Humanos , Federación de RusiaRESUMEN
BACKGROUND: PWS is challenging to diagnose prenatally due to a lack of precise and well-characterized fetal phenotypes and noninvasive markers. Here we present the case of prenatal diagnosis of Prader-Willi syndrome, which was suspected with whole-genome NIPS. METHODS: Whole-genome noninvasive prenatal screening showed a high risk for trisomy 15. Amniocentesis followed by FISH analysis and SNP-based chromosomal microarray was performed. RESULTS: Simultaneous analysis of maternal and fetal samples with SNP microarrays demonstrated maternal uniparental disomy (UPD). CONCLUSION: The presented case is the first case of PWS described in detail, which was suspected by NIPS results. It demonstrates that the choice of confirmation methods concerning the time needed is crucial for the right diagnosis. We suppose that prenatal testing of UPD is essential for chromosome regions, which play a key role in the appearance of various gene-imprinting failure syndromes like PWS or AS.
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Pruebas Prenatales no Invasivas/métodos , Síndrome de Prader-Willi/genética , Disomía Uniparental/genética , Adulto , Amniocentesis/métodos , Cromosomas Humanos Par 15/genética , Femenino , Humanos , Hibridación Fluorescente in Situ/métodos , Síndrome de Prader-Willi/diagnóstico , Embarazo , Disomía Uniparental/patologíaRESUMEN
BACKGROUND: The association of exposure to endocrine disrupting chemicals in the peripubertal period with subsequent sperm DNA methylation is unknown. OBJECTIVE: We examined the association of peripubertal serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations with whole-genome bisulfite sequencing (WGBS) of sperm collected in young adulthood. METHODS: The Russian Children's Study is a prospective cohort of 516 boys who were enrolled at 8-9 years of age and provided semen samples at 18-19 years of age. WGBS of sperm was conducted to identify differentially methylated regions (DMR) between highest (nâ¯=â¯4) and lowest (nâ¯=â¯4) peripubertal TCDD groups. RESULTS: We found 52 DMRs that distinguished lowest and highest peripubertal serum TCDD concentrations. One of the top scoring networks, "Cellular Assembly and Organization, Cellular Function and Maintenance, Carbohydrate Metabolism", identified estrogen receptor alpha as its central regulator. CONCLUSION: Findings from our limited sample size suggest that peripubertal environmental exposures are associated with sperm DNA methylation in young adults.
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Metilación de ADN , Disruptores Endocrinos/sangre , Contaminantes Ambientales/sangre , Dibenzodioxinas Policloradas/sangre , Espermatozoides/metabolismo , Adolescente , Adulto , Niño , Monitoreo del Ambiente , Humanos , Masculino , Pubertad , Federación de Rusia , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
Genome-wide association studies have identified novel risk variants for Alzheimer's disease (AD). Among these, a gene carrying one of the highest risks for AD is PICALM. The PICALM rs3851179 A allele is thought to have a protective effect, whereas the G allele appears to confer risk for AD. The influence of the PICALM genotype on brain function in nondemented subjects remains largely unknown. We examined the possible effect of the PICALM rs3851179 genotype on quantitative electroencephalography recording at rest in 137 nondemented volunteers (age range: 20-79 years) subdivided into cohorts of those younger than and those older than 50 years of age. The homozygous presence of the AD risk variant PICALM GG was associated with an increase in beta relative power, with the effect being more pronounced in the older cohort. Beta power elevation in resting-state electroencephalography has previously been linked to cortical disinhibition and hyperexcitability. The increase in beta relative power in the carriers of the AD risk PICALM GG genotype suggests changes in the cortical excitatory-inhibitory balance, which are heightened during normal aging.
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Envejecimiento/fisiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Electroencefalografía , Estudio de Asociación del Genoma Completo , Genotipo , Proteínas de Ensamble de Clatrina Monoméricas/genética , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Riesgo , Adulto JovenRESUMEN
The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/PS2) underlie production of ß-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the γ-cleavage activities of PSENs that produce Aß, but not the ε-like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1. We tested them in vitro and in vivo assays and compared their activities with mutant isoforms of presenilin-related intramembrane di-aspartyl protease (IMPAS1 (IMP1)/signal peptide peptidase (SPP)). PSEN1 auto-cleavage was more resistant to the mutation remodeling than the ε-like proteolysis. PSEN1 with a G382A or a P433A mutation in evolutionary invariant sites retains functionally important APP ε- and Notch S3- cleavage activities, but G382A inhibits APP γ-cleavage and Aß production and a P433A elevates Aß. The G382A variant cannot restore the normal cellular ER Ca2+ leak in PSEN1/PSEN2 double knockout cells, but efficiently rescues the loss-of-function (Egl) phenotype of presenilin in C. elegans. We found that, unlike in PSEN1 knockout cells, endoplasmic reticulum (ER) Ca2+ leak is not changed in the absence of IMP1/SPP. IMP1/SPP with the analogous mutations retained efficiency in cleavage of transmembrane substrates and rescued the lethality of Ce-imp-2 knockouts. In summary, our data show that mutations near the active catalytic sites of intramembrane di-aspartyl proteases have different consequences on proteolytic and signaling functions.
RESUMEN
X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders.
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Transportadoras de Casetes de Unión a ATP/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación Missense , Ataxias Espinocerebelosas/genética , Adenosina Trifosfatasas/genética , Adulto , Proteínas de Transporte de Catión/genética , Niño , ATPasas Transportadoras de Cobre , Femenino , Genoma Humano , Heterocigoto , Humanos , Lactante , Masculino , LinajeRESUMEN
The epsilon4 allele of the apolipoprotein E gene (ApoE), as well as aging increase the risk of Alzheimer's and vascular diseases. Electroencephalogram (EEG) reactivity to hyperventilation (HV) depends on hypocapnia-induced cerebral vasoconstriction, which may be impaired in subjects with subclinical cerebrovascular disease. Quantitative EEG at rest and under 3-minute HV was examined in 125 healthy subjects divided into younger (age range 28-50) and older (age range 51-82) cohorts and stratified by ApoE genotype. The younger ApoE-epsilon4 carriers had excessive EEG reactivity to HV characterized by the manifestation of high-voltage delta, theta activity and sharp waves, and larger HV-induced changes in EEG relative powers than in the younger ApoE-epsilon4 noncarriers. EEG reactivity to HV decreased with aging, and in the ApoE-epsilon4 carriers the decrease was more pronounced than in the ApoE-epsilon4 noncarriers. The older ApoE-epsilon4 carriers had smaller HV-induced changes in EEG relative powers than the older ApoE-epsilon4 noncarriers. A marked decline of EEG reactivity to HV in the older ApoE-epsilon4 carriers suggests the possible impact of vascular factors on the pathogenesis of ApoE-induced Alzheimer disease.
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Envejecimiento/fisiología , Apolipoproteína E4/genética , Ondas Encefálicas/genética , Encéfalo/fisiología , Estrés Oxidativo/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Electroencefalografía , Femenino , Genotipo , Humanos , Hiperventilación/fisiopatología , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
The molecular mechanisms controlling human hair growth and scalp hair loss are poorly understood. By screening about 350,000 individuals in two populations from the Volga-Ural region of Russia, we identified a gene mutation in families who show an inherited form of hair loss and a hair growth defect. Affected individuals were homozygous for a deletion in the LIPH gene on chromosome 3q27, caused by short interspersed nuclear element-retrotransposon-mediated recombination. The LIPH gene is expressed in hair follicles and encodes a phospholipase called lipase H (alternatively known as membrane-associated phosphatidic acid-selective phospholipase A1alpha), an enzyme that regulates the production of bioactive lipids. These results suggest that lipase H participates in hair growth and development.