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1.
Nat Commun ; 14(1): 3377, 2023 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-37291107

RESUMO

The benefits of large-scale genetic studies for healthcare of the populations studied are well documented, but these genetic studies have traditionally ignored people from some parts of the world, such as South Asia. Here we describe whole genome sequence (WGS) data from 4806 individuals recruited from the healthcare delivery systems of Pakistan, India and Bangladesh, combined with WGS from 927 individuals from isolated South Asian populations. We characterize population structure in South Asia and describe a genotyping array (SARGAM) and imputation reference panel that are optimized for South Asian genomes. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of rare homozygotes that reach 100 times that seen in outbred populations. Founder effects increase the power to associate functional variants with disease processes and make South Asia a uniquely powerful place for population-scale genetic studies.


Assuntos
Povo Asiático , Efeito Fundador , Humanos , Povo Asiático/genética , Bangladesh , Homozigoto , Índia , Paquistão , População do Sul da Ásia
2.
Nat Hum Behav ; 6(9): 1292-1309, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35710621

RESUMO

Moving in synchrony to the beat is a fundamental component of musicality. Here we conducted a genome-wide association study to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat synchronization exhibited a highly polygenic architecture, with 69 loci reaching genome-wide significance (P < 5 × 10-8) and single-nucleotide-polymorphism-based heritability (on the liability scale) of 13%-16%. Heritability was enriched for genes expressed in brain tissues and for fetal and adult brain-specific gene regulatory elements, underscoring the role of central-nervous-system-expressed genes linked to the genetic basis of the trait. We performed validations of the self-report phenotype (through separate experiments) and of the genome-wide association study (polygenic scores for beat synchronization were associated with patients algorithmically classified as musicians in medical records of a separate biobank). Genetic correlations with breathing function, motor function, processing speed and chronotype suggest shared genetic architecture with beat synchronization and provide avenues for new phenotypic and genetic explorations.


Assuntos
Estudo de Associação Genômica Ampla , Música , Humanos , Herança Multifatorial/genética , Nucleotídeos , Polimorfismo de Nucleotídeo Único/genética
3.
Commun Biol ; 4(1): 475, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846513

RESUMO

COVID-19 is a respiratory illness caused by a novel coronavirus called SARS-CoV-2. The viral spike (S) protein engages the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells with ~10-15-fold higher affinity compared to SARS-CoV S-protein, making it highly infectious. Here, we assessed if ACE2 polymorphisms can alter host susceptibility to SARS-CoV-2 by affecting this interaction. We analyzed over 290,000 samples representing >400 population groups from public genomic datasets and identified multiple ACE2 protein-altering variants. Using reported structural data, we identified natural ACE2 variants that could potentially affect virus-host interaction and thereby alter host susceptibility. These include variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R that were predicted to increase susceptibility, while variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y were predicted to be protective variants that show decreased binding to S-protein. Using biochemical assays, we confirmed that K31R and E37K had decreased affinity, and K26R and T92I variants showed increased affinity for S-protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 K26R and T92I were more effective in blocking entry of S-protein pseudotyped virus suggesting that ACE2 variants can modulate susceptibility to SARS-CoV-2.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto/genética , Polimorfismo Genético , Receptores Virais/genética , Sequência de Aminoácidos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , Receptores Virais/química , Receptores Virais/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Homologia de Sequência de Aminoácidos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
4.
Science ; 371(6536)2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33766859

RESUMO

Hamer et al argue that the variable "ever versus never had a same-sex partner" does not capture the complexity of human sexuality. We agree and said so in our paper. But Hamer et al neglect to mention that we also reported follow-up analyses showing substantial overlap of the genetic influences on our main variable and on more nuanced measures of sexual behavior, attraction, and identity.


Assuntos
Estudo de Associação Genômica Ampla , Comportamento Sexual , Humanos , Resolução de Problemas
7.
Am J Hum Genet ; 105(5): 921-932, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31607426

RESUMO

Meiotic nondisjunction and resulting aneuploidy can lead to severe health consequences in humans. Aneuploidy rescue can restore euploidy but may result in uniparental disomy (UPD), the inheritance of both homologs of a chromosome from one parent with no representative copy from the other. Current understanding of UPD is limited to ∼3,300 case subjects for which UPD was associated with clinical presentation due to imprinting disorders or recessive diseases. Thus, the prevalence of UPD and its phenotypic consequences in the general population are unknown. We searched for instances of UPD across 4,400,363 consented research participants from the personal genetics company 23andMe, Inc., and 431,094 UK Biobank participants. Using computationally detected DNA segments identical-by-descent (IBD) and runs of homozygosity (ROH), we identified 675 instances of UPD across both databases. We estimate that UPD is twice as common as previously thought, and we present a machine-learning framework to detect UPD using ROH. While we find a nominally significant association between UPD of chromosome 22 and autism risk, we do not find significant associations between UPD and deleterious traits in the 23andMe database.


Assuntos
Dissomia Uniparental/genética , Aneuploidia , Feminino , Impressão Genômica/genética , Homozigoto , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Prevalência
8.
Science ; 365(6456)2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31467194

RESUMO

Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.


Assuntos
Homossexualidade Feminina/genética , Homossexualidade Masculina/genética , Locos de Características Quantitativas , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Reino Unido
9.
Nat Commun ; 10(1): 1052, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837455

RESUMO

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.


Assuntos
Loci Gênicos/imunologia , Predisposição Genética para Doença , Fatores Imunológicos/genética , Úlceras Orais/genética , Estomatite Aftosa/genética , Adulto , Idoso , Estudos de Coortes , Simulação por Computador , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fatores Imunológicos/imunologia , Masculino , Pessoa de Meia-Idade , Úlceras Orais/imunologia , Estomatite Aftosa/imunologia , Linfócitos T/imunologia
10.
Nat Commun ; 9(1): 1178, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29563502

RESUMO

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3-2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10-8) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease.


Assuntos
Fator 15 de Diferenciação de Crescimento/genética , Hiperêmese Gravídica/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Náusea/genética , Placenta/metabolismo , Complicações na Gravidez/genética , Vômito/genética , Adulto , Apetite/genética , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 4 , Estudos de Coortes , Feminino , Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Hiperêmese Gravídica/metabolismo , Hiperêmese Gravídica/fisiopatologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Náusea/etiologia , Náusea/metabolismo , Náusea/fisiopatologia , Fenótipo , Placenta/patologia , Gravidez , Complicações na Gravidez/metabolismo , Complicações na Gravidez/fisiopatologia , Locos de Características Quantitativas , Fatores de Risco , Índice de Gravidade de Doença , Vômito/metabolismo , Vômito/fisiopatologia
11.
Sci Transl Med ; 8(322): 322ra9, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26791950

RESUMO

More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.


Assuntos
Penetrância , Doenças Priônicas/genética , Estudos de Casos e Controles , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Mutação/genética , Príons/genética , Fatores de Risco
12.
J Clin Invest ; 123(12): 5212-30, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24200693

RESUMO

Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1+/- or Map1lc3B-/-) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 (Hdac6-/Y) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired Becn1-/-, Map1lc3B-/-, and Hdac6-/Y mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD.


Assuntos
Autofagia/fisiologia , Cílios/fisiologia , Histona Desacetilases/fisiologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Proteínas Reguladoras de Apoptose/deficiência , Proteína Beclina-1 , Células Cultivadas , Cílios/ultraestrutura , Citosol/enzimologia , Células Epiteliais/ultraestrutura , Feminino , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Varredura , Proteínas Associadas aos Microtúbulos/deficiência , Muco , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/fisiologia , Fenótipo , Fenilbutiratos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Sirtuína 1/deficiência , Sirtuína 1/fisiologia , Produtos do Tabaco , Traqueia/citologia , Ubiquitinação
13.
Genomics ; 101(5): 263-72, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23459001

RESUMO

Hedgehog interacting protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS). However, it remains unclear how HHIP contributes to COPD pathogenesis. To identify genes regulated by HHIP, we performed gene expression microarray analysis in a human bronchial epithelial cell line (Beas-2B) stably infected with HHIP shRNAs. HHIP silencing led to differential expression of 296 genes; enrichment for variants nominally associated with COPD was found. Eighteen of the differentially expressed genes were validated by real-time PCR in Beas-2B cells. Seven of 11 validated genes tested in human COPD and control lung tissues demonstrated significant gene expression differences. Functional annotation indicated enrichment for extracellular matrix and cell growth genes. Network modeling demonstrated that the extracellular matrix and cell proliferation genes influenced by HHIP tended to be interconnected. Thus, we identified potential HHIP targets in human bronchial epithelial cells that may contribute to COPD pathogenesis.


Assuntos
Proteínas de Transporte/metabolismo , Células Epiteliais/metabolismo , Glicoproteínas de Membrana/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Transcriptoma , Brônquios/metabolismo , Brônquios/patologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Linhagem Celular , Proliferação de Células , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Humanos , Pulmão/metabolismo , Pulmão/patologia , Glicoproteínas de Membrana/genética , Anotação de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Doença Pulmonar Obstrutiva Crônica/genética , RNA Interferente Pequeno/genética , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais , Regulação para Cima
14.
PLoS Comput Biol ; 8(7): e1002606, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22807668

RESUMO

The healthy microbiota show remarkable variability within and among individuals. In addition to external exposures, ecological relationships (both oppositional and symbiotic) between microbial inhabitants are important contributors to this variation. It is thus of interest to assess what relationships might exist among microbes and determine their underlying reasons. The initial Human Microbiome Project (HMP) cohort, comprising 239 individuals and 18 different microbial habitats, provides an unprecedented resource to detect, catalog, and analyze such relationships. Here, we applied an ensemble method based on multiple similarity measures in combination with generalized boosted linear models (GBLMs) to taxonomic marker (16S rRNA gene) profiles of this cohort, resulting in a global network of 3,005 significant co-occurrence and co-exclusion relationships between 197 clades occurring throughout the human microbiome. This network revealed strong niche specialization, with most microbial associations occurring within body sites and a number of accompanying inter-body site relationships. Microbial communities within the oropharynx grouped into three distinct habitats, which themselves showed no direct influence on the composition of the gut microbiota. Conversely, niches such as the vagina demonstrated little to no decomposition into region-specific interactions. Diverse mechanisms underlay individual interactions, with some such as the co-exclusion of Porphyromonaceae family members and Streptococcus in the subgingival plaque supported by known biochemical dependencies. These differences varied among broad phylogenetic groups as well, with the Bacilli and Fusobacteria, for example, both enriched for exclusion of taxa from other clades. Comparing phylogenetic versus functional similarities among bacteria, we show that dominant commensal taxa (such as Prevotellaceae and Bacteroides in the gut) often compete, while potential pathogens (e.g. Treponema and Prevotella in the dental plaque) are more likely to co-occur in complementary niches. This approach thus serves to open new opportunities for future targeted mechanistic studies of the microbial ecology of the human microbiome.


Assuntos
Bactérias/classificação , Fenômenos Fisiológicos Bacterianos , Metagenoma/fisiologia , Biologia Computacional , DNA Bacteriano/química , Ecossistema , Feminino , Trato Gastrointestinal/microbiologia , Genes de RNAr/genética , Humanos , Modelos Lineares , Masculino , Interações Microbianas/fisiologia , Cavidade Nasal/microbiologia , Filogenia , Pele/microbiologia , Vagina/microbiologia
15.
Nucleic Acids Res ; 39(6): 1967-79, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21062826

RESUMO

Ultraconservation, defined as perfect human-to-rodent sequence identity at least 200-bp long, is a strong indicator of evolutionary and functional importance and has been explored extensively at the genome level. However, it has not been investigated at the transcript level, where such extreme conservation might highlight loci with important post-transcriptional regulatory roles. We present 96 ultraconserved cDNA segments (UCSs), stretches of human mature mRNAs that match identically with orthologous regions in the mouse and rat genomes. UCSs can span multiple exons, a feature we leverage here to elucidate the role of ultraconservation in post-transcriptional regulation. UCS sites are implicated in functions at essentially every post-transcriptional stage: pre-mRNA splicing and degradation through alternative splicing and nonsense-mediated decay (AS-NMD), mature mRNA silencing by miRNA, fast mRNA decay rate and translational repression by upstream AUGs. We also found UCSs to exhibit resistance to formation of RNA secondary structure. These multiple layers of regulation underscore the importance of the UCS-containing genes as key global RNA processing regulators, including members of the serine/arginine-rich protein and heterogeneous nuclear ribonucleoprotein (hnRNP) families of essential splicing regulators. The discovery of UCSs shed new light on the multifaceted, fine-tuned and tight post-transcriptional regulation of gene families as conserved through the majority of the mammalian lineage.


Assuntos
Processamento Alternativo , DNA Complementar/química , Processamento Pós-Transcricional do RNA , RNA Mensageiro/química , Sequências Reguladoras de Ácido Ribonucleico , Regiões 5' não Traduzidas , Animais , Sequência de Bases , Códon de Iniciação , Códon sem Sentido , Sequência Conservada , Doença/genética , Evolução Molecular , Perfilação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Camundongos , MicroRNAs/metabolismo , Proteínas Nucleares/genética , Conformação de Ácido Nucleico , Biossíntese de Proteínas , Estabilidade de RNA , Proteínas de Ligação a RNA/genética , Ratos , Fatores de Processamento de Serina-Arginina
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