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1.
Nature ; 575(7784): 679-682, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31723262

RESUMO

Caspase-8 is a protease with both pro-death and pro-survival functions: it mediates apoptosis induced by death receptors such as TNFR11, and suppresses necroptosis mediated by the kinase RIPK3 and the pseudokinase MLKL2-4. Mice that lack caspase-8 display MLKL-dependent embryonic lethality4, as do mice that express catalytically inactive CASP8(C362A)5. Casp8C362A/C362AMlkl-/- mice die during the perinatal period5, whereas Casp8-/-Mlkl-/- mice are viable4, which indicates that inactive caspase-8 also has a pro-death scaffolding function. Here we show that mutant CASP8(C362A) induces the formation of ASC (also known as PYCARD) specks, and caspase-1-dependent cleavage of GSDMD and caspases 3 and 7 in MLKL-deficient mouse intestines around embryonic day 18. Caspase-1 and its adaptor ASC contributed to the perinatal lethal phenotype because a number of Casp8C362A/C362AMlkl-/-Casp1-/- and Casp8C362A/C362AMlkl-/-Asc-/- mice survived beyond weaning. Transfection studies suggest that inactive caspase-8 adopts a distinct conformation to active caspase-8, enabling its prodomain to engage ASC. Upregulation of the lipopolysaccharide sensor caspase-11 in the intestines of both Casp8C362A/C362AMlkl-/- and Casp8C362A/C362AMlkl-/-Casp1-/- mice also contributed to lethality because Casp8C362A/C362AMlkl-/-Casp1-/-Casp11-/- (Casp11 is also known as Casp4) neonates survived more often than Casp8C362A/C362AMlkl-/-Casp1-/- neonates. Finally, Casp8C362A/C362ARipk3-/-Casp1-/-Casp11-/- mice survived longer than Casp8C362A/C362AMlkl-/-Casp1-/-Casp11-/- mice, indicating that a necroptosis-independent function of RIPK3 also contributes to lethality. Thus, unanticipated plasticity in death pathways is revealed when caspase-8-dependent apoptosis and MLKL-dependent necroptosis are inhibited.

2.
Nature ; 574(7777): 249-253, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578523

RESUMO

The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells1. The kinase RIPK4 and the transcription factor IRF6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft-tissue fusions that result in neonatal lethality2-5. Our understanding of how these genes control epidermal differentiation is incomplete. Here we show that the role of RIPK4 in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biological processes; and that the phosphorylation of IRF6 at Ser413 and Ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wild-type and IRF6-deficient mouse embryos, we define the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6-/- skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Collectively, our results explain how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provide mechanistic insights into why developmental syndromes that are characterized by orofacial, skin and genital abnormalities result when this axis goes awry.


Assuntos
Diferenciação Celular , Células Epidérmicas/citologia , Epiderme/fisiologia , Fatores Reguladores de Interferon/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Anormalidades Múltiplas/genética , Animais , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Células Epidérmicas/metabolismo , Epiderme/embriologia , Anormalidades do Olho/genética , Feminino , Dedos/anormalidades , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Joelho/anormalidades , Articulação do Joelho/anormalidades , Lábio/anormalidades , Metabolismo dos Lipídeos/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fosfosserina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Sindactilia/genética , Anormalidades Urogenitais/genética
3.
Sci Signal ; 12(582)2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113851

RESUMO

Gasdermin-D (GSDMD) is cleaved by caspase-1, caspase-4, and caspase-11 in response to canonical and noncanonical inflammasome activation. Upon cleavage, GSDMD oligomerizes and forms plasma membrane pores, resulting in interleukin-1ß (IL-1ß) secretion, pyroptotic cell death, and inflammatory pathologies, including periodic fever syndromes and septic shock-a plague on modern medicine. Here, we showed that IRF2, a member of the interferon regulatory factor (IRF) family of transcription factors, was essential for the transcriptional activation of GSDMD. A forward genetic screen with N-ethyl-N-nitrosourea (ENU)-mutagenized mice linked IRF2 to inflammasome signaling. GSDMD expression was substantially attenuated in IRF2-deficient macrophages, endothelial cells, and multiple tissues, which corresponded with reduced IL-1ß secretion and inhibited pyroptosis. Mechanistically, IRF2 bound to a previously uncharacterized but unique site within the GSDMD promoter to directly drive GSDMD transcription for the execution of pyroptosis. Disruption of this single IRF2-binding site abolished signaling by both the canonical and noncanonical inflammasomes. Together, our data illuminate a key transcriptional mechanism for expression of the gene encoding GSDMD, a critical mediator of inflammatory pathologies.

4.
PLoS One ; 14(4): e0214110, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30951545

RESUMO

Peg10 (paternally expressed gene 10) is an imprinted gene that is essential for placental development. It is thought to derive from a Ty3-gyspy LTR (long terminal repeat) retrotransposon and retains Gag and Pol-like domains. Here we show that the Gag domain of PEG10 can promote vesicle budding similar to the HIV p24 Gag protein. Expressed in a subset of mouse endocrine organs in addition to the placenta, PEG10 was identified as a substrate of the deubiquitinating enzyme USP9X. Consistent with PEG10 having a critical role in placental development, PEG10-deficient trophoblast stem cells (TSCs) exhibited impaired differentiation into placental lineages. PEG10 expressed in wild-type, differentiating TSCs was bound to many cellular RNAs including Hbegf (Heparin-binding EGF-like growth factor), which is known to play an important role in placentation. Expression of Hbegf was reduced in PEG10-deficient TSCs suggesting that PEG10 might bind to and stabilize RNAs that are critical for normal placental development.


Assuntos
Diferenciação Celular/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Proteínas Nucleares/genética , Placentação/genética , Fatores de Transcrição/genética , Animais , Linhagem da Célula/genética , Elementos de DNA Transponíveis/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Produtos do Gene gag/genética , Impressão Genômica/genética , Humanos , Camundongos , Placenta/metabolismo , Gravidez , Proteínas de Ligação a RNA/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Trofoblastos/citologia , Trofoblastos/metabolismo
5.
Science ; 364(6437): 283-285, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31000662

RESUMO

Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example, BAP1 encodes a widely expressed deubiquitinase for histone H2A, but germline mutations are predominantly associated with uveal melanomas and mesotheliomas. We show that BAP1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, and pancreatic tissue but not in melanocytes and mesothelial cells. Ubiquitin ligase RNF2, which silences genes by monoubiquitinating H2A, promoted apoptosis in BAP1-deficient cells by suppressing expression of the prosurvival genes Bcl2 and Mcl1. In contrast, BAP1 loss in melanocytes had little impact on expression of prosurvival genes, instead inducing Mitf Thus, BAP1 appears to modulate gene expression by countering H2A ubiquitination, but its loss only promotes tumorigenesis in cells that do not engage an RNF2-dependent apoptotic program.


Assuntos
Apoptose/genética , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias Uveais/genética , Animais , Técnicas de Introdução de Genes , Mutação em Linhagem Germinativa , Histonas , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/patologia , Mesotelioma/genética , Mesotelioma/patologia , Camundongos , Camundongos Mutantes , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ubiquitinação , Neoplasias Uveais/patologia
6.
Proc Natl Acad Sci U S A ; 115(44): 11244-11249, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30322923

RESUMO

The E3 ubiquitin ligase CRL4COP1/DET1 is active in the absence of ERK signaling, modifying the transcription factors ETV1, ETV4, ETV5, and c-JUN with polyubiquitin that targets them for proteasomal degradation. Here we show that this posttranslational regulatory mechanism is active in neurons, with ETV5 and c-JUN accumulating within minutes of ERK activation. Mice with constitutive photomorphogenesis 1 (Cop1) deleted in neural stem cells showed abnormally elevated expression of ETV1, ETV4, ETV5, and c-JUN in the developing brain and spinal cord. Expression of c-JUN target genes Vimentin and Gfap was increased, whereas ETV5 and c-JUN both contributed to an expanded number of cells expressing genes associated with gliogenesis, including Olig1, Olig2, and Sox10. The mice had subtle morphological abnormalities in the cerebral cortex, hippocampus, and cerebellum by embryonic day 18 and died soon after birth. Elevated c-JUN, ETV5, and ETV1 contributed to the perinatal lethality, as several Cop1-deficient mice also lacking c-Jun and Etv5, or lacking Etv5 and heterozygous for Etv1, were viable.


Assuntos
Encéfalo/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fatores de Transcrição/metabolismo
7.
Epigenetics Chromatin ; 11(1): 13, 2018 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-29598828

RESUMO

BACKGROUND: Eukaryotic transcription is regulated through two complexes, the general transcription factor IID (TFIID) and the coactivator Spt-Ada-Gcn5 acetyltransferase (SAGA). Recent findings confirm that both TFIID and SAGA contribute to the synthesis of nearly all transcripts and are recruited genome-wide in yeast. However, how this broad recruitment confers selectivity under specific conditions remains an open question. RESULTS: Here we find that the SAGA/TREX-2 subunit Sus1 associates with upstream regulatory regions of many yeast genes and that heat shock drastically changes Sus1 binding. While Sus1 binding to TFIID-dominated genes is not affected by temperature, its recruitment to SAGA-dominated genes and RP genes is significantly disturbed under heat shock, with Sus1 relocated to environmental stress-responsive genes in these conditions. Moreover, in contrast to recent results showing that SAGA deubiquitinating enzyme Ubp8 is dispensable for RNA synthesis, genomic run-on experiments demonstrate that Sus1 contributes to synthesis and stability of a wide range of transcripts. CONCLUSIONS: Our study provides support for a model in which SAGA/TREX-2 factor Sus1 acts as a global transcriptional regulator in yeast but has differential activity at yeast genes as a function of their transcription rate or during stress conditions.


Assuntos
Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Estresse Fisiológico , Transcrição Genética , Regulação Fúngica da Expressão Gênica , Regiões Promotoras Genéticas , Ligação Proteica , RNA Fúngico/metabolismo , RNA Mensageiro/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Transativadores/genética , Transativadores/metabolismo
8.
Genome Res ; 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29444801

RESUMO

Gene expression is controlled by a variety of proteins that interact with the genome. Their precise organization and mechanism of action at every promoter remains to be worked out. To better understand the physical interplay among genome-interacting proteins, we examined the temporal binding of a functionally diverse subset of these proteins: nucleosomes (H3), H2AZ (Htz1), SWR (Swr1), RSC (Rsc1, Rsc3, Rsc58, Rsc6, Rsc9, Sth1), SAGA (Spt3, Spt7, Ubp8, Sgf11), Hsf1, TFIID (Spt15/TBP and Taf1), TFIIB (Sua7), TFIIH (Ssl2), FACT (Spt16), Pol II (Rpb3), and Pol II carboxyl-terminal domain (CTD) phosphorylation at serines 2, 5, and 7. They were examined under normal and acute heat shock conditions, using the ultrahigh resolution genome-wide ChIP-exo assay in Saccharomyces cerevisiae Our findings reveal a precise positional organization of proteins bound at most genes, some of which rapidly reorganize within minutes of heat shock. This includes more precise positional transitions of Pol II CTD phosphorylation along the 5' ends of genes than previously seen. Reorganization upon heat shock includes colocalization of SAGA with promoter-bound Hsf1, a change in RSC subunit enrichment from gene bodies to promoters, and Pol II accumulation within promoter/+1 nucleosome regions. Most of these events are widespread and not necessarily coupled to changes in gene expression. Together, these findings reveal protein-genome interactions that are robustly reprogrammed in precise and uniform ways far beyond what is elicited by changes in gene expression.

9.
EMBO J ; 35(13): 1465-82, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27225933

RESUMO

Nap1 is a histone chaperone involved in the nuclear import of H2A-H2B and nucleosome assembly. Here, we report the crystal structure of Nap1 bound to H2A-H2B together with in vitro and in vivo functional studies that elucidate the principles underlying Nap1-mediated H2A-H2B chaperoning and nucleosome assembly. A Nap1 dimer provides an acidic binding surface and asymmetrically engages a single H2A-H2B heterodimer. Oligomerization of the Nap1-H2A-H2B complex results in burial of surfaces required for deposition of H2A-H2B into nucleosomes. Chromatin immunoprecipitation-exonuclease (ChIP-exo) analysis shows that Nap1 is required for H2A-H2B deposition across the genome. Mutants that interfere with Nap1 oligomerization exhibit severe nucleosome assembly defects showing that oligomerization is essential for the chaperone function. These findings establish the molecular basis for Nap1-mediated H2A-H2B deposition and nucleosome assembly.


Assuntos
Histonas/química , Histonas/metabolismo , Proteína 1 de Modelagem do Nucleossomo/química , Proteína 1 de Modelagem do Nucleossomo/metabolismo , Nucleossomos/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Imunoprecipitação da Cromatina , Cristalografia por Raios X , Análise Mutacional de DNA , Modelos Moleculares , Proteína 1 de Modelagem do Nucleossomo/genética , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética
10.
Genes Dev ; 29(18): 1942-54, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26385964

RESUMO

The 137 ribosomal protein genes (RPGs) of Saccharomyces provide a model for gene coregulation. We examined the positional and functional organization of their regulators (Rap1 [repressor activator protein 1], Fhl1, Ifh1, Sfp1, and Hmo1), the transcription machinery (TFIIB, TFIID, and RNA polymerase II), and chromatin at near-base-pair resolution using ChIP-exo, as RPGs are coordinately reprogrammed. Where Hmo1 is enriched, Fhl1, Ifh1, Sfp1, and Hmo1 cross-linked broadly to promoter DNA in an RPG-specific manner and demarcated by general minor groove widening. Importantly, Hmo1 extended 20-50 base pairs (bp) downstream from Fhl1. Upon RPG repression, Fhl1 remained in place. Hmo1 dissociated, which was coupled to an upstream shift of the +1 nucleosome, as reflected by the Hmo1 extension and core promoter region. Fhl1 and Hmo1 may create two regulatable and positionally distinct barriers, against which chromatin remodelers position the +1 nucleosome into either an activating or a repressive state. Consistent with in vitro studies, we found that specific TFIID subunits, in addition to cross-linking at the core promoter, made precise cross-links at Rap1 sites, which we interpret to reflect native Rap1-TFIID interactions. Our findings suggest how sequence-specific DNA binding regulates nucleosome positioning and transcription complex assembly >300 bp away and how coregulation coevolved with coding sequences.


Assuntos
Regulação Fúngica da Expressão Gênica , Proteínas Ribossômicas/genética , Proteínas de Saccharomyces cerevisiae/genética , Nucleossomos/metabolismo , Proteínas Ribossômicas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
11.
Cell ; 162(5): 1016-28, 2015 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-26317468

RESUMO

Nuclear pore complexes (NPCs) influence gene expression besides their established function in nuclear transport. The TREX-2 complex localizes to the NPC basket and affects gene-NPC interactions, transcription, and mRNA export. How TREX-2 regulates the gene expression machinery is unknown. Here, we show that TREX-2 interacts with the Mediator complex, an essential regulator of RNA Polymerase (Pol) II. Structural and biochemical studies identify a conserved region on TREX-2, which directly binds the Mediator Med31/Med7N submodule. TREX-2 regulates assembly of Mediator with the Cdk8 kinase and is required for recruitment and site-specific phosphorylation of Pol II. Transcriptome and phenotypic profiling confirm that TREX-2 and Med31 are functionally interdependent at specific genes. TREX-2 additionally uses its Mediator-interacting surface to regulate mRNA export suggesting a mechanism for coupling transcription initiation and early steps of mRNA processing. Our data provide mechanistic insight into how an NPC-associated adaptor complex accesses the core transcription machinery.


Assuntos
Complexo Mediador/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas de Transporte Nucleocitoplasmático/química , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Porinas/química , Porinas/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transcrição Genética , Sequência de Aminoácidos , Animais , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Complexos Multiproteicos/química , Poro Nuclear/metabolismo , Proteínas de Transporte Nucleocitoplasmático/genética , Porinas/genética , Regiões Promotoras Genéticas , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Polimerase II/metabolismo , Ribonucleoproteínas/química , Ribonucleoproteínas/metabolismo , Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Alinhamento de Sequência , Transcriptoma , Difração de Raios X
12.
BMC Genomics ; 10 Suppl 3: S20, 2009 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-19958484

RESUMO

BACKGROUND: Mitochondria play a vital role in the energy production and apoptotic process of eukaryotic cells. Proteins in the mitochondria are encoded by nuclear and mitochondrial genes. Owing to a large increase in the number of identified mitochondrial protein sequences and completed mitochondrial genomes, it has become necessary to provide a web-based database of mitochondrial protein information. RESULTS: We present 'MitoInteractome', a consolidated web-based portal containing a wealth of information on predicted protein-protein interactions, physico-chemical properties, polymorphism, and diseases related to the mitochondrial proteome. MitoInteractome contains 6,549 protein sequences which were extracted from the following databases: SwissProt, MitoP, MitoProteome, HPRD and Gene Ontology database. The first general mitochondrial interactome has been constructed based on the concept of 'homologous interaction' using PSIMAP (Protein Structural Interactome MAP) and PEIMAP (Protein Experimental Interactome MAP). Using the above mentioned methods, protein-protein interactions were predicted for 74 species. The mitochondrial protein interaction data of humans was used to construct a network for the aging process. Analysis of the 'aging network' gave us vital insights into the interactions among proteins that influence the aging process. CONCLUSION: MitoInteractome is a comprehensive database that would (1) aid in increasing our understanding of the molecular functions and interaction networks of mitochondrial proteins, (2) help in identifying new target proteins for experimental research using predicted protein-protein interaction information, and (3) help in identifying biomarkers for diagnosis and new molecular targets for drug development related to mitochondria. MitoInteractome is available at http://mitointeractome.kobic.kr/.


Assuntos
Envelhecimento , Bases de Dados de Proteínas , Proteínas Mitocondriais/análise , Proteoma/análise , Análise de Sequência de Proteína/métodos , Biologia Computacional , Humanos , Internet , Proteínas Mitocondriais/química , Proteoma/química
13.
Genome Res ; 19(9): 1622-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19470904

RESUMO

We present the first Korean individual genome sequence (SJK) and analysis results. The diploid genome of a Korean male was sequenced to 28.95-fold redundancy using the Illumina paired-end sequencing method. SJK covered 99.9% of the NCBI human reference genome. We identified 420,083 novel single nucleotide polymorphisms (SNPs) that are not in the dbSNP database. Despite a close similarity, significant differences were observed between the Chinese genome (YH), the only other Asian genome available, and SJK: (1) 39.87% (1,371,239 out of 3,439,107) SNPs were SJK-specific (49.51% against Venter's, 46.94% against Watson's, and 44.17% against the Yoruba genomes); (2) 99.5% (22,495 out of 22,605) of short indels (< 4 bp) discovered on the same loci had the same size and type as YH; and (3) 11.3% (331 out of 2920) deletion structural variants were SJK-specific. Even after attempting to map unmapped reads of SJK to unanchored NCBI scaffolds, HGSV, and available personal genomes, there were still 5.77% SJK reads that could not be mapped. All these findings indicate that the overall genetic differences among individuals from closely related ethnic groups may be significant. Hence, constructing reference genomes for minor socio-ethnic groups will be useful for massive individual genome sequencing.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Genoma Humano/genética , Análise de Sequência de DNA/métodos , Biologia Computacional/métodos , Bases de Dados Genéticas , Feminino , Genômica/métodos , Humanos , Mutação INDEL , Coreia (Geográfico) , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Padrões de Referência
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