RESUMEN
In the course of experiments aimed at deciphering the inhibition mechanism of mycophenolic acid and ribavirin in hepatitis C virus (HCV) infection, we observed an inhibitory effect of the nucleoside guanosine (Gua). Here, we report that Gua, and not the other standard nucleosides, inhibits HCV replication in human hepatoma cells. Gua did not directly inhibit the in vitro polymerase activity of NS5B, but it modified the intracellular levels of nucleoside di- and tri-phosphates (NDPs and NTPs), leading to deficient HCV RNA replication and reduction of infectious progeny virus production. Changes in the concentrations of NTPs or NDPs modified NS5B RNA polymerase activity in vitro, in particular de novo RNA synthesis and template switching. Furthermore, the Gua-mediated changes were associated with a significant increase in the number of indels in viral RNA, which may account for the reduction of the specific infectivity of the viral progeny, suggesting the presence of defective genomes. Thus, a proper NTP:NDP balance appears to be critical to ensure HCV polymerase fidelity and minimal production of defective genomes.
Asunto(s)
Guanosina/metabolismo , Hepacivirus/metabolismo , Mutación INDEL/fisiología , Nucleótidos/metabolismo , Replicación Viral/fisiología , Línea Celular Tumoral , Guanosina/farmacología , Hepatitis C/metabolismo , Humanos , ARN Viral/genética , Replicación Viral/efectos de los fármacosRESUMEN
The origin of large genomes that underlies the long standing "C-value enigma" is only partially explained by selfish DNA. We investigated insertions and deletions (indels) of nucleotides and discussed their relevance in size evolution of random biological sequences (RBS) and genomes. By developing a probabilistic model of RBS based on size evolution of expandable sites in a thought perfect genome, it was found that insertion bias engenders exponential increase of average RBS sizes. When combined with existing large segments of genome that are not subject to selection pressure (e.g. selfish DNA), such insertion bias results in explosive expansion of genomes, and therefore helps explain the "C value enigma" besides selfish DNA. Such increase of RBS size is caused by the fundamental asymmetry of indels, with insertions result in more available sites and deletions result in less deletable nucleotides. In qualitative agreement with the size distribution of known genomes, tails of RBS size distributions exhibit exponential decay with probabilities of larger RBS segments being smaller. Unsurprisingly, a slight deletion bias (higher deletions probabilities) results in a slow decrease of average RBS size and may lead to their eventual vanishing. Contrary to intuition, strictly balanced insertion and deletion results in linearly increasing instead of completely fixed RBS size. Nonetheless, such slow linear increase of average RBS sizes with time are small in magnitude and are consequently not influential on genome size evolution, and certainly not a major contributor for the "C-value enigma". Our model suggested that insertion bias of nucleotides may provide complementary explanation for large genomes besides selfish DNA. The fundamental indel asymmetry is applicable for all forms of genomic insertions and deletions. Long-lasting exponential increase of genome size present energy and material requirement that is impossible to sustain. We therefore concluded that if there were explosively accelerating expansion caused by significant effective insertion bias for any survival species, it must have occurred sporadically. Our model also provided an explanation for the observed proportional evolution of genome size.
Asunto(s)
Evolución Molecular , Tamaño del Genoma/genética , Mutación INDEL/fisiología , Alineación de Secuencia , Animales , Secuencia de Bases , Humanos , Modelos Teóricos , Mutagénesis Insercional/fisiología , Distribución Aleatoria , Alineación de Secuencia/métodos , Eliminación de Secuencia/fisiologíaRESUMEN
Differentiation between phenotypically neutral and disease-causing genetic variation remains an open and relevant problem. Among different types of variation, non-frameshifting insertions and deletions (indels) represent an understudied group with widespread phenotypic consequences. To address this challenge, we present a machine learning method, MutPred-Indel, that predicts pathogenicity and identifies types of functional residues impacted by non-frameshifting insertion/deletion variation. The model shows good predictive performance as well as the ability to identify impacted structural and functional residues including secondary structure, intrinsic disorder, metal and macromolecular binding, post-translational modifications, allosteric sites, and catalytic residues. We identify structural and functional mechanisms impacted preferentially by germline variation from the Human Gene Mutation Database, recurrent somatic variation from COSMIC in the context of different cancers, as well as de novo variants from families with autism spectrum disorder. Further, the distributions of pathogenicity prediction scores generated by MutPred-Indel are shown to differentiate highly recurrent from non-recurrent somatic variation. Collectively, we present a framework to facilitate the interrogation of both pathogenicity and the functional effects of non-frameshifting insertion/deletion variants. The MutPred-Indel webserver is available at http://mutpred.mutdb.org/.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Genoma Humano , Mutación INDEL , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Biología Computacional , Bases de Datos Genéticas , Genoma Humano/genética , Genoma Humano/fisiología , Humanos , Mutación INDEL/genética , Mutación INDEL/fisiología , Aprendizaje Automático , Curva ROCRESUMEN
Many studies have reported that cyclin-dependent kinase inhibitor 3 (CDKN3) is involved in the cell cycle. However, the function of CDKN3 has not been well elucidated in organisms. In this study, a multiallelic indel caused by a 19-bp fragment and a 2 × 19 bp fragment was shown for the first time to be inserted into the promoter of the CDKN3 gene in 1994 chickens from 9 different breeds. In addition, 6 genotypes (C5C5, C4C4, C3C3, C4C5, C3C4, and C3C5) were observed (C3C3, C4C4, C5C5 have 3 × 19 bp, 4 × 19 bp, and 5 × 19 bp, respectively). Among these genotypes, the C4C4 genotype was the most dominant genotype in 9 breeds. The results of χ2 analysis of CDKN3 gene in different breeds showed that there were significant differences in the distribution of genotypes among different cultivars (P < 0.01). In addition, association study with F2 chicken resource population which produced by Anka and Gushi chickens showed that the C3C4 genotypes had the greatest semi-evisceration weight (SEW, 1163.94 ± 46.84), evisceration weight (EW, 964.15 ± 41.16), head weight (HW, 45.55 ± 1.43), claw weight (CW, 63.42±2.86), wing weight (WW, 129.15±5.48), liver weight (LW, 29.96±1.27), carcass weight (cW, 1286.96±49.53), weight at 10 (1190.68±45.68) and 12 (1430.65±54.45) wk, followed by C3C3, C4C4, C5C5, C4C5, whereas C3C5 genotypes having the lowest SEW (989.21±47.71), EW (841.38±40.55), HW (41.03±1.46), CW (54.36±2.81), WW (116.31±5.39), LW (27.31±1.25), cW (1093.29±49.99), weight at 10 (1036.10±44.99) and 12 (1246.28±53.59) wk. Expression levels of CDKN3 in breast muscle of chickens with C4C4 (0.72±0.02), C3C3 (0.95±0.41), and C4C5 (0.74±0.13) genotypes were significantly lower than those with C5C5 (1.80±0.01) and C3C5 (2.14±0.17) genotypes (P < 0.05). In conclusion, we investigated the effect of a multiallelic indel in the CDKN3 gene on the economic traits of chickens, and this indel was significantly associated with growth and carcass traits in chickens. Collectively, our findings provide useful information about the repeat sequence indel in the promoter region of the CDKN3 gene as a potential molecular marker for chicken breeding.
Asunto(s)
Proteínas Aviares/genética , Peso Corporal/genética , Pollos/fisiología , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/genética , Mutación INDEL/fisiología , Alelos , Animales , Proteínas Aviares/metabolismo , Secuencia de Bases , Pollos/genética , Pollos/crecimiento & desarrollo , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Genotipo , Masculino , Modelos Genéticos , Regiones Promotoras GenéticasRESUMEN
Narrow-leafed lupin (Lupinus angustifolius L.) cultivation was transformed by 2 dominant vernalization-insensitive, early flowering time loci known as Ku and Julius (Jul), which allowed expansion into shorter season environments. However, reliance on these loci has limited genetic and phenotypic diversity for environmental adaptation in cultivated lupin. We recently predicted that a 1,423-bp deletion in the cis-regulatory region of LanFTc1, a FLOWERING LOCUS T (FT) homologue, derepressed expression of LanFTc1 and was the underlying cause of the Ku phenotype. Here, we surveyed diverse germplasm for LanFTc1 cis-regulatory variation and identified 2 further deletions of 1,208 and 5,162 bp in the 5' regulatory region, which overlap the 1,423-bp deletion. Additionally, we confirmed that no other polymorphisms were perfectly associated with vernalization responsiveness. Phenotyping and gene expression analyses revealed that Jul accessions possessed the 5,162-bp deletion and that the Jul and Ku deletions were equally capable of removing vernalization requirement and up-regulating gene expression. The 1,208-bp deletion was associated with intermediate phenology, vernalization responsiveness, and gene expression and therefore may be useful for expanding agronomic adaptation of lupin. This insertion/deletion series may also help resolve how the vernalization response is mediated at the molecular level in legumes.
Asunto(s)
Flores/crecimiento & desarrollo , Genes de Plantas/genética , Mutación INDEL/genética , Lupinus/genética , Flores/genética , Regulación de la Expresión Génica de las Plantas/genética , Regulación de la Expresión Génica de las Plantas/fisiología , Genes de Plantas/fisiología , Variación Genética/genética , Mutación INDEL/fisiología , Desequilibrio de Ligamiento/genética , Lupinus/crecimiento & desarrollo , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Estaciones del AñoRESUMEN
BACKGROUND: Water permeability governed by seed coat is a major facet of seed crops, especially soybean, whose seeds lack physiological dormancy and experience rapid deterioration in seed viability under prolonged storage. Moreover, the physiological and chemical characteristics of soybean seeds are known to vary with seed coat color. Thus, to underpin the genes controlling water permeability in soybean seeds, we carried out an in-depth characterization of the associated genomic variation. RESULTS: In the present study, we have analyzed genomic variation between cultivated soybean and its wild progenitor with implications on seed permeability, a trait related to seed storability. Whole genome resequencing of G.max and G. soja, identified SNPs and InDels which were further characterized on the basis of their genomic location and impact on gene expression. Chromosomal density distribution of the variation was assessed across the genome and genes carrying SNPs and InDels were characterized into different metabolic pathways. Seed hardiness is a complex trait that is affected by the allelic constitution of a genetic locus as well as by a tricky web of plant hormone interactions. Seven genes that hold a probable role in the determination of seed permeability were selected and their expression differences at different stages of water imbibition were analyzed. Variant interaction network derived 205 downstream interacting partners of 7 genes confirmed their role in seed related traits. Interestingly, genes encoding for Type I- Inositol polyphosphate 5 phosphatase1 and E3 Ubiquitin ligase could differentiate parental genotypes, revealed protein conformational deformations and were found to segregate among RILs in coherence with their permeability scores. The 2 identified genes, thus showed a preliminary association with the desirable permeability characteristics. CONCLUSION: In the light of above outcomes, 2 genes were identified that revealed preliminary, but a relevant association with soybean seed permeability trait and hence could serve as a primary material for understanding the molecular pathways controlling seed permeability traits in soybean.
Asunto(s)
Glycine max/genética , Mutación INDEL/genética , Polimorfismo de Nucleótido Simple/genética , Semillas/metabolismo , Cromosomas de las Plantas/genética , Genes de Plantas/genética , Genes de Plantas/fisiología , Estudio de Asociación del Genoma Completo , Mutación INDEL/fisiología , Permeabilidad , Polimorfismo de Nucleótido Simple/fisiología , Glycine max/metabolismo , Glycine max/fisiologíaRESUMEN
BACKGROUND: With the development of sequencing technologies, more and more sequence variants are available for investigation. Different classes of variants in the human genome have been identified, including single nucleotide substitutions, insertion and deletion, and large structural variations such as duplications and deletions. Insertion and deletion (indel) variants comprise a major proportion of human genetic variation. However, little is known about their effects on humans. The absence of understanding is largely due to the lack of both biological data and computational resources. RESULTS: This paper presents a new indel functional prediction method HMMvar based on HMM profiles, which capture the conservation information in sequences. The results demonstrate that a scoring strategy based on HMM profiles can achieve good performance in identifying deleterious or neutral variants for different data sets, and can predict the protein functional effects of both single and multiple mutations. CONCLUSIONS: This paper proposed a quantitative prediction method, HMMvar, to predict the effect of genetic variation using hidden Markov models. The HMM based pipeline program implementing the method HMMvar is freely available at https://bioinformatics.cs.vt.edu/zhanglab/hmm.
Asunto(s)
Variación Genética , Genoma Humano/genética , Mutación INDEL/genética , Mutación INDEL/fisiología , Biología Computacional/métodos , Genoma Humano/fisiología , Humanos , Cadenas de Markov , Modelos Genéticos , Modelos Estadísticos , Proteínas/genética , Proteínas/metabolismo , Proteínas/fisiología , Curva ROCRESUMEN
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Apart from environmental factors such as hepatitis B virus (HBV) or hepatitis C virus, alcohol abuse, and exposure to dietary aflatoxin, genetic factors are also involved in the pathogenesis of HCC. By analyzing 390 HCC cases and 431 healthy controls in a Chinese population, we used a candidate gene approach to evaluate the association between a 15-bp insertion/deletion (indel) polymorphism (rs28381975) in the promoter region of the programmed cell death 6 interacting protein (PDCD6IP) gene and HCC susceptibility. Logistic regression analysis demonstrated that subjects carrying ins/del or ins/ins genotypes had significantly increased risk for HCC than individuals carrying del/del genotypes (adjusted odds ratio=1.39, 95% confidence interval=1.01-1.91, p=0.033]. Carrying the 15-bp insertion allele was associated with a 1.26-fold risk for HCC (95% CI=1.04-1.54, p=0.018). Moreover, significant differences were observed within HCC patients concerning genotypic frequencies of rs28381975 after stratifying by tumor stages and HBV infection. Computational modeling suggests that rs28381975 could disrupt the binding patterns of c-rel, a key subunit of nuclear factor-kappaB transcription factor. Further luciferase-based transient transfection assays revealed that rs28381975 can affect the promoter activity of PDCD6IP, indicating its possible functional significance. Taken together, our data suggest that common genetic variations in PDCD6IP may influence HCC risk, possibly through promoter activity-mediated regulation. Replication of our studies in other populations and further functional analysis will strengthen our understanding of this association.
Asunto(s)
Proteínas de Unión al Calcio/genética , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Mutación INDEL/fisiología , Neoplasias Hepáticas/genética , Regiones Promotoras Genéticas , Adulto , Pueblo Asiatico/genética , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etnología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/etnología , Genotipo , Humanos , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etnología , Masculino , Persona de Mediana Edad , Polimorfismo Genético/fisiología , Regiones Promotoras Genéticas/genéticaRESUMEN
Growing evidence suggests that the angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS) genes are associated with risk in a wide range of cancers. The objective of this study was to examine whether two DNA polymorphisms at the ACE insertion/deletion (I/D) and the variable number of tandem repeats in NOS intron 4 (4a/4b) were linked to the risk of developing hepatocellular carcinoma (HCC) in a Chinese population. The polymorphisms at ACE I/D and eNOS 4a/4b were genotyped in 293 HCC patients and 384 healthy control subjects using polymerase chain reaction. The frequencies of the D allele (p=0.003, OR=0.72, 95% CI=0.58-0.90) in the ACE gene of HCC patients were significantly different from the healthy controls, and a significantly decreased HCC risk was associated with the DD genotype in both the recessive (p<0.001, OR=0.19, 95% CI=0.11-0.34) and codominant models (p<0.001, OR=0.26, 95% CI=0.14-0.48). This study provided evidence that the ACE I/D polymorphism is associated with HCC, indicating that the ACE I/D polymorphism contributes to HCC progression in the Chinese population.
Asunto(s)
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Adulto , Anciano , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etnología , China/epidemiología , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Mutación INDEL/fisiología , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etnología , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III/genética , Polimorfismo Genético/fisiología , Factores de RiesgoRESUMEN
In this meta-analysis study, SNPs were investigated for their association with type 2 diabetes (T2D) in both Arab and Caucasian ethnicities. A total of 55 SNPs were analyzed, of which 11 fulfilled the selection criteria, and were used for analysis. It was found that TCF7L2 rs7903146 was significantly associated with a pooled OR of 1.155 (95%C.I.=1.059-1.259), p<0.0001 and I(2)=78.30% among the Arab population, whereas among Caucasians, the pooled OR was 1.45 (95%C.I.=1.386-1.516), p<0.0001 and I(2)=77.20%. KCNJ11 rs5219 was significantly associated in both the populations with a pooled OR of 1.176(1.092-1.268), p<0.0001 and I(2)=32.40% in Caucasians and a pooled OR of 1.28(1.111-1.475), p=0.001 among Arabs. The ACE I/D polymorphism was found to be significantly associated with a pooled OR of 1.992 (95%C.I.=1.774-2.236), p<0.0001 and I(2)=83.20% among the Arab population, whereas among Caucasians, the pooled OR was 1.078 (95%C.I.=0.993-1.17), p=0.073 and I(2)=0%. Similarly, MTHFR C677T polymorphism was also found to be significantly associated among Arabs with a pooled OR of 1.924 (95%C.I.=1.606-2.304), p<0.0001 and I(2)=27.20%, whereas among Caucasians, the pooled OR was 0.986 (95%C.I.=0.868-1.122), p=0.835 and I(2)=0%. Meanwhile PPARG-2 Pro12Ala, CDKN2A/2B rs10811661, IGF2BP2 rs4402960, HHEX rs7923837, CDKAL1 rs7754840, EXT2 rs1113132 and SLC30A8 rs13266634 were found to have no significant association with T2D among Arabs. In conclusion, it seems from this study that both Arabs and Caucasians have different SNPs associated with T2D. Moreover, this study sheds light on the profound necessity for further investigations addressing the question of the genetic components of T2D in Arabs.
Asunto(s)
Árabes/genética , Diabetes Mellitus Tipo 2/genética , Mutación INDEL , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo de Nucleótido Simple , Árabes/estadística & datos numéricos , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etnología , Etnicidad/genética , Etnicidad/estadística & datos numéricos , Estudios de Asociación Genética , Humanos , Mutación INDEL/fisiología , Polimorfismo de Nucleótido Simple/fisiología , PrevalenciaRESUMEN
Congenital heart disease (CHD) is the most frequently occurring congenital disorder in newborns and is the most frequent cause of infant death from birth defects. Human genetic studies have identified that numerous genes encoding transcription factors that regulate specific events in heart development are responsible for inherited and sporadic CHD. Nuclear factor-kappa B (NF-κB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes. The aim of this study was to investigate whether the functional -94 insertion/deletion ATTG polymorphism (rs28362491) in the promoter of nuclear factor κB gene (NFKB1) is associated with susceptibility to CHD. Polymerase chain reaction (PCR)-polyacrylamide gel electrophoresis (PAGE) method was used to genotype rs28362491 in 122 atrial septal defect (ASD) patients, 114 ventricular septal defect (VSD) patients, and 412 controls. The frequencies of II (Insertion/Insertion) genotype in the ASD and VSD patients were significantly higher than that of controls (p=0.004 for ASD Vs. controls, and p=0.009 for VSD Vs. controls, respectively), and the frequencies for I allele in CHD patients were also significantly higher than that in controls (p=0.01 for ASD Vs. controls, and p=0.009 for VSD Vs. controls, respectively). This study suggests that the functional -94 insertion/deletion ATTG polymorphism in the promoter of NFKB1 is associated with CHD.
Asunto(s)
Pueblo Asiatico/genética , Cardiopatías Congénitas/genética , Mutación INDEL/fisiología , Subunidad p50 de NF-kappa B/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genética de Población , Genotipo , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/etnología , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
RIG-I (retinoic acid-inducible gene I) is an essential cytosolic pathogen recognition receptor that binds to a variety of viral RNA or DNA to induce type I interferons. In the present study, insert-deletion polymorphisms in promoter and introns of CiRIG-I (Ctenopharyngodon idella RIG-I) were explored, their associations with resistance/susceptibility to grass carp reovirus (GCRV) were analyzed. To this end, genomic sequence of CiRIG-I gene was obtained, and twenty pairs of primers were prepared for the detection of insert-deletion polymorphisms. Five insert-deletion mutations were found, a 2-bp mutation and an 8-bp mutation existed in the promoter and other three sizes in 74 bp, 146 bp and 53 bp were sited in the intron 8. After a challenge experiment, only the genotype and allele of -740 insert-deletion mutation in the promoter and allele of 6804 insert-deletion mutation were significantly associated with resistance/susceptibility to GCRV among the five mutations (P<0.05). To further identify this correlation, another independent challenge test was carried out. The result revealed that the cumulative mortality in ins/ins genotype individuals (43.75%) at -740 insert-deletion mutation was significantly lower than that in ins/del (72.09%) and del/del (74.19%) genotypes (P<0.05). Linkage disequilibrium and haplotype analysis showed 6610 insert-deletion mutation and 6804 insert-deletion mutation were linkage disequilibrium. The haplotype ins-ins (6610ins-6804ins) was significantly susceptible to GCRV, and ins-del (6610ins-6804del) was significantly resistant to GCRV (P<0.05). Those could be potential gene markers for the future molecular selection of strains that are resistant to GCRV.
Asunto(s)
Carpas , Resistencia a la Enfermedad/genética , Enfermedades de los Peces/genética , Mutación INDEL , ARN Helicasas/genética , Infecciones por Reoviridae/genética , Reoviridae/inmunología , Animales , Secuencia de Bases , Carpas/genética , Carpas/inmunología , Enfermedades de los Peces/inmunología , Predisposición Genética a la Enfermedad , Mutación INDEL/fisiología , Intrones/genética , Datos de Secuencia Molecular , Polimorfismo Genético/fisiología , Regiones Promotoras Genéticas/genética , Infecciones por Reoviridae/inmunologíaRESUMEN
BACKGROUND: Transient tachypnea of neonate (TTN) and respiratory distress syndrome (RDS) of the newborn are the most common cause of early respiratory distress in the immediate neonatal period. There is increasing evidence to support the role for the activation of the renin angiotensin system during acute lung injury. OBJECTIVES: The purpose of this study was to determine if there is a relationship between angiotensin-converting enzyme (ACE) I/D polymorphism, ACE activity and TTN and respiratory distress syndromes. METHODS: Nineteen neonates with TTN, 20 neonates with RDS and 21 control infants are studied for ACE polymorphism and serum ACE activity. RESULTS: Twenty six (43.3%) patients have DD polymorphism, 19 (31.7%) patients have ID polymorphism and 15 (25%) patients have II polymorphism. Serum ACE activity is 43.5 ± 1.8 (40-46) U/L in DD, 31.5 ± 2.3 (28-36) U/L in ID and 22.1 ± 2.1(19-46) U/L in II patient. CONCLUSIONS: The study could not find any difference in DD alleles and ACE activity between control group and TTN group. ACE polymorphism was not different between RDS group and control group in this study.
Asunto(s)
Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Polimorfismo Genético , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Taquipnea Transitoria del Recién Nacido/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Edad Gestacional , Humanos , Mutación INDEL/fisiología , Recién Nacido , Masculino , Polimorfismo Genético/fisiología , Síndrome de Dificultad Respiratoria del Recién Nacido/complicaciones , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Taquipnea Transitoria del Recién Nacido/complicaciones , Taquipnea Transitoria del Recién Nacido/metabolismoRESUMEN
OBJECTIVE: The polycystic ovary syndrome (PCOS) is a common and complex disease with unclear pattern of inheritance, characterized by an androgen excess, while hyperinsulinemia and insulin resistance (IR) are common features of the syndrome. The angiotensin I converting enzyme (ACE) insertion (I)/deletion (D) gene polymorphism was proved to be involved in many pathophysiological conditions, including hypertension and IR. DESIGN: The purpose of this study was to evaluate the involvement of the ACE gene polymorphism in the pathogenesis of PCOS. METHODS: In a case-control association study involving 801 PCOS women and 266 healthy controls, hormonal determinations and ACE polymorphism genotyping were performed. The PCOS women were classified into three groups: Group A presented biochemical hyperandrogenism, combined with anovulation and polycystic ovarian morphology; Group B, clinical hyperandrogenism combined with anovulation and polycystic ovarian morphology; and Group C, chronic anovulation and polycystic ovarian morphology. RESULTS: A significant increase in the frequency of the DI genotype of the ACE polymorphism was detected in PCOS women as a whole (P=0.035), in PCOS Group A (P=0.039) and Group B (P=0.010), while there was no difference in Group C (P=0.939). Significant difference was also observed in hyperandrogenic PCOS women as a whole (Group A+B) (P=0.017). The II genotype was positively correlated with HOMA-IR and QUICKI and with fasting insulin and glucose/insulin ratio in these groups. CONCLUSIONS: The association study of the ACE I/D polymorphism in PCOS women demonstrates an increase in the DI genotype incidence and an association of the II genotype with IR.
Asunto(s)
Mutación INDEL , Resistencia a la Insulina/genética , Peptidil-Dipeptidasa A/genética , Síndrome del Ovario Poliquístico/genética , Polimorfismo Genético , Adolescente , Adulto , Glucemia/análisis , Glucemia/metabolismo , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Mutación INDEL/fisiología , Insulina/sangre , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/metabolismo , Polimorfismo Genético/fisiología , Adulto JovenRESUMEN
The prairie vole (Microtus ochrogaster) is an important model organism for the study of social behavior, yet our ability to correlate genes and behavior in this species has been limited due to a lack of genetic and genomic resources. Here we report the BAC-based targeted sequencing of behaviorally-relevant genes and flanking regions in the prairie vole. A total of 6.4 Mb of non-redundant or haplotype-specific sequence assemblies were generated that span the partial or complete sequence of 21 behaviorally-relevant genes as well as an additional 55 flanking genes. Estimates of nucleotide diversity from 13 loci based on alignments of 1.7 Mb of haplotype-specific assemblies revealed an average pair-wise heterozygosity (8.4×10(-3)). Comparative analyses of the prairie vole proteins encoded by the behaviorally-relevant genes identified >100 substitutions specific to the prairie vole lineage. Finally, our sequencing data indicate that a duplication of the prairie vole AVPR1A locus likely originated from a recent segmental duplication spanning a minimum of 105 kb. In summary, the results of our study provide the genomic resources necessary for the molecular and genetic characterization of a high-priority set of candidate genes for regulating social behavior in the prairie vole.
Asunto(s)
Arvicolinae/genética , Arvicolinae/fisiología , Conducta Animal/fisiología , Cromosomas Artificiales Bacterianos/genética , Análisis de Secuencia de ADN/métodos , Secuencia de Aminoácidos , Animales , Frecuencia de los Genes , Genes/fisiología , Variación Genética/fisiología , Mutación INDEL/fisiología , Filogenia , Polimorfismo de Nucleótido Simple/fisiología , Duplicaciones Segmentarias en el Genoma , Alineación de SecuenciaRESUMEN
We investigated the effect of traditional risk factors (hypertension, dyslipidemia and smoking) on the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and peripheral arterial disease (PAD) in 945 (454 men and 491 women) Taiwanese type 2 diabetic patients with a mean age of 63.5 (SD: 11.4) years. Among them, 81 (31 men and 50 women) had PAD (ankle-brachial index <0.9). The adjusted odds ratios (95% confidence intervals) were 2.48 (1.18-5.21), 1.69 (1.00-2.85) and 1.64 (1.12-2.39), respectively, for recessive (DD versus II + ID), dominant (DD + ID versus II) and additive (II = 0, ID = 1 and DD = 2) models. While analyzing the interaction between DD and the individual risk factor of hypertension, smoking and dyslipidemia, patients with the risk factor and with DD had the highest risk compared to referent patients without the risk factor and with II/ID. The respective adjusted odds ratios were 5.41 (2.05-14.31), 7.38 (1.87-29.06) and 4.64 (1.70-12.64). We did not find a significant interaction between DD and any of the risk factors under multiplicative or additive scale. In conclusion, traditional risk factors (hypertension, smoking and dyslipidemia) play an important role in the association between ACE genotypes and PAD. Patients with DD genotype and traditional risk factors are at the highest risk.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Angiopatías Diabéticas/genética , Peptidil-Dipeptidasa A/genética , Enfermedad Arterial Periférica/genética , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etnología , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/etnología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Mutación INDEL/fisiología , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/epidemiología , Enfermedad Arterial Periférica/etnología , Enfermedad Arterial Periférica/etiología , Polimorfismo Genético/fisiología , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
AIMS/HYPOTHESES: The aim of this study was to determine whether the angiotensin-converting enzyme (ACE) gene I/D polymorphisms independently predict severe hypoglycemia in community-dwelling type 2 patients. METHODS: Six hundred and two patients who were ACE genotyped at baseline and assessed in 1998 were followed up to the end of June 2006. Severe hypoglycemia was defined as that requiring documented health service use as the primary diagnosis. Cox proportional hazards modeling was used to determine the predictors of first episode and zero-inflated negative binomial regression modeling identified predictors of frequency. RESULTS: Forty-nine patients (8.1%) experienced 63 episodes of severe hypoglycemia. After adjusting for previously identified significant independent predictors of time to first episode, both ACE DD genotype and ACE inhibitor therapy, but not their interaction, added to the model [hazard ratio (95% confidence interval): 2.34 (1.29-4.26), P = 0.006, and 1.77 (0.99-3.13), P = 0.052, respectively]. Similarly, after adjusting for previously identified risk factors for multiple episodes of severe hypoglycemia, ACE DD genotype was independently associated with increased risk [incidence relative risk (95% confidence interval): 1.80 (1.00-3.24), P = 0.050]. CONCLUSIONS/INTERPRETATION: ACE DD genotype was associated with an approximately 2-fold increased risk of the first episode of severe hypoglycemia and its subsequent frequency in well-characterized patients with type 2 diabetes. Consistent with previous case-control studies, ACE inhibitor therapy was a weak predictor of severe hypoglycemia. ACE I/D genotyping might provide useful adjunctive prognostic information when intensive glycemic control measures are contemplated.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Hipoglucemia/genética , Mutación INDEL , Peptidil-Dipeptidasa A/genética , Anciano , Australia , Estudios de Casos y Controles , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Hipoglucemia/complicaciones , Hipoglucemia/diagnóstico , Mutación INDEL/fisiología , Masculino , Persona de Mediana Edad , Polimorfismo Genético/fisiología , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
We investigated the association of the angiotensin converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism, alone or in combination with the α-actinin-3 gene (ACTN3) R577X polymorphism, with jumping (vertical squat and counter-movement jump tests) and sprint ability (30 m dash) in non-athletic, healthy young adults [N = 281 (214 male), mean (SD) age 21 (2) years]. We did not observe any effect of the ACE I/D polymorphism on study phenotypes. We repeated the analyses separately in men and women and the results did not materially change. Likewise, the mean estimates of the study phenotypes were similar in subjects with the genotype combinations ACE II + ID and ACTN3 XX or ACE DD and ACTN3 RR + RX. We found no association between the ACE DD and ACTN3 RR + RX genotype combination and performance (≥90th of the sex-specific percentile). In summary, though the ACE I/D polymorphism is a strong candidate to modulate some exercise-related phenotypes or athletic performance status, this polymorphism, alone or in combination with the ACTN3 R577X polymorphism, does not seem to exert a major influence in the muscle 'explosive' power of young healthy adults, as assessed during multi-joint exercise tests.
Asunto(s)
Actinina/genética , Mutación INDEL , Fuerza Muscular/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo de Nucleótido Simple , Adulto , Sustitución de Aminoácidos/genética , Sustitución de Aminoácidos/fisiología , Arginina/genética , Atletas , Rendimiento Atlético/fisiología , Prueba de Esfuerzo , Femenino , Humanos , Mutación INDEL/fisiología , Masculino , Fuerza Muscular/fisiología , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Mutación Missense/fisiología , Polimorfismo de Nucleótido Simple/fisiología , Adulto JovenRESUMEN
Cathelicidins (CATHLs) are small, cationic antimicrobial peptides that establish an early innate immune defense against infections in mammals. Beyond their wide spectrum of antimicrobial activity, these peptides play important roles in wound repair, chemotactic activity, and apoptosis. Thus, polymorphisms present in bovine CATHLs 2, 5, 6, and 7 could potentially underlie inherited differences in innate immunity and disease resistance. The purpose of the present study was to characterize single nucleotide polymorphisms (SNPs) and insertion-deletion (indel) polymorphisms within the bovine CATHL gene family. Comparative sequence analysis for 10 domestic cattle breeds representing both Bos taurus and Bos indicus revealed 60 SNPs, 7 of which were nonsynonymous and 5 indel mutations. Characterization of these novel polymorphisms is central to developing a firm understanding regarding what effects, if any, nonsynonymous CATHL variation has with respect to bovine innate immunity.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/genética , Bovinos/genética , Polimorfismo Genético , Análisis de Secuencia de ADN , Alelos , Animales , Estudios de Casos y Controles , Bovinos/inmunología , Frecuencia de los Genes , Mutación INDEL/fisiología , Inmunidad Innata/genética , Familia de Multigenes/genética , Mutación Puntual , Proteínas/genética , CatelicidinasRESUMEN
BACKGROUND: Whole-genome sequencing represents a promising approach to pinpoint chemically induced mutations in genetic model organisms, thereby short-cutting time-consuming genetic mapping efforts. PRINCIPAL FINDINGS: We compare here the ability of two leading high-throughput platforms for paired-end deep sequencing, SOLiD (ABI) and Genome Analyzer (Illumina; "Solexa"), to achieve the goal of mutant detection. As a test case we used a mutant C. elegans strain that harbors a mutation in the lsy-12 locus which we compare to the reference wild-type genome sequence. We analyzed the accuracy, sensitivity, and depth-coverage characteristics of the two platforms. Both platforms were able to identify the mutation that causes the phenotype of the mutant C. elegans strain, lsy-12. Based on a 4 MB genomic region in which individual variants were validated by Sanger sequencing, we observe tradeoffs between rates of false positives and false negatives when using both platforms under similar coverage and mapping criteria. SIGNIFICANCE: In conclusion, whole-genome sequencing conducted by either platform is a viable approach for the identification of single-nucleotide variations in the C. elegans genome.