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2.
Genes Immun ; 21(4): 269-272, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32759995

RESUMEN

The entry of SARS-CoV-2 into host cells is dependent upon angiotensin-converting enzyme 2 (ACE2), which serves as a functional attachment receptor for the viral spike glycoprotein, and the serine protease TMPRSS2 which allows fusion of the viral and host cell membranes. We devised a quantitative measure to estimate genetic determinants of ACE2 and TMPRSS2 expression and applied this measure to >2500 individuals. Our data show significant variability in genetic determinants of ACE2 and TMPRSS2 expression among individuals and between populations, and indicate a genetic predisposition for lower expression levels of both key viral entry genes in African populations. These data suggest that host genetics related to viral entry mechanisms might influence interindividual variability in disease susceptibility and severity of COVID-19.


Asunto(s)
Infecciones por Coronavirus/genética , Peptidil-Dipeptidasa A/genética , Neumonía Viral/genética , Serina Endopeptidasas/genética , Grupos de Población Continentales/genética , Infecciones por Coronavirus/etnología , Femenino , Humanos , Masculino , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/etnología , Serina Endopeptidasas/metabolismo
3.
Curr Atheroscler Rep ; 22(9): 48, 2020 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-32710255

RESUMEN

PURPOSE OF REVIEW: The COVID-19 pandemic has infected over > 11 million as of today people worldwide and is associated with significant cardiovascular manifestations, particularly in subjects with preexisting comorbidities and cardiovascular risk factors. Recently, a predisposition for arterial and venous thromboses has been reported in COVID-19 infection. We hypothesize that besides conventional risk factors, subjects with elevated lipoprotein(a) (Lp(a)) may have a particularly high risk of developing cardiovascular complications. RECENT FINDINGS: The Lp(a) molecule has the propensity for inhibiting endogenous fibrinolysis through its apolipoprotein(a) component and for enhancing proinflammatory effects such as through its content of oxidized phospholipids. The LPA gene contains an interleukin-6 (IL-6) response element that may induce an acute phase-type increase in Lp(a) levels following a cytokine storm from COVID-19. Thus, subjects with either baseline elevated Lp(a) or those who have an increase following COVID-19 infection, or both, may be at very high risk of developing thromboses. Elevated Lp(a) may also lead to acute destabilization of preexisting but quiescent atherosclerotic plaques, which might induce acute myocardial infarction and stroke. Ongoing studies with IL-6 antagonists may be informative in understanding this relationship, and registries are being initiated to measure Lp(a) in subjects infected with COVID-19. If indeed an association is suggestive of being causal, consideration can be given to systematic testing of Lp(a) and prophylactic systemic anticoagulation in infected inpatients. Therapeutic lipid apheresis and pharmacotherapy for the reduction of Lp(a) levels may minimize thrombogenic potential and proinflammatory effects. We propose studies to test the hypothesis that Lp(a) may contribute to cardiovascular complications of COVID-19.


Asunto(s)
Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/complicaciones , Inflamación/etiología , Lipoproteína(a)/sangre , Neumonía Viral/sangre , Neumonía Viral/complicaciones , Trombosis/etiología , Proteínas de Fase Aguda/análisis , Proteínas de Fase Aguda/genética , Anticoagulantes/uso terapéutico , Apolipoproteína E4/genética , Aterosclerosis/etiología , Betacoronavirus , Biomarcadores/sangre , Investigación Biomédica , Eliminación de Componentes Sanguíneos , Grupos de Población Continentales/genética , Infecciones por Coronavirus/epidemiología , Genotipo , Humanos , Inflamación/prevención & control , Interleucina-6/antagonistas & inhibidores , Interleucina-6/sangre , Lipoproteína(a)/genética , Pandemias , Neumonía Viral/epidemiología , Factores Raciales , Factores de Riesgo , Índice de Severidad de la Enfermedad , Trombosis/prevención & control
4.
S Afr Med J ; 110(2): 159-166, 2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-32657689

RESUMEN

BACKGROUND: Tacrolimus forms the cornerstone for immunosuppression in solid-organ transplantation. It has a narrow therapeutic window with wide inter- and intra-patient variability (IPV). Cytochrome P-450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The rs776746A>G (i.e. CYP3A5*3) single-nucleotide polymorphism in CYP3A5 alters tacrolimus predose trough concentration (C0) and may also affect IPV, which may lead to immune- and/or drug-mediated allograft injury. CYP3A5*3 may result in absent (*3/*3), partial (*1/*3) or normal (*1/*1) CYP3A5 expression. The effect of CYP3A5*3 on tacrolimus exposure and variability has not been examined in South African (SA) transplant recipients. OBJECTIVES: To determine the frequencies and effect of CYP3A5 and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) polymorphisms on tacrolimus C0/dose ratios in different ethnic groups attending a tertiary renal transplant clinic in SA, and other factors that may explain inter- and IPV in tacrolimus C0. METHODS: All consenting stable renal transplant recipients on tacrolimus at the Livingstone Hospital Renal Unit in Port Elizabeth, SA, were included. Tacrolimus concentrations were obtained using a microparticle enzyme immunoassay method (ARCHITECT analyser, Abbott Laboratories). Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 and *6 allelic variants. RESULTS: There were 43 participants (35% black African, 44% mixed ancestry and 21% white), with a mean age of 44.5 years, median duration post-transplant of 47 months and median (interquartile range) creatinine and estimated glomerular filtration rate levels of 118 (92 - 140) µmol/L and 62 (49 - 76) mL/min at study inclusion. The mean tacrolimus C0 in the study was 6.7 ng/mL, with no difference across the different ethnic groups. However, the mean total daily dose of tacrolimus required was 9.1 mg (0.12 mg/kg), 7.2 mg (0.09 mg/kg) and 4.3 mg (0.06 mg/kg) in black, mixed-ancestry and white patients, respectively (p=0.017). The frequencies for CYP3A5 expressors (i.e. CYP3A5*1/*1 + CYP3A5*1/*3 genotypes) were 72%, 100%, 76% and 12% for all patients combined and black, mixed-ancestry and white patients, respectively. The frequencies for CYP3A5 non-expressors (i.e. CYP3A5*3/*3 genotypes) were 0%, 24% and 88% among the black, mixed-ancestry and white patients, respectively. None of the patients carried the CYP3A5*6 allele. CYP3A5*1/*1 and CYP3A5*1/*3 genotype carriers required a two-fold increase in dose compared with the non-expressor genotype carriers, CYP3A5*3/*3 (p<0.05). CYP3A5*3/*3 carriers also demonstrated higher IPV than CYP3A5*1/*1 and *1/*3 carriers (18.1% v. 14.2%; p=0.125). CONCLUSIONS: Compared with global transplant populations, SA renal transplant recipients demonstrated a very high rate of CYP3A5 expression, with a significant impact on tacrolimus pharmacokinetics. Genetic variation in CYP3A5 expression affects tacrolimus dosing requirements, and knowing the CYP3A5 genotype of transplant patients may allow better dose prediction compared with current standard dosing recommendations in a multi-ethnic population. Overall, black African patients required higher doses of tacrolimus than their white counterparts. While further prospective studies are needed to better evaluate dosing algorithms, it would appear that the starting dose of tacrolimus should be higher in black and mixed-race patients.


Asunto(s)
Citocromo P-450 CYP3A/genética , Inmunosupresores/administración & dosificación , Trasplante de Riñón/métodos , Tacrolimus/administración & dosificación , Adulto , Estudios de Cohortes , Grupos de Población Continentales/genética , Relación Dosis-Respuesta a Droga , Femenino , Variación Genética , Genotipo , Humanos , Inmunosupresores/farmacocinética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Sudáfrica , Tacrolimus/farmacocinética
5.
Anticancer Res ; 40(6): 3307-3314, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32487626

RESUMEN

BACKGROUND/AIM: Recent evidence has shown that African American men with prostate cancer may have more radiosensitive disease with greater overall survival (OS) with radiotherapy compared to Caucasian men. We compared OS in African American and Caucasian men receiving radiotherapy utilizing the National Cancer Database. PATIENTS AND METHODS: African American or Caucasian men with N0M0 prostate adenocarcinoma diagnosed between 2004 and 2013 were selected and grouped into favorable and unfavorable risk based on clinical T-stage, clinical Gleason score, and prostate-specific antigen. Patients with favorable risk received brachytherapy or dose-escalated external beam radiation (EBRT); those with unfavorable risk received EBRT plus anti-androgen therapy with/without brachytherapy. African American and Caucasian men in each subgroup were propensity score-matched and analyzed for survival. Sensitivity analysis used treatment-race and age-race interaction terms. RESULTS: 27,150 patients met the inclusion criteria, with a median age of 68 (range=38-90) years and median follow-up of 59.93 (range=48-142.62) months. OS was equivalent between African American and Caucasian race in favorable risk [log-rank p=0.82; hazard ratio (HR)=0.928; 95% confidence intervaI (CI)=0.583-1.477, p=0.753] and unfavorable-risk subgroups (log-rank p=0.87, HR=1.078, 95% CI=0.843-1.379, p=0.550). No significant interaction existed between treatment and race for either cohort but there was a significant interaction between race and age in those with unfavorable risk (HR=1.046, 95% CI=1.009-1.084, p=0.015), with greater OS in those of Caucasian race ≤60 years (HR=0.320, 95% CI=0.137-0.752, p=0.009). CONCLUSION: African American and Caucasian men have similar survival when treated with risk-appropriate definitive radiotherapy. However, younger (age ≤60 years) African American men with unfavorable risk have poorer survival than their Caucasian counterparts and may harbor a significantly different biology of disease.


Asunto(s)
Grupos de Población Continentales/genética , Neoplasias de la Próstata/etnología , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/radioterapia , Análisis de Supervivencia
7.
Nature ; 581(7809): 444-451, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32461652

RESUMEN

Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.


Asunto(s)
Enfermedad/genética , Variación Genética , Genética Médica/normas , Genética de Población/normas , Genoma Humano/genética , Grupos de Población Continentales/genética , Femenino , Pruebas Genéticas , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple/genética , Estándares de Referencia , Selección Genética , Secuenciación Completa del Genoma
8.
Nature ; 583(7814): 83-89, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32460305

RESUMEN

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.


Asunto(s)
Variación Genética , Genoma Humano/genética , Secuenciación Completa del Genoma , Alelos , Estudios de Casos y Controles , Grupos de Población Continentales/genética , Epigénesis Genética , Femenino , Dosificación de Gen/genética , Genética de Población , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Anotación de Secuencia Molecular , Sitios de Carácter Cuantitativo , Programas Informáticos
10.
PLoS Genet ; 16(3): e1008684, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32226016

RESUMEN

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.


Asunto(s)
Grupos de Población Continentales/genética , Lípidos/sangre , Lípidos/genética , Bases de Datos Genéticas , Femenino , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Lípidos/análisis , Masculino , Metagenómica/métodos , Grupos Minoritarios , Herencia Multifactorial/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Estados Unidos/epidemiología
12.
Science ; 367(6484)2020 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-32193295

RESUMEN

Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the past 10,000 years, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations.


Asunto(s)
Variación Genética , Genética de Población , Genoma Humano , Secuenciación Completa del Genoma , África , Américas , Animales , Asia , Grupos de Población Continentales/genética , Variaciones en el Número de Copia de ADN , Haplotipos , Hominidae/genética , Humanos , Mutación INDEL , Hombre de Neandertal/genética , Oceanía , Filogenia , Polimorfismo de Nucleótido Simple , Densidad de Población
13.
Mol Genet Genomics ; 295(4): 1027-1038, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32206883

RESUMEN

When traditional short tandem repeat profiling fails to provide valuable information to arrest the criminal, forensic ancestry inference of the biological samples left at the crime scene will probably offer investigative leads and facilitate the investigation process of the case. That is why there are consistent efforts in developing panels for ancestry inference in forensic science. Presently, a 30-plex next generation sequencing-based assay was exploited in this study by assembling well-differentiated single nucleotide polymorphisms for ancestry assignment of unknown individuals from three continental populations (African, European and East Asian). And meanwhile, relatively balanced population-specific differentiation values were maintained to avoid the over-estimation or under-estimation of co-ancestry proportions in individuals with admixed ancestry. The principal component analysis and STRUCTURE analysis of reference populations, test populations and the studied Mongolian group indicated that the novel assay was efficient enough to determine the ancestry origin of an unknown individual from the three continental populations. Besides, ancestry membership proportion estimations for the Mongolian group revealed that a large fraction of the ancestry was contributed by East Asian genetic component (approximately 83.9%), followed by European (approximately 12.6%) and African genetic components (approximately 3.5%), respectively. And next generation sequencing technology applied in this study offers possibility to incorporate more single nucleotide polymorphisms for individual identification and phenotype prediction into the same assay to provide as many as possible investigative clues in the future.


Asunto(s)
Antropología Forense/métodos , Genética Forense/métodos , Genética de Población , Secuenciación de Nucleótidos de Alto Rendimiento , Grupo de Ascendencia Continental Africana/genética , Grupo de Ascendencia Continental Asiática/genética , Grupos de Población Continentales/genética , Grupo de Ascendencia Continental Europea/genética , Lejano Oriente/epidemiología , Genotipo , Humanos , Repeticiones de Microsatélite/genética , Polimorfismo de Nucleótido Simple/genética
14.
J Neuroimmunol ; 341: 577166, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-32062178

RESUMEN

BACKGROUND: Multiple sclerosis (MS) is recognized as the most prevalent chronic inflammatory neurological disorder diagnosed in young adults. Recent evidence suggests that the T244I polymorphism of the IL7Rα gene (rs6897932) May influence MS susceptibility; however, individual studies have provided conflicting and controversial results. Therefore, this meta-analysis was conducted to assess the association between the IL7R T244I polymorphism and the risk of MS. METHOD: An extensive search for published literature up to May 2019 was accomplished in the electronic databases, and 28 studies consisting of 16,260 MS patients and 18,335 controls were included. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to investigate the strength of association. RESULTS: The results of the present meta-analysis represented significant association between the IL7R T244I polymorphism and MS susceptibility. (recessive model: OR = 1.126, 95% CI 1.026-1.236, P = .012; dominant model: OR = 1.172, 95% CI 1.024-1.341, P = .021; homozygous model: OR = 1.213, 95% CI 1.038-1.417, P = .015; and allelic model: OR = 1.109, 95% CI 1.025-1.200, P = .010, respectively). In the subgroup analysis according to region, our findings showed significant association in Europe. However, no association was found in Middle East. CONCLUSION: The current meta-analysis demonstrated that the C allele of IL7R T244I polymorphism might be a risk factor for the MS susceptibility in Europe but not in Middle East.


Asunto(s)
Subunidad alfa del Receptor de Interleucina-7/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Alelos , Sustitución de Aminoácidos , Intervalos de Confianza , Grupos de Población Continentales/genética , Grupos Étnicos/genética , Europa (Continente)/etnología , Predisposición Genética a la Enfermedad , Humanos , Subunidad alfa del Receptor de Interleucina-7/fisiología , Medio Oriente/etnología , Modelos Genéticos , Esclerosis Múltiple/etnología , Oportunidad Relativa , Factores de Riesgo
15.
PLoS Biol ; 18(1): e3000586, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31951611

RESUMEN

The origin and fate of new mutations within species is the fundamental process underlying evolution. However, while much attention has been focused on characterizing the presence, frequency, and phenotypic impact of genetic variation, the evolutionary histories of most variants are largely unexplored. We have developed a nonparametric approach for estimating the date of origin of genetic variants in large-scale sequencing data sets. The accuracy and robustness of the approach is demonstrated through simulation. Using data from two publicly available human genomic diversity resources, we estimated the age of more than 45 million single-nucleotide polymorphisms (SNPs) in the human genome and release the Atlas of Variant Age as a public online database. We characterize the relationship between variant age and frequency in different geographical regions and demonstrate the value of age information in interpreting variants of functional and selective importance. Finally, we use allele age estimates to power a rapid approach for inferring the ancestry shared between individual genomes and to quantify genealogical relationships at different points in the past, as well as to describe and explore the evolutionary history of modern human populations.


Asunto(s)
Grupos de Población Continentales/genética , Especiación Genética , Genética de Población/métodos , Polimorfismo de Nucleótido Simple , Factores de Edad , Alelos , Simulación por Computador , Conjuntos de Datos como Asunto , Evolución Molecular , Frecuencia de los Genes , Variación Genética , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linaje , Filogenia , Análisis de Secuencia de ADN , Estadística como Asunto/métodos , Factores de Tiempo
16.
Forensic Sci Int ; 306: 110050, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31790892

RESUMEN

In 1995, the historical shipwreck of La Belle was discovered off the coast of Texas. One partial human skeleton was recovered from alongside cargo in the rear portion of the ship; a second (complete) skeleton was found atop coiled anchor rope in the bow. In late 2015, comprehensive forensic genetic testing began on multiple samplings from each set of remains. For the partial skeleton recovered from the ship's rear cargo area, results were obtained for 26/27 Y-STRs using traditional CE; with MPS technology, results were obtained for 18/24 Y-STRs, 56/56 ancestry-informative SNPs (aiSNPs), 22/22 phenotype-informative SNPs (piSNPs), 22/27 autosomal STRs, 4/7 X-STRs, and 94/94 identity-informative SNPs (iiSNPs). For the complete skeleton of the second individual, results were obtained for 7/17 Y-STRs using traditional CE; with MPS technology, results were obtained for 5/24 Y-STRs, 49/56 aiSNPs, 18/22 piSNPs, 15/27 autosomal STRs, 1/7 X-STRs, and 66/94 iiSNPs. Biogeographic ancestry for each set of skeletal remains was predicted using the ancestry feature and metapopulation tool of the Y-STR Haplotype Reference Database (YHRD), Haplogroup Predictor, and the Forensic Research/Reference on Genetics knowledge base (FROG-kb). Phenotype prediction was performed using piSNP data and the HIrisplex eye color and hair color DNA phenotyping webtool. mtDNA whole genome sequencing also was performed successfully. This study highlights the sensitivity of current forensic laboratory methods in recovering DNA from historical and archaeological human remains. Using advanced sequencing technology provided by MiSeq™ FGx (Verogen) and Ion S5™ (Thermo Fisher Scientific) instrumentation, degraded skeletal remains can be characterized using a panel of diverse and highly informative markers, producing data which can be useful in both forensic and genealogical investigations.


Asunto(s)
Restos Mortales , Dermatoglifia del ADN , Genética Forense , Fenotipo , Navíos/historia , Accidentes/historia , Cromosomas Humanos Y , Grupos de Población Continentales/genética , ADN Mitocondrial/genética , Electroforesis Capilar , Francia , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Historia del Siglo XVII , Humanos , Masculino , Repeticiones de Microsatélite , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Texas , Secuenciación Completa del Genoma
17.
Gene ; 730: 144289, 2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-31846709

RESUMEN

Interferon lambda proteins activate the JAK-STAT signalling pathway, resulting in upregulation of genes with antiviral effects. The interferon lambda family was initially thought to be redundant to the interferon alpha family, which signals through the same pathway, except for the more limited expression of the IFNLR1 receptor. However, recent studies show that interferon lambdas uniquely protect tissue barriers against a wide range of important viral infections. The interferon lambda 4 gene (IFNL4) was discovered in 2013. The IFNL4 protein is determined by the IFNL4-ΔG/TT (rs368234815) variant. The ancestral IFNL4-ΔG allele generates IFNL4, whereas IFNL4-TT causes pre-mature termination of the protein. Surprisingly, although interferons are generally antiviral proteins, the genotypes that generate the IFNL4 protein are strongly linked to impaired clearance of hepatitis C virus (HCV). IFNL4 genotype has also been linked to variation within the HCV genome, as well as risk of hepatic fibrosis, certain cancers and some infectious diseases. There has been very strong evolutionary selection against the ancestral IFNL4-ΔG allele, which is the major form in African populations, but the minor allele in Europeans and Asians. The reason for this selection and the biological mechanisms underlying observed phenotypic associations remain to be explained.


Asunto(s)
Interleucinas/genética , Interleucinas/metabolismo , Alelos , Grupos de Población Continentales/genética , Evolución Molecular , Frecuencia de los Genes/genética , Variación Genética/genética , Genotipo , Hepacivirus/genética , Hepatitis/genética , Humanos , Interleucinas/fisiología , Fenotipo , Polimorfismo de Nucleótido Simple/genética
18.
Gene ; 730: 144302, 2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-31884106

RESUMEN

OBJECTIVES: This study aimed to investigate the roles of adiponectin (ADIPOQ) rs266729 and melatonin receptor 1B (MTNR1B) rs10830963 polymorphisms in patients with gestational diabetes mellitus (GDM). METHODS: The databases including Web of science, PubMed, Embase and Cochrane Library were searched for case-control studies updating on Feb 15th, 2019. 12 studies were finally included containing 3759 GDM patients and 4422 controls. The associations between two polymorphic sites (rs266729 and rs10830963) and GDM susceptibility were analyzed according to the pooled odds ratios (OR) and corresponding 95% confidence intervals (CI). RESULTS: Our pooled results indicated that ADIPOQ rs266729 can increase the GDM risk in Asian (dominant: GG+CG vs. CC, OR = 2.079, 95%CI: 1.012-4.270, P = 0.046) and European (allele: G vs. C, OR = 1.353, 95%CI: 1.001-1.829, P = 0.049 dominant: GG+CG vs. CC, OR = 1.522, 95%CI: 1.031-2.245, P = 0.034 heterozygote: CG vs. CC, OR = 1.517, 95%CI: 1.006-2.287, P = 0.047), but decrease in American population (allele: G vs. C, OR = 0.663, 95%CI: 0.501-0.878, P = 0.004 (dominant: GG+CG vs. CC, OR = 0.642, 95%CI: 0.456-0.903, P = 0.011 recessive: GG vs. CC+CG, OR = 0.496, 95%CI: 0.250-0.981, P = 0.044). The data demonstrated that the correlation between MTNR1B rs10830963 and GDM susceptibility is significant in Asian (allele: G vs. C, OR = 1.236, 95%CI: 1.109-1.378, P < 0.001 dominant: GG+CG vs. CC, OR = 1.285, 95%CI: 1.135-1.455, P < 0.001 recessive: GG vs. CC+CG, OR = 1.884, 95%CI: 1.307-2.716, P = 0.001 homozygote: GG vs. CC, OR = 1.514, 95%CI: 1.231-1.864, P < 0.001 heterozygote: CG vs. CC, OR = 1.198, 95%CI: 1.050-1.367, P = 0.007), and European (heterozygote: CG vs. CC, OR = 1.302, 95%CI: 1.011-1.677, P = 0.041). CONCLUSIONS: This Meta-analysis suggests that the variation of ADIPOQ rs266729 can increase the risk of GDM in Asian and European, while reduce in American population. Additionally, the association between MTNR1B rs10830963 and GDM susceptibility is significant in Asian, European and when using TaqMan assay.


Asunto(s)
Adiponectina/genética , Diabetes Gestacional/genética , Receptor de Melatonina MT2/genética , Adiponectina/metabolismo , Alelos , Estudios de Casos y Controles , Grupos de Población Continentales/genética , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Embarazo , Receptor de Melatonina MT2/metabolismo , Factores de Riesgo
19.
Forensic Sci Int ; 305: 110012, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31759292

RESUMEN

Familial search is a statistical approach that is used to infer genetic relationships between a forensic sample and individuals in a DNA database. Several authors have proposed likelihood ratio-based statistics for testing parent-child and full sibling relationships when population substructure exists. This paper proposes three new statistics and investigates performance of each statistic based on Type I error and power. Three statistics, defined by (1) the local allele frequency, (2) the Balding-Nichols approach and (3) the ratio between the maximum of the genotype probabilities over racial subgroup, were found to be good for testing these two types of familial relationships. Power analyses within racial groups are also included, with the power highest for African-American samples and lowest for Caucasian samples. Finally, simulation studies were done on both original and extended CODIS core loci. There were clear differences in power, with the power substantially higher for extended CODIS core loci.


Asunto(s)
Dermatoglifia del ADN , Modelos Estadísticos , Padres , Linaje , Hermanos , Grupos de Población Continentales/genética , Genética Forense , Frecuencia de los Genes , Genotipo , Humanos , Modelos Genéticos
20.
J Anthropol Sci ; 96: 91-106, 2019 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-31589588

RESUMEN

The sequencing of the human genome at the turn of the 21st century was hailed as revealing the overwhelming genetic similarity of human groups. Scholars of genomics have critiqued the subsequent persistence of race-based genetic science, but were reassured that the wide availability of gene sequencing would end the use of race as a proxy for genetic difference. Once an individual's whole gene sequence could be read, they hoped, their ethnoracial classification would become redundant. At the same time, genome science was recognising that the differences between human genomes went beyond the genome sequence to the structure of the genome itself. 'Structural variation' between genomes, including insertions, deletions, translocations, inversions, and copy number variations, mean that the 'universal' reference genome used for genome sequencing is not so universal. As conventional, 'short-read' sequencing wrongly assumes that all genomes have the same structure, significant genetic variation can be missed. This paper examines the twin phenomena that have been posed as a solution to the biases of short-read sequencing: 'long-read' sequencing and 'ethnicity-specific reference genomes'. Long-read sequencing is a method of generating a genome sequence that can be assembled de novo rather than relying on the reference genome. In recent years, a number of countries including China, Korea, and Denmark have used long-read sequencing and de novo assembly to develop 'national' reference genomes. Our analysis of one ethnicity-specific reference genome project, the Korean Reference Genome (KOREF), finds that it unduly emphasises the importance of population structural variation, framed in nationalist terms, and discounts the importance of individual structural variation. We argue that the intellectual labour required to make a Korean reference genome a coherent concept works to extend the horizon of race, prolonging the temporality of the 'meantime' in which race remains a seemingly valid concept in genomic science.


Asunto(s)
Grupos de Población Continentales/genética , Genoma Humano/genética , Análisis de Secuencia de ADN/métodos , Antropología Física , Bases de Datos Genéticas , Variación Genética/genética , Genómica , Humanos , Racismo
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