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1.
Nature ; 476(7359): 214-9, 2011 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-21833088

RESUMO

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.


Assuntos
Predisposição Genética para Doença/genética , Imunidade Celular/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Alelos , Diferenciação Celular/imunologia , Europa (Continente)/etnologia , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Antígenos HLA-A/genética , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Imunidade Celular/genética , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único/genética , Tamanho da Amostra , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia
2.
Genome Res ; 20(4): 434-9, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20219945

RESUMO

There is a growing realization that some aging-associated phenotypes/diseases have an epigenetic basis. Here, we report the first genome-scale study of epigenomic dynamics during normal human aging. We identify aging-associated differentially methylated regions (aDMRs) in whole blood in a discovery cohort, and then replicate these aDMRs in sorted CD4(+) T-cells and CD14(+) monocytes in an independent cohort, suggesting that aDMRs occur in precursor haematopoietic cells. Further replication of the aDMRs in buccal cells, representing a tissue that originates from a different germ layer compared with blood, demonstrates that the aDMR signature is a multitissue phenomenon. Moreover, we demonstrate that aging-associated DNA hypermethylation occurs predominantly at bivalent chromatin domain promoters. This same category of promoters, associated with key developmental genes, is frequently hypermethylated in cancers and in vitro cell culture, pointing to a novel mechanistic link between aberrant hypermethylation in cancer, aging, and cell culture.


Assuntos
Envelhecimento/genética , Cromatina/genética , Metilação de DNA , Adulto , Idoso , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Células Sanguíneas/metabolismo , Linhagem Celular Tumoral/metabolismo , Transformação Celular Neoplásica , Cromatina/química , Cromatina/metabolismo , Estudos de Coortes , Metilação de DNA/fisiologia , Epigênese Genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes Controladores do Desenvolvimento/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Regiões Promotoras Genéticas/genética , Especificidade por Substrato , Gêmeos/genética , Adulto Jovem
3.
Nat Genet ; 42(4): 295-302, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20190752

RESUMO

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.


Assuntos
Doença Celíaca/genética , Genes MHC Classe I , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Expressão Gênica , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Metanálise como Assunto , Risco
4.
Genome Biol ; 9(5): R78, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18477386

RESUMO

BACKGROUND: Although the human genome sequence was declared complete in 2004, the sequence was interrupted by 341 gaps of which 308 lay in an estimated approximately 28 Mb of euchromatin. While these gaps constitute only approximately 1% of the sequence, knowledge of the full complement of human genes and regulatory elements is incomplete without their sequences. RESULTS: We have used a combination of conventional chromosome walking (aided by the availability of end sequences) in fosmid and bacterial artificial chromosome (BAC) libraries, whole chromosome shotgun sequencing, comparative genome analysis and long PCR to finish 8 of the 11 gaps in the initial chromosome 22 sequence. In addition, we have patched four regions of the initial sequence where the original clones were found to be deleted, or contained a deletion allele of a known gene, with a further 126 kb of new sequence. Over 1.018 Mb of new sequence has been generated to extend into and close the gaps, and we have annotated 16 new or extended gene structures and one pseudogene. CONCLUSION: Thus, we have made significant progress to completing the sequence of the euchromatic regions of human chromosome 22 using a combination of detailed approaches. Our experience suggests that substantial work remains to close the outstanding gaps in the human genome sequence.


Assuntos
Cromossomos Humanos Par 22 , Genoma Humano , Análise de Sequência de DNA , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Artificiais Bacterianos/genética , Humanos
5.
Hum Mol Genet ; 13(2): 191-202, 2004 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-14645202

RESUMO

We have developed a directly quantitative method utilizing genomic clone DNA microarrays to assess the replication timing of sequences during the S phase of the cell cycle. The genomic resolution of the replication timing measurements is limited only by the genomic clone size and density. We demonstrate the power of this approach by constructing a genome-wide map of replication timing in human lymphoblastoid cells using an array with clones spaced at 1 Mb intervals and a high-resolution replication timing map of 22q with an array utilizing overlapping sequencing tile path clones. We show a positive correlation, both genome-wide and at a high resolution, between replication timing and a range of genome parameters including GC content, gene density and transcriptional activity.


Assuntos
Replicação do DNA , Genoma Humano , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Composição de Bases , Células Cultivadas , Cromossomos Humanos Par 22 , Expressão Gênica , Humanos , Fase S/genética
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