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1.
Hum Gene Ther ; 30(7): 814-828, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30793977

RESUMO

This study identified 35 new sites for targeted transgene insertion that have the potential to serve as new human genomic "safe harbor" sites (SHS). SHS potential for these 35 sites, located on 16 chromosomes, including both arms of the human X chromosome, and for the existing human SHS AAVS1, hROSA26, and CCR5 was assessed using eight different desirable, widely accepted criteria for SHS verifiable with human genomic data. Three representative newly identified sites on human chromosomes 2 and 4 were then experimentally validated by in vitro and in vivo cleavage-sensitivity tests, and analyzed for population-level and cell line-specific sequence variants that might confound site targeting. The highly ranked site on chromosome 4 (SHS231) was further characterized by targeted homology-dependent and -independent transgene insertion and expression in different human cell lines. The structure and fidelity of transgene insertions at this site were confirmed, together with analyses that demonstrated stable expression and function of transgene-encoded proteins, including fluorescent protein markers, selectable marker cassettes, and Cas9 protein variants. SHS-integrated transgene-encoded Cas9 proteins were shown to be capable of introducing a large (17 kb) gRNA-specified deletion in the PAX3/FOXO1 fusion oncogene in human rhabdomyosarcoma cells and as a Cas9-VPR fusion protein to upregulate expression of the muscle-specific transcription factor MYF5 in human rhabdomyosarcoma cells. An engineering "toolkit" was developed to enable easy use of the most extensively characterized of these new human sites, SHS231, located on the proximal long arm of chromosome 4. The target sites identified here have the potential to serve as additional human SHS to enable basic and clinical gene editing and genome-engineering applications.

2.
Science ; 361(6401): 511-516, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30072539

RESUMO

Flores Island, Indonesia, was inhabited by the small-bodied hominin species Homo floresiensis, which has an unknown evolutionary relationship to modern humans. This island is also home to an extant human pygmy population. Here we describe genome-scale single-nucleotide polymorphism data and whole-genome sequences from a contemporary human pygmy population living on Flores near the cave where H. floresiensis was found. The genomes of Flores pygmies reveal a complex history of admixture with Denisovans and Neanderthals but no evidence for gene flow with other archaic hominins. Modern individuals bear the signatures of recent positive selection encompassing the FADS (fatty acid desaturase) gene cluster, likely related to diet, and polygenic selection acting on standing variation that contributed to their short-stature phenotype. Thus, multiple independent instances of hominin insular dwarfism occurred on Flores.


Assuntos
Adaptação Biológica/genética , Evolução Biológica , Estatura/genética , Nanismo/genética , Ilhas , População/genética , Seleção Genética , Animais , Fluxo Gênico , Genoma Humano , Humanos , Indonésia , Homem de Neandertal/genética
3.
Hum Mutat ; 38(2): 193-203, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27859906

RESUMO

Heritable loss of function mutations in the human RECQ helicase genes BLM, WRN, and RECQL4 cause Bloom, Werner, and Rothmund-Thomson syndromes, cancer predispositions with additional developmental or progeroid features. In order to better understand RECQ pathogenic and population variation, we systematically analyzed genetic variation in all five human RECQ helicase genes. A total of 3,741 unique base pair-level variants were identified, across 17,605 potential mutation sites. Direct counting of BLM, RECQL4, and WRN pathogenic variants was used to determine aggregate and disease-specific carrier frequencies. The use of biochemical and model organism data, together with computational prediction, identified over 300 potentially pathogenic population variants in RECQL and RECQL5, the two RECQ helicases that are not yet linked to a heritable deficiency syndrome. Despite the presence of these predicted pathogenic variants in the human population, we identified no individuals homozygous for any biochemically verified or predicted pathogenic RECQL or RECQL5 variant. Nor did we find any individual heterozygous for known pathogenic variants in two or more of the disease-associated RECQ helicase genes BLM, RECQL4, or WRN. Several postulated RECQ helicase deficiency syndromes-RECQL or RECQL5 loss of function, or compound haploinsufficiency for the disease-associated RECQ helicases-may remain missing, as they likely incompatible with life.


Assuntos
Estudos de Associação Genética , Genética Populacional , Mutação , RecQ Helicases/genética , Biologia Computacional/métodos , Análise Mutacional de DNA , Bases de Dados de Ácidos Nucleicos , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Curva ROC , Software , Navegador
4.
Am J Hum Genet ; 99(5): 1106-1116, 2016 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-27745837

RESUMO

Identifying and characterizing genomic regions that are shared identical by descent (IBD) among individuals can yield insight into population history, facilitate the identification of adaptively evolving loci, and be an important tool in disease gene mapping. Although increasingly large collections of exome sequences have been generated, it is challenging to detect IBD segments in exomes, precluding many potentially informative downstream analyses. Here, we describe an approach, ExIBD, to robustly detect IBD segments in exome-sequencing data, rigorously evaluate its performance, and apply this method to high-coverage exomes from 6,515 European and African Americans. Furthermore, we show how IBD networks, constructed from patterns of pairwise IBD between individuals, and principles from graph theory provide insight into recent population history and reveal cryptic population structure in European Americans. Our results enable IBD analyses to be performed on exome data, which will expand the scope of inferences that can be made from existing massively large exome-sequencing datasets.


Assuntos
Bases de Dados Genéticas , Exoma , Genética Populacional/métodos , Análise de Sequência de DNA , Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano , Genômica , Técnicas de Genotipagem , Humanos , Modelos Biológicos , Polimorfismo de Nucleotídeo Único
5.
Nat Commun ; 7: 12522, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27725671

RESUMO

The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Fluxo Gênico , Genoma Humano , Migração Humana , Sequência de Bases , DNA Intergênico/genética , Feminino , Heterogeneidade Genética , Geografia , Humanos , Masculino , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Sexismo
6.
Curr Biol ; 26(14): 1791-801, 2016 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-27345162

RESUMO

Mutations in genes encoding autophagy proteins have been associated with human autoimmune diseases, suggesting that diversity in autophagy responses could be associated with disease susceptibility or severity. A cellular genome-wide association study (GWAS) screen was performed to explore normal human diversity in responses to rapamycin, a microbial product that induces autophagy. Cells from several human populations demonstrated variability in expression of a cell surface receptor, CD244 (SlamF4, 2B4), that correlated with changes in rapamycin-induced autophagy. High expression of CD244 and receptor activation with its endogenous ligand CD48 inhibited starvation- and rapamycin-induced autophagy by promoting association of CD244 with the autophagy complex proteins Vps34 and Beclin-1. The association of CD244 with this complex reduced Vps34 lipid kinase activity. Lack of CD244 is associated with auto-antibody production in mice, and lower expression of human CD244 has previously been implicated in severity of human rheumatoid arthritis and systemic lupus erythematosus, indicating that increased autophagy as a result of low levels of CD244 may alter disease outcomes.


Assuntos
Autofagia/genética , Expressão Gênica , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Proteína Beclina-1/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo
7.
Hum Mol Genet ; 24(5): 1225-33, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25324539

RESUMO

Non-allelic homologous recombination (NAHR) is one of the key mechanisms of DNA rearrangement. NAHR occurring between direct homologous repeats can generate genomic copy number variation (CNV) and make significant contributions to both genome evolution and human diseases such as cancer. Intriguingly, previous observations on the rare CNVs at certain genomic disorder loci suggested that NAHR frequency could be dependent on homology properties. However, such a correlation remains unclear at the other NAHR-mediated CNV loci, especially the common CNVs in human populations. Different from the rare CNVs associated with genomic disorders, it is challenging to identify de novo NAHR events at common CNV loci. Therefore, our previously proposed statistic M was employed in estimating relative mutation rate for the NAHR-mediated CNVs in human populations. By utilizing generalized regression neural network and principal component analysis in studying 4330 CNVs ascertained in 3 HapMap populations, we identified the CNVs mediated by NAHR between paired segmental duplications (SDs) and further revealed the correlations between SD properties and NAHR probability. SD length and inter-SD distance were shown to make major contributions to the occurrence of NAHR, whereas chromosomal position and sequence similarity of paired SDs are also involved in NAHR. An integrated effect of SD properties on NAHR frequency was revealed for the common CNVs in human populations. These observations can be well explained by ectopic synapsis in NAHR together with our proposed model of chromosomal compression/extension/looping (CCEL) for homology mis-pairing. Our findings showed the important roles of SDs in NAHR and human genomic evolution.


Assuntos
Variações do Número de Cópias de DNA , Genoma Humano , Recombinação Homóloga , Alelos , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , Evolução Molecular , Rearranjo Gênico , Loci Gênicos , Genômica , Humanos , Modelos Teóricos , Taxa de Mutação , Análise de Componente Principal , Sequências Repetitivas de Ácido Nucleico , Duplicações Segmentares Genômicas , Alinhamento de Sequência
8.
Mol Biol Evol ; 32(3): 653-60, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25415970

RESUMO

Understanding the genetic structure of human populations has important implications for the design and interpretation of disease mapping studies and reconstructing human evolutionary history. To date, inferences of human population structure have primarily been made with common variants. However, recent large-scale resequencing studies have shown an abundance of rare variation in humans, which may be particularly useful for making inferences of fine-scale population structure. To this end, we used an information theory framework and extensive coalescent simulations to rigorously quantify the informativeness of rare and common variation to detect signatures of fine-scale population structure. We show that rare variation affords unique insights into patterns of recent population structure. Furthermore, to empirically assess our theoretical findings, we analyzed high-coverage exome sequences in 6,515 European and African American individuals. As predicted, rare variants are more informative than common polymorphisms in revealing a distinct cluster of European-American individuals, and subsequent analyses demonstrate that these individuals are likely of Ashkenazi Jewish ancestry. Our results provide new insights into the population structure using rare variation, which will be an important factor to account for in rare variant association studies.


Assuntos
Exoma/genética , Genética Populacional/métodos , Grupos Étnicos/genética , Humanos , Teoria da Informação , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal
9.
Arch Dermatol Res ; 307(2): 171-81, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25501647

RESUMO

Neuropeptide substance P (SP) and reactive oxygen species (ROS) have been demonstrated to play an important role in psychological stress-induced alteration of hair cycle, the underlying mechanism remains unknown. The present study aims to investigate possible contribution of SP and ROS in chronic restraint stress (CRS, a chronic psychological stress model) induced abnormal of hair cycle and induction of autophagy. Mouse CRS model was applied for 18 days with or without treatment antioxidant Tempol (a free radical scavenger) or SP receptor (NK1) antagonist (RP67580). After CRS procedure, hair growth cycle, oxidative stress markers and skin tissue autophagy levels were analyzed by ELISA or western blot. Our results revealed that CRS reduced body weight gain, distance of movement and times of standing, affected hair cycle by prolonging the telogen stage and delaying subsequent anagen and catagen stage. In addition, CRS resulted in increase of lipid peroxidation levels and reduction of the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and increase of autophagy markers (microtubule-associated proteins, light chain 3-II, LC3-II, and Beclin-1) in mice skin. Treatment with Tempol restored GSH-Px activity, and significantly reduced increases of lipid peroxidation levels and LC3-II and Beclin-1 expressions, as well as normalized hair cycle. In addition; RP67580 also restored SOD and GSH-Px activities, and markedly reduced increases of lipid peroxidation levels and LC3-II and Beclin-1 expressions, and normalized hair cycle. Our study provides the first strong evidence for SP and ROS play a role not only in alteration of hair cycle but also in induction of autophagy in psychological stress model, suggesting autophagy may contribute to psychological stress-induced abnormal of hair cycle.


Assuntos
Autofagia , Cabelo/crescimento & desenvolvimento , Estresse Oxidativo/fisiologia , Estresse Psicológico/metabolismo , Substância P/metabolismo , Animais , Antioxidantes/farmacologia , Western Blotting/métodos , Óxidos N-Cíclicos/farmacologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Glutationa Peroxidase/metabolismo , Isoindóis , Peroxidação de Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Marcadores de Spin , Superóxido Dismutase/metabolismo
10.
Am J Hum Genet ; 95(4): 421-36, 2014 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-25279984

RESUMO

Whole-genome and exome data sets continue to be produced at a frenetic pace, resulting in massively large catalogs of human genomic variation. However, a clear picture of the characteristics and patterns of neutral and deleterious variation within and between populations has yet to emerge, given that recent large-scale sequencing studies have often emphasized different aspects of the data and sometimes appear to have conflicting conclusions. Here, we comprehensively studied characteristics of protein-coding variation in high-coverage exome sequence data from 6,515 European American (EA) and African American (AA) individuals. We developed an unbiased approach to identify putatively deleterious variants and investigated patterns of neutral and deleterious single-nucleotide variants and alleles between individuals and populations. We show that there are substantial differences in the composition of genotypes between EA and AA populations and that small but statistically significant differences exist in the average number of deleterious alleles carried by EA and AA individuals. Furthermore, we performed extensive simulations to delineate the temporal dynamics of deleterious alleles for a broad range of demographic models and use these data to inform the interpretation of empirical patterns of deleterious variation. Finally, we illustrate that the effects of demographic perturbations, such as bottlenecks and expansions, often manifest in opposing patterns of neutral and deleterious variation depending on whether the focus is on populations or individuals. Our results clarify seemingly disparate empirical characteristics of protein-coding variation and provide substantial insights into how natural selection and demographic history have patterned neutral and deleterious variation within and between populations.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Exoma/genética , Éxons/genética , Genética Populacional , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , África/etnologia , Europa (Continente)/etnologia , Evolução Molecular , Deriva Genética , Genoma Humano , Humanos , Modelos Teóricos , Seleção Genética
11.
Hum Mol Genet ; 23(25): 6815-25, 2014 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-25104853

RESUMO

Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population genetic variation in FANC genes and the segregation of this variation in the human population, we identified 2948 unique FANC gene variants including 493 FA DA variants across 57,240 potential base pair variation sites in the 16 FANC genes. We then analyzed the segregation of this variation in the 7578 subjects included in the Exome Sequencing Project (ESP) and the 1000 Genomes Project (1KGP). There was a remarkably high frequency of FA DA variants in ESP/1KGP subjects: at least 1 FA DA variant was identified in 78.5% (5950 of 7578) individuals included in these two studies. Six widely used functional prediction algorithms correctly identified only a third of the known, DA FANC missense variants. We also identified FA DA variants that may be good candidates for different types of mutation-specific therapies. Our results demonstrate the power of direct DNA sequencing to detect, estimate the frequency of and follow the segregation of deleterious genetic variation in human populations.


Assuntos
Exoma , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Variação Genética , Família Multigênica , Algoritmos , Proteína BRCA2/genética , Proteínas de Ligação a DNA/genética , Anemia de Fanconi/patologia , Proteína do Grupo de Complementação N da Anemia de Fanconi , Expressão Gênica , Genes Recessivos , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Taxa de Mutação , Proteínas Nucleares/genética , RNA Helicases/genética , Proteínas Supressoras de Tumor/genética
12.
PLoS One ; 9(8): e105691, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25170956

RESUMO

Demographic change of human populations is one of the central questions for delving into the past of human beings. To identify major population expansions related to male lineages, we sequenced 78 East Asian Y chromosomes at 3.9 Mbp of the non-recombining region, discovered >4,000 new SNPs, and identified many new clades. The relative divergence dates can be estimated much more precisely using a molecular clock. We found that all the Paleolithic divergences were binary; however, three strong star-like Neolithic expansions at ∼6 kya (thousand years ago) (assuming a constant substitution rate of 1×10(-9)/bp/year) indicates that ∼40% of modern Chinese are patrilineal descendants of only three super-grandfathers at that time. This observation suggests that the main patrilineal expansion in China occurred in the Neolithic Era and might be related to the development of agriculture.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Y/genética , Genética Populacional/métodos , Polimorfismo de Nucleotídeo Único , Algoritmos , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , China , Cromossomos Humanos Y/classificação , Variação Genética , Genética Populacional/estatística & dados numéricos , Genótipo , Geografia , Haplótipos , Humanos , Masculino , Modelos Genéticos , Taxa de Mutação , Filogenia , Dinâmica Populacional , Análise de Sequência de DNA , Fatores de Tempo
13.
Science ; 342(6164): 1367-72, 2013 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-24337295

RESUMO

Genomes contain both a genetic code specifying amino acids and a regulatory code specifying transcription factor (TF) recognition sequences. We used genomic deoxyribonuclease I footprinting to map nucleotide resolution TF occupancy across the human exome in 81 diverse cell types. We found that ~15% of human codons are dual-use codons ("duons") that simultaneously specify both amino acids and TF recognition sites. Duons are highly conserved and have shaped protein evolution, and TF-imposed constraint appears to be a major driver of codon usage bias. Conversely, the regulatory code has been selectively depleted of TFs that recognize stop codons. More than 17% of single-nucleotide variants within duons directly alter TF binding. Pervasive dual encoding of amino acid and regulatory information appears to be a fundamental feature of genome evolution.


Assuntos
Códon/genética , Evolução Molecular , Exoma , Éxons , Genoma Humano , Fatores de Transcrição/metabolismo , Pegada de DNA , Desoxirribonuclease I/química , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética
14.
Curr Opin Genet Dev ; 23(6): 678-83, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24287334

RESUMO

More than 150 years after Mendel discovered the laws of heredity, the genetic architecture of phenotypic variation remains elusive. Here, we discuss recent progress in deciphering how genotypes map onto phenotypes, sources of genetic complexity, and how model organisms are illuminating general principles about the relationship between genetic and phenotypic variation. Moreover, we highlight insights gleaned from large-scale sequencing studies in humans, and how this knowledge informs outstanding questions about the genetic architecture of quantitative traits and complex diseases. Finally, we articulate how the confluence of technologies enabling whole-genome sequencing, comprehensive phenotyping, and high-throughput functional assays of polymorphisms will facilitate a more principled and mechanistic understanding of the genetic architecture of phenotypic variation.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Locos de Características Quantitativas/genética , Interação Gene-Ambiente , Genótipo , Humanos , Modelos Genéticos , Fenótipo
15.
Annu Rev Genomics Hum Genet ; 14: 467-89, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23834317

RESUMO

An enduring goal of evolutionary biology is to understand how natural selection has shaped patterns of polymorphism and divergence within and between species and to map the genetic basis of adaptations. The rapid maturation of next-generation sequencing technology has generated a deluge of genomics data from nonhuman primates, extinct hominins, and diverse human populations. These emerging genome data sets have simultaneously broadened our understanding of human evolution and sharply defined existing gaps in knowledge about the mechanistic basis of evolutionary change. In this review, we summarize recent insights into how natural selection has influenced the human genome across different timescales. Although the path to a more comprehensive understanding of selection and adaptation in humans remains arduous, some general insights are beginning to emerge, such as the importance of adaptive regulatory evolution, the absence of pervasive classic selective sweeps, and the potential roles that selection from standing variation and polygenic adaptation have likely played in recent human evolutionary history.


Assuntos
Evolução Molecular , Genoma Humano , Seleção Genética , Animais , Sequenciamento de Nucleotídeos em Larga Escala , Hominidae/genética , Humanos , Análise de Sequência de DNA
16.
Virology ; 443(2): 329-37, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23755966

RESUMO

There are seven members of the APOBEC3 family in humans (APOBEC3A through APOBEC3H) that have antiviral activity against retroviruses and/or retroelements. To determine whether variants in APOBEC3 genes in human populations have altered antiviral activity, we identified and functionally tested novel single nucleotide variants (SNVs) in APOBEC3 genes present in the 1000 Genome Project dataset. We found that common variants minor allele frequency (> 1%) of APOBEC3A, C, F, and G do not affect protein function. However, we found that two common novel polymorphisms in APOBEC3D decrease antiviral activity against HIV-1, and one polymorphism decreases activity against Alu retrotransposons. We characterized the diversity of APOBEC3 genes in three human populations and find significant evidence that APOBEC3D has evolved under purifying selection in recent human history. These data suggest that the activity of APOBEC3D has been maintained in human populations for a cellular function in host defense.


Assuntos
Antivirais/farmacologia , Citidina Desaminase/genética , Citidina Desaminase/farmacologia , Citosina Desaminase/genética , HIV-1/efeitos dos fármacos , Polimorfismo Genético , Elementos Alu/efeitos dos fármacos , Elementos Alu/genética , Citosina Desaminase/metabolismo , Evolução Molecular , Frequência do Gene , Genética Populacional , Genoma Humano/genética , Humanos
17.
PLoS One ; 8(4): e61574, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23637859

RESUMO

BACKGROUNDS: Solid evidence has demonstrated that psychoemotional stress induced alteration of hair cycle through neuropeptide substance P (SP) mediated immune response, the role of reactive oxygen species (ROS) in brain-skin-axis regulation system remains unknown. OBJECTIVES: The present study aims to investigate possible mechanisms of ROS in regulation of SP-mast cell signal pathway in chronic restraint stress (CRS, a model of chronic psychoemotional stress) which induced abnormal of hair cycle. METHODS AND RESULTS: Our results have demonstrated that CRS actually altered hair cycle by inhibiting hair follicle growth in vivo, prolonging the telogen stage and delaying subsequent anagen and catagen stage. Up-regulation of SP protein expression in cutaneous peripheral nerve fibers and activation of mast cell were observed accompanied with increase of lipid peroxidation levels and reduction of the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in CRS mice skin. In addition, SP receptor antagonist (RP67580) reduced mast cell activations and lipid peroxidation levels as well as increased GSH-Px activity and normalized hair cycle. Furthermore, antioxidant Tempol (a free radical scavenger) also restored hair cycle, reduced SP protein expression and mast cell activation. CONCLUSIONS: Our study provides the first solid evidence for how ROS play a role in regulation of psychoemotional stress induced SP-Mast cell pathway which may provide a convincing rationale for antioxidant application in clinical treatment with psychological stress induced hair loss.


Assuntos
Cabelo/crescimento & desenvolvimento , Espécies Reativas de Oxigênio/metabolismo , Restrição Física , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Substância P/metabolismo , Animais , Antioxidantes/farmacologia , Doença Crônica , Corticosterona/sangue , Derme/efeitos dos fármacos , Derme/enzimologia , Derme/patologia , Glutationa Peroxidase/metabolismo , Cabelo/efeitos dos fármacos , Cabelo/metabolismo , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/crescimento & desenvolvimento , Folículo Piloso/patologia , Masculino , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas do Receptor de Neuroquinina-1 , Estresse Oxidativo/efeitos dos fármacos , Receptores da Neurocinina-1/metabolismo , Estresse Psicológico/sangue , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Ganho de Peso/efeitos dos fármacos
18.
Nature ; 493(7431): 216-20, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23201682

RESUMO

Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.


Assuntos
Evolução Molecular , Exoma/genética , Variação Genética/genética , Fases de Leitura Aberta/genética , África/etnologia , Grupo com Ancestrais do Continente Africano/genética , Alelos , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Éxons/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos
19.
Science ; 338(6114): 1619-22, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23160955

RESUMO

Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes-CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1-may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a ß-catenin-chromatin-remodeling network to ASD etiology.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Estudos de Associação Genética , Mutação , Análise de Sequência de DNA/métodos , Cefalometria , Criança , Pré-Escolar , Montagem e Desmontagem da Cromatina , Estudos de Coortes , Sondas de DNA , Proteínas de Ligação a DNA/genética , Exoma , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Megalencefalia/genética , Microcefalia/genética , Proteínas Nucleares/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Receptores Citoplasmáticos e Nucleares/genética , Receptores de N-Metil-D-Aspartato/genética , Proteínas Repressoras/genética , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , beta Catenina/genética , beta Catenina/metabolismo
20.
PLoS One ; 7(9): e44926, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23028684

RESUMO

Long chain polyunsaturated fatty acids (LC-PUFAs) are essential for brain structure, development, and function, and adequate dietary quantities of LC-PUFAs are thought to have been necessary for both brain expansion and the increase in brain complexity observed during modern human evolution. Previous studies conducted in largely European populations suggest that humans have limited capacity to synthesize brain LC-PUFAs such as docosahexaenoic acid (DHA) from plant-based medium chain (MC) PUFAs due to limited desaturase activity. Population-based differences in LC-PUFA levels and their product-to-substrate ratios can, in part, be explained by polymorphisms in the fatty acid desaturase (FADS) gene cluster, which have been associated with increased conversion of MC-PUFAs to LC-PUFAs. Here, we show evidence that these high efficiency converter alleles in the FADS gene cluster were likely driven to near fixation in African populations by positive selection ∼85 kya. We hypothesize that selection at FADS variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60-80 kya.


Assuntos
Adaptação Fisiológica/genética , Grupo com Ancestrais do Continente Africano/genética , Evolução Molecular , Ácidos Graxos Dessaturases/genética , Família Multigênica/genética , África , Grupo com Ancestrais do Continente Europeu/genética , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/metabolismo , Frequência do Gene , Humanos
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