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1.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360852

RESUMO

Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites. Here, we built upon this work by assessing residual effects of fluoxetine administration on the expression of genes and abundance of lipids and polar metabolites in the prelimbic cortex of 10 treated and 11 control macaques representing two monoamine oxidase A (MAOA) genotypes. Analysis of 8871 mRNA transcripts, 3608 lipids, and 1829 polar metabolites revealed substantial alterations of the brain lipid content, including significant abundance changes of 106 lipid features, accompanied by subtle changes in gene expression. Lipid alterations in the drug-treated animals were most evident for polyunsaturated fatty acids (PUFAs). A decrease in PUFAs levels was observed in all quantified lipid classes excluding sphingolipids, which do not usually contain PUFAs, suggesting systemic changes in fatty acid metabolism. Furthermore, the residual effect of the drug on lipid abundances was more pronounced in macaques carrying the MAOA-L genotype, mirroring reported behavioral effects of the treatment. We speculate that a decrease in PUFAs may be associated with adverse effects in depressive patients and could potentially account for the variation in individual response to fluoxetine in young people.


Assuntos
Antidepressivos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Fluoxetina/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Animais , Ácidos Graxos Insaturados/metabolismo , Macaca mulatta , Masculino
2.
Aging (Albany NY) ; 13(11): 14843-14861, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115613

RESUMO

Aging is a factor associated with poor prognosis in glioblastoma (GBM). It is therefore important to understand the molecular features of aging contributing to GBM morbidity. TP73-AS1 is a long noncoding RNA (lncRNA) over expressed in GBM tumors shown to promote resistance to the chemotherapeutic temozolomide (TMZ), and tumor aggressiveness. How the expression of TP73-AS1 is regulated is not known, nor is it known if its expression is associated with aging. By analyzing transcriptional data obtained from natural and pathological aging brain, we found that the expression of TP73-AS1 is high in pathological and naturally aging brains. YY1 physically associates with the promoter of TP73-AS1 and we found that along with TP73-AS1, YY1 is induced by TMZ. We found that the TP73-AS1 promoter is activated by TMZ, and by YY1 over expression. Using CRISPRi to deplete YY1, we found that YY1 promotes up regulation of TP73-AS1 and the activation of its promoter during TMZ treatment. In addition, we identified two putative YY1 binding sites within the TP73-AS1 promoter, and used mutagenesis to find that they are essential for TMZ mediated promoter activation. Together, our data positions YY1 as an important TP73-AS1 regulator, demonstrating that TP73-AS1 is expressed in the natural and pathological aging brain, including during neurodegeneration and cancer. Our findings advance our understanding of TP73-AS1 expression, bringing forth a new link between TMZ resistance and aging, both of which contribute to GBM morbidity.


Assuntos
Envelhecimento/genética , Encéfalo/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , RNA Longo não Codificante/genética , Temozolomida/farmacologia , Fator de Transcrição YY1/metabolismo , Sequência de Bases , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular Tumoral , Humanos , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante/metabolismo
3.
Elife ; 102021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33942714

RESUMO

We analyze the metabolomes of humans, chimpanzees, and macaques in muscle, kidney and three different regions of the brain. Although several compounds in amino acid metabolism occur at either higher or lower concentrations in humans than in the other primates, metabolites downstream of adenylosuccinate lyase, which catalyzes two reactions in purine synthesis, occur at lower concentrations in humans. This enzyme carries an amino acid substitution that is present in all humans today but absent in Neandertals. By introducing the modern human substitution into the genomes of mice, as well as the ancestral, Neandertal-like substitution into the genomes of human cells, we show that this amino acid substitution contributes to much or all of the reduction of de novo synthesis of purines in humans.

4.
Aging (Albany NY) ; 13(5): 6420-6441, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33690173

RESUMO

Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer's patients. To understand SIRT6 roles in transcript pattern changes, we analyzed transcriptomes of young WT, old WT and young SIRT6-KO mice brains, and found changes in gene expression related to healthy and pathological aging. In addition, we traced these differences in human and mouse samples of Alzheimer's and Parkinson's diseases, healthy aging and calorie restriction (CR). Our results define four gene expression categories that change with age in a pathological or non-pathological manner, which are either reversed or not by CR. We found that each of these gene expression categories is associated with specific transcription factors, thus serving as potential candidates for their category-specific regulation. One of these candidates is YY1, which we found to act together with SIRT6 regulating specific processes. We thus argue that SIRT6 has a pivotal role in preventing age-related transcriptional changes in brains. Therefore, reduced SIRT6 activity may drive pathological age-related gene expression signatures in the brain.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Sirtuínas/metabolismo , Envelhecimento/genética , Animais , Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Sirtuínas/genética , Transcriptoma , Fator de Transcrição YY1/metabolismo
5.
Nat Commun ; 12(1): 41, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397980

RESUMO

Mammalian and Drosophila genomes are partitioned into topologically associating domains (TADs). Although this partitioning has been reported to be functionally relevant, it is unclear whether TADs represent true physical units located at the same genomic positions in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, we use a single-nucleus Hi-C technique to construct high-resolution Hi-C maps in individual Drosophila genomes. These maps demonstrate chromatin compartmentalization at the megabase scale and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which closely resembles the TAD profile in the bulk in situ Hi-C data. Over 40% of TAD boundaries are conserved between individual nuclei and possess a high level of active epigenetic marks. Polymer simulations demonstrate that chromatin folding is best described by the random walk model within TADs and is most suitably approximated by a crumpled globule build of Gaussian blobs at longer distances. We observe prominent cell-to-cell variability in the long-range contacts between either active genome loci or between Polycomb-bound regions, suggesting an important contribution of stochastic processes to the formation of the Drosophila 3D genome.


Assuntos
Drosophila melanogaster/genética , Genoma de Inseto , Conformação de Ácido Nucleico , Animais , Biopolímeros/metabolismo , Cromatina/genética , Bases de Dados Genéticas , Epigênese Genética , Haploidia , Modelos Genéticos , Processos Estocásticos , Cromossomo X/genética
6.
PeerJ ; 8: e9566, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32864204

RESUMO

Regulation of gene transcription is a complex process controlled by many factors, including the conformation of chromatin in the nucleus. Insights into chromatin conformation on both local and global scales can be provided by the Hi-C (high-throughput chromosomes conformation capture) method. One of the drawbacks of Hi-C analysis and interpretation is the presence of systematic biases, such as different accessibility to enzymes, amplification, and mappability of DNA regions, which all result in different visibility of the regions. Iterative correction (IC) is one of the most popular techniques developed for the elimination of these systematic biases. IC is based on the assumption that all chromatin regions have an equal number of observed contacts in Hi-C. In other words, the IC procedure is equalizing the experimental visibility approximated by the cumulative contact frequency (CCF) for all genomic regions. However, the differences in experimental visibility might be explained by biological factors such as chromatin openness, which is characteristic of distinct chromatin states. Here we show that CCF is positively correlated with active transcription. It is associated with compartment organization, since compartment A demonstrates higher CCF and gene expression levels than compartment B. Notably, this observation holds for a wide range of species, including human, mouse, and Drosophila. Moreover, we track the CCF state for syntenic blocks between human and mouse and conclude that active state assessed by CCF is an intrinsic property of the DNA region, which is independent of local genomic and epigenomic context. Our findings establish a missing link between Hi-C normalization procedures removing CCF from the data and poorly investigated and possibly relevant biological factors contributing to CCF.

7.
Genome Res ; 30(5): 776-789, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32424074

RESUMO

Identification of gene expression traits unique to the human brain sheds light on the molecular mechanisms underlying human evolution. Here, we searched for uniquely human gene expression traits by analyzing 422 brain samples from humans, chimpanzees, bonobos, and macaques representing 33 anatomical regions, as well as 88,047 cell nuclei composing three of these regions. Among 33 regions, cerebral cortex areas, hypothalamus, and cerebellar gray and white matter evolved rapidly in humans. At the cellular level, astrocytes and oligodendrocyte progenitors displayed more differences in the human evolutionary lineage than the neurons. Comparison of the bulk tissue and single-nuclei sequencing revealed that conventional RNA sequencing did not detect up to two-thirds of cell-type-specific evolutionary differences.

8.
Cancers (Basel) ; 12(2)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028632

RESUMO

Most head and neck cancer (HNC) patients are resistant to cetuximab, an antibody against the epidermal growth factor receptor. Such therapy resistance is known to be mediated, in part, by stromal cells surrounding the tumor cells; however, the mechanisms underlying such a resistance phenotype remain unclear. To identify the mechanisms of cetuximab resistance in an unbiased manner, RNA-sequencing (RNA-seq) of HNC patient-derived xenografts (PDXs) was performed. Comparing the gene expression of HNC-PDXs before and after treatment with cetuximab indicated that the transforming growth factor-beta (TGF-beta) signaling pathway was upregulated in the stromal cells of PDXs that progressed on cetuximab treatment (CetuximabProg-PDX). However, in PDXs that were extremely sensitive to cetuximab (CetuximabSen-PDX), the TGF-beta pathway was downregulated in the stromal compartment. Histopathological analysis of PDXs showed that TGF-beta-activation was detected in cancer-associated fibroblasts (CAFs) of CetuximabProg-PDX. These TGF-beta-activated CAFs were sufficient to limit cetuximab efficacy in vitro and in vivo. Moreover, blocking the TGF-beta pathway using the SMAD3 inhibitor, SIS3, enhanced cetuximab efficacy and prevented the progression of CetuximabProg-PDX. Altogether, our findings indicate that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC.

9.
Sci Rep ; 9(1): 18348, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31797944

RESUMO

Human populations, despite their overwhelming similarity, contain some distinct phenotypic, genetic, epigenetic, and gene expression features. In this study, we explore population differences at yet another level of molecular phenotype: the abundance of non-polar and polar low molecular weight compounds, lipids and metabolites in the prefrontal cortical region of the brain. We assessed the abundance of 1,670 lipids and 258 metabolites in 146 Han Chinese, 97 Western European, and 60 African American individuals of varying ages, covering most of the lifespan. The statistical analysis and logistic regression models both demonstrated extensive lipid and metabolic divergence of the Han Chinese individuals from the other two populations. This divergence was age-dependent, peaking in young adults, and involved metabolites and lipids clustering in specific metabolic pathways.


Assuntos
Encéfalo/metabolismo , Evolução Molecular , Lipidômica , Córtex Pré-Frontal/metabolismo , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Lactente , Recém-Nascido , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Masculino , Metaboloma/genética , Pessoa de Meia-Idade , Fenótipo , Vigilância da População , Adulto Jovem
10.
Commun Biol ; 2: 234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263778

RESUMO

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with yet incompletely uncovered molecular determinants. Alterations in the abundance of low molecular weight compounds (metabolites) in ASD could add to our understanding of the disease. Indeed, such alterations take place in the urine, plasma and cerebellum of ASD individuals. In this work, we investigated mass-spectrometric signal intensities of 1,366 metabolites in the prefrontal cortex grey matter of 32 ASD and 40 control individuals. 15% of these metabolites showed significantly different intensities in ASD and clustered in 16 metabolic pathways. Of them, ten pathways were altered in urine and blood of ASD individuals (Fisher test, p < 0.05), opening an opportunity for the design of new diagnostic instruments. Furthermore, metabolic measurements conducted in 40 chimpanzees and 40 macaques showed an excess of metabolite intensity differences unique to humans, supporting the hypothesized disruption of evolutionary novel cortical mechanisms in ASD.


Assuntos
Transtorno Autístico/metabolismo , Metaboloma , Córtex Pré-Frontal/metabolismo , Animais , Evolução Molecular , Substância Cinzenta/metabolismo , Humanos , Macaca mulatta , Aprendizado de Máquina , Redes e Vias Metabólicas , Pan troglodytes
11.
BMC Genomics ; 20(1): 399, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117933

RESUMO

BACKGROUND: The three epidemiologically important Opisthorchiidae liver flukes Opisthorchis felineus, O. viverrini, and Clonorchis sinensis, are believed to harbour similar potencies to provoke hepatobiliary diseases in their definitive hosts, although their populations have substantially different ecogeographical aspects including habitat, preferred hosts, population structure. Lack of O. felineus genomic data is an obstacle to the development of comparative molecular biological approaches necessary to obtain new knowledge about the biology of Opisthorchiidae trematodes, to identify essential pathways linked to parasite-host interaction, to predict genes that contribute to liver fluke pathogenesis and for the effective prevention and control of the disease. RESULTS: Here we present the first draft genome assembly of O. felineus and its gene repertoire accompanied by a comparative analysis with that of O. viverrini and Clonorchis sinensis. We observed both noticeably high heterozygosity of the sequenced individual and substantial genetic diversity in a pooled sample. This indicates that potency of O. felineus population for rapid adaptive response to control and preventive measures of opisthorchiasis is higher than in O. viverrini and C. sinensis. We also have found that all three species are characterized by more intensive involvement of trans-splicing in RNA processing compared to other trematodes. CONCLUSION: All revealed peculiarities of structural organization of genomes are of extreme importance for a proper description of genes and their products in these parasitic species. This should be taken into account both in academic and applied research of epidemiologically important liver flukes. Further comparative genomics studies of liver flukes and non-carcinogenic flatworms allow for generation of well-grounded hypotheses on the mechanisms underlying development of cholangiocarcinoma associated with opisthorchiasis and clonorchiasis as well as species-specific mechanisms of these diseases.


Assuntos
Cricetinae/parasitologia , Cyprinidae/parasitologia , Genoma Helmíntico , Genômica/métodos , Proteínas de Helminto/genética , Opistorquíase/epidemiologia , Opisthorchis/genética , Sequência de Aminoácidos , Animais , Clonorquíase/epidemiologia , Clonorquíase/genética , Clonorquíase/parasitologia , Clonorchis sinensis/genética , Opistorquíase/genética , Opistorquíase/parasitologia , Homologia de Sequência
13.
Nat Commun ; 10(1): 1176, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30862957

RESUMO

How the nuclear lamina (NL) impacts on global chromatin architecture is poorly understood. Here, we show that NL disruption in Drosophila S2 cells leads to chromatin compaction and repositioning from the nuclear envelope. This increases the chromatin density in a fraction of topologically-associating domains (TADs) enriched in active chromatin and enhances interactions between active and inactive chromatin. Importantly, upon NL disruption the NL-associated TADs become more acetylated at histone H3 and less compact, while background transcription is derepressed. Two-colour FISH confirms that a TAD becomes less compact following its release from the NL. Finally, polymer simulations show that chromatin binding to the NL can per se compact attached TADs. Collectively, our findings demonstrate a dual function of the NL in shaping the 3D genome. Attachment of TADs to the NL makes them more condensed but decreases the overall chromatin density in the nucleus by stretching interphase chromosomes.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Cromatina/metabolismo , Histonas/metabolismo , Lâmina Nuclear/metabolismo , Animais , Linhagem Celular , Cromossomos de Insetos/metabolismo , Regulação para Baixo , Drosophila melanogaster , Perfilação da Expressão Gênica , Genes de Insetos/genética , Hibridização in Situ Fluorescente , Modelos Animais , Regulação para Cima
14.
J Cell Biochem ; 120(3): 4494-4503, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30260021

RESUMO

Chromosomes in many organisms, including Drosophila and mammals, are folded into topologically associating domains (TADs). Increasing evidence suggests that TAD folding is hierarchical, wherein subdomains combine to form larger superdomains, instead of a sequence of nonoverlapping domains. Here, we studied the hierarchical structure of TADs in Drosophila. We show that the boundaries of TADs of different hierarchical levels are characterized by the presence of different portions of active chromatin, but do not vary in the binding of architectural proteins, such as CCCTC binding factor or cohesin. The apparent hierarchy of TADs in Drosophila chromosomes is not likely to have functional importance but rather reflects various options of long-range chromatin folding directed by the distribution of active and inactive chromatin segments and may represent population average.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Cromatina/metabolismo , Cromossomos de Insetos/metabolismo , Proteínas de Drosophila/metabolismo , Animais , Fator de Ligação a CCCTC/genética , Cromatina/genética , Cromossomos de Insetos/genética , Proteínas de Drosophila/genética , Drosophila melanogaster
15.
J Bioinform Comput Biol ; 16(2): 1840011, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29739306

RESUMO

Sequencing of complete nuclear genomes of Neanderthal and Denisovan stimulated studies about their relationship with modern humans demonstrating, in particular, that DNA alleles from both Neanderthal and Denisovan genomes are present in genomes of modern humans. The Papuan genome is a unique object because it contains both Neanderthal and Denisovan alleles. Here, we have shown that the Papuan genomes contain different gene functional groups inherited from each of the ancient people. The Papuan genomes demonstrate a relative prevalence of Neanderthal alleles in genes responsible for the regulation of transcription and neurogenesis. The enrichment of specific functional groups with Denisovan alleles is less pronounced; these groups are responsible for bone and tissue remodeling. This analysis shows that introgression of alleles from Neanderthals and Denisovans to Papuans occurred independently and retention of these alleles may carry specific adaptive advantages.


Assuntos
Genoma Humano , Hominidae/genética , Grupo com Ancestrais do Continente Africano/genética , Alelos , Animais , Remodelação Óssea/genética , Análise por Conglomerados , Genética Populacional , Humanos , Família Multigênica , Homem de Neandertal/genética , Papua Nova Guiné , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
16.
Mol Biol Evol ; 35(8): 1947-1957, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29762743

RESUMO

Lipids are essential structural and functional components of cells. Little is known, however, about the evolution of lipid composition in different tissues. Here, we report a large-scale analysis of the lipidome evolution in six tissues of 32 species representing primates, rodents, and bats. While changes in genes' sequence and expression accumulate proportionally to the phylogenetic distances, <2% of the lipidome evolves this way. Yet, lipids constituting this 2% cluster in specific functions shared among all tissues. Among species, human show the largest amount of species-specific lipidome differences. Many of the uniquely human lipidome features localize in the brain cortex and cluster in specific pathways implicated in cognitive disorders.


Assuntos
Evolução Biológica , Metabolismo dos Lipídeos , Mamíferos/genética , Mamíferos/metabolismo , Animais , Córtex Cerebral/metabolismo , Humanos , Especificidade da Espécie
17.
Epigenetics Chromatin ; 10(1): 35, 2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28693562

RESUMO

BACKGROUND: In homeotherms, the alpha-globin gene clusters are located within permanently open genome regions enriched in housekeeping genes. Terminal erythroid differentiation results in dramatic upregulation of alpha-globin genes making their expression comparable to the rRNA transcriptional output. Little is known about the influence of the erythroid-specific alpha-globin gene transcription outburst on adjacent, widely expressed genes and large-scale chromatin organization. Here, we have analyzed the total transcription output, the overall chromatin contact profile, and CTCF binding within the 2.7 Mb segment of chicken chromosome 14 harboring the alpha-globin gene cluster in cultured lymphoid cells and cultured erythroid cells before and after induction of terminal erythroid differentiation. RESULTS: We found that, similarly to mammalian genome, the chicken genomes is organized in TADs and compartments. Full activation of the alpha-globin gene transcription in differentiated erythroid cells is correlated with upregulation of several adjacent housekeeping genes and the emergence of abundant intergenic transcription. An extended chromosome region encompassing the alpha-globin cluster becomes significantly decompacted in differentiated erythroid cells, and depleted in CTCF binding and CTCF-anchored chromatin loops, while the sub-TAD harboring alpha-globin gene cluster and the upstream major regulatory element (MRE) becomes highly enriched with chromatin interactions as compared to lymphoid and proliferating erythroid cells. The alpha-globin gene domain and the neighboring loci reside within the A-like chromatin compartment in both lymphoid and erythroid cells and become further segregated from the upstream gene desert upon terminal erythroid differentiation. CONCLUSIONS: Our findings demonstrate that the effects of tissue-specific transcription activation are not restricted to the host genomic locus but affect the overall chromatin structure and transcriptional output of the encompassing topologically associating domain.


Assuntos
Proteínas Aviárias/genética , Cromatina/genética , Ativação Transcricional , Regulação para Cima , alfa-Globinas/genética , Animais , Proteínas Aviárias/metabolismo , Fator de Ligação a CCCTC/metabolismo , Linhagem Celular , Galinhas , Cromatina/metabolismo , Células Eritroides/citologia , Células Eritroides/metabolismo , Eritropoese , Genes Essenciais , Ligação Proteica , alfa-Globinas/metabolismo
18.
Sci Rep ; 7(1): 5, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28127055

RESUMO

Maximal lifespan of mammalian species, even if closely related, may differ more than 10-fold, however the nature of the mechanisms that determine this variability is unresolved. Here, we assess the relationship between maximal lifespan duration and concentrations of more than 20,000 lipid compounds, measured in 669 tissue samples from 6 tissues of 35 species representing three mammalian clades: primates, rodents and bats. We identify lipids associated with species' longevity across the three clades, uncoupled from other parameters, such as basal metabolic rate, body size, or body temperature. These lipids clustered in specific lipid classes and pathways, and enzymes linked to them display signatures of greater stabilizing selection in long-living species, and cluster in functional groups related to signaling and protein-modification processes. These findings point towards the existence of defined molecular mechanisms underlying variation in maximal lifespan among mammals.


Assuntos
Quirópteros/fisiologia , Lipídeos/análise , Longevidade , Primatas/fisiologia , Roedores/fisiologia , Animais , Redes e Vias Metabólicas
19.
BMC Genet ; 18(Suppl 1): 110, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29297395

RESUMO

BACKGROUND: The history of human populations occupying the plains and mountain ridges separating Europe from Asia has been eventful, as these natural obstacles were crossed westward by multiple waves of Turkic and Uralic-speaking migrants as well as eastward by Europeans. Unfortunately, the material records of history of this region are not dense enough to reconstruct details of population history. These considerations stimulate growing interest to obtain a genetic picture of the demographic history of migrations and admixture in Northern Eurasia. RESULTS: We genotyped and analyzed 1076 individuals from 30 populations with geographical coverage spanning from Baltic Sea to Baikal Lake. Our dense sampling allowed us to describe in detail the population structure, provide insight into genomic history of numerous European and Asian populations, and significantly increase quantity of genetic data available for modern populations in region of North Eurasia. Our study doubles the amount of genome-wide profiles available for this region. We detected unusually high amount of shared identical-by-descent (IBD) genomic segments between several Siberian populations, such as Khanty and Ket, providing evidence of genetic relatedness across vast geographic distances and between speakers of different language families. Additionally, we observed excessive IBD sharing between Khanty and Bashkir, a group of Turkic speakers from Southern Urals region. While adding some weight to the "Finno-Ugric" origin of Bashkir, our studies highlighted that the Bashkir genepool lacks the main "core", being a multi-layered amalgamation of Turkic, Ugric, Finnish and Indo-European contributions, which points at intricacy of genetic interface between Turkic and Uralic populations. Comparison of the genetic structure of Siberian ethnicities and the geography of the region they inhabit point at existence of the "Great Siberian Vortex" directing genetic exchanges in populations across the Siberian part of Asia. Slavic speakers of Eastern Europe are, in general, very similar in their genetic composition. Ukrainians, Belarusians and Russians have almost identical proportions of Caucasus and Northern European components and have virtually no Asian influence. We capitalized on wide geographic span of our sampling to address intriguing question about the place of origin of Russian Starovers, an enigmatic Eastern Orthodox Old Believers religious group relocated to Siberia in seventeenth century. A comparative reAdmix analysis, complemented by IBD sharing, placed their roots in the region of the Northern European Plain, occupied by North Russians and Finno-Ugric Komi and Karelian people. Russians from Novosibirsk and Russian Starover exhibit ancestral proportions close to that of European Eastern Slavs, however, they also include between five to 10 % of Central Siberian ancestry, not present at this level in their European counterparts. CONCLUSIONS: Our project has patched the hole in the genetic map of Eurasia: we demonstrated complexity of genetic structure of Northern Eurasians, existence of East-West and North-South genetic gradients, and assessed different inputs of ancient populations into modern populations.


Assuntos
Emigração e Imigração/história , Grupos Étnicos/genética , Genética Populacional , Algoritmos , Ásia , DNA , Conjuntos de Dados como Assunto , Europa (Continente) , Feminino , Variação Genética , Técnicas de Genotipagem , História do Século XV , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , História Medieval , Humanos , Masculino , Federação Russa
20.
Nucleus ; 7(3): 319-24, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-27249516

RESUMO

Recent data indicate that eukaryotic chromosomes are organized into Topologically Associating Domains (TADs); however, the mechanisms underlying TAD formation remain obscure. Based on the results of Hi-C analysis performed on 4 Drosophila melanogaster cell lines, we have proposed that specific properties of nucleosomes in active and repressed chromatin play a key role in the formation of TADs. Our computer simulations showed that the ability of "inactive" nucleosomes to stick to each other and the lack of such ability in "active" nucleosomes is sufficient for spatial segregation of these types of chromatin, which is revealed in the Hi-C analysis as TAD/inter-TAD partitioning. However, some Drosophila and mammalian TADs contain both active and inactive chromatin, a fact that does not fit this model. Herein, we present additional arguments for the model by postulating that transcriptionally active chromatin is extruded on the surface of a TAD, and discuss the possible impact of this organization on the enhancer-promoter communication and on the segregation of TADs.


Assuntos
Cromatina/química , Cromatina/metabolismo , Animais , Cromossomos de Insetos/genética , Drosophila melanogaster/genética , Humanos
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