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2.
Anim Sci J ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701624

RESUMO

The aim of this study was to estimate genetic parameters for lactation yields of milk (MY), fat (FY), protein (PY), and somatic cell score (SCS) of New Zealand dairy goats. The analysis used 64,604 lactation records from 23,583 does, kidding between 2004 and 2017, distributed in 21 flocks and representing 915 bucks. Estimates of genetic and residual (co) variances, heritabilities, and repeatabilities were obtained using a multiple-trait repeatability animal model. The model included the fixed effects of contemporary group (does kidding in the same flock and year), age of the doe (in years), and as covariates, kidding day, proportion of Alpine, Nubian, Toggenburg, and "unknown" breeds (Saanen was used as the base breed), and heterosis. Random effects included additive animal genetic and doe permanent environmental effects. Estimates of heritabilities were 0.25 for MY, 0.24 for FY, 0.24 for PY, and 0.21 for SCS. The phenotypic correlations between MY, FY, and PY ranged from 0.90 to 0.96, and the genetic correlations ranged from 0.81 to 0.93. These results indicate lactation yield traits exhibit useful heritable variation and that multiple trait selection for these traits could improve milk revenue produced from successive generations of New Zealand dairy goats.

3.
Sci Rep ; 9(1): 16934, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729446

RESUMO

The popularisation and decreased cost of genome resequencing has resulted in an increased use in molecular diagnostics. While there are a number of established and high quality bioinfomatic tools for identifying small genetic variants including single nucleotide variants and indels, currently there is no established standard for the detection of copy number variants (CNVs) from sequence data. The requirement for CNV detection from high throughput sequencing has resulted in the development of a large number of software packages. These tools typically utilise the sequence data characteristics: read depth, split reads, read pairs, and assembly-based techniques. However, the additional source of information from read balance (defined as relative proportion of reads of each allele at each position) has been underutilised in the existing applications. Here we present Read Balance Validator (RBV), a bioinformatic tool that uses read balance for prioritisation and validation of putative CNVs. The software simultaneously interrogates nominated regions for the presence of deletions or multiplications, and can differentiate larger CNVs from diploid regions. Additionally, the utility of RBV to test for inheritance of CNVs is demonstrated in this report. RBV is a CNV validation and prioritisation bioinformatic tool for both genome and exome sequencing available as a python package from https://github.com/whitneywhitford/RBV.

4.
J Biomed Inform ; 94: 103174, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30965134

RESUMO

BACKGROUND: Whole genome sequencing (WGS) has increased in popularity and decreased in cost over the past decade, rendering this approach as a viable and sensitive method for variant detection. In addition to its utility for single nucleotide variant detection, WGS data has the potential to detect Copy Number Variants (CNV) to fine resolution. Many CNV detection software packages have been developed exploiting four main types of data: read pair, split read, read depth, and assembly based methods. The aim of this study was to evaluate the efficiency of each of these main approaches in detecting germline deletions. METHODS: WGS data and high confidence deletion calls for the individual NA12878 from the Genome in a Bottle consortium were the benchmark dataset. The performance of BreakDancer, CNVnator, Delly, FermiKit, and Pindel was assessed by comparing the accuracy and sensitivity of each software package in detecting deletions exceeding 1 kb. RESULTS: There was considerable variability in the outputs of the different WGS CNV detection programs. The best performance was seen from BreakDancer and Delly, with 92.6% and 96.7% sensitivity, respectively and 34.5% and 68.5% false discovery rate (FDR), respectively. In comparison, Pindel, CNVnator, and FermiKit were less effective with sensitivities of 69.1%, 66.0%, and 15.8%, respectively and FDR of 91.3%, 69.0%, and 31.7%, respectively. Concordance across software packages was poor, with only 27 of the total 612 benchmark deletions identified by all five methodologies. CONCLUSIONS: The WGS based CNV detection tools evaluated show disparate performance in identifying deletions ≥1 kb, particularly those utilising different input data characteristics. Software that exploits read pair based data had the highest sensitivity, namely BreakDancer and Delly. BreakDancer also had the second lowest false discovery rate. Therefore, in this analysis read pair methods (BreakDancer in particular) were the best performing approaches for the identification of deletions ≥1 kb, balancing accuracy and sensitivity. There is potential for improvement in the detection algorithms, particularly for reducing FDR. This analysis has validated the utility of WGS based CNV detection software to reliably identify deletions, and these findings will be of use when choosing appropriate software for deletion detection, in both research and diagnostic medicine.

5.
Mol Genet Genomic Med ; 7(1): e00476, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30345660

RESUMO

BACKGROUND: Isolated cardiac arrhythmia due to a variant in CACNA1C is of recent knowledge. Most reports have been of singleton cases or of quite small families, and estimates of penetrance and expressivity have been difficult to obtain. We here describe a large pedigree, from which such estimates have been calculated. METHODS: We studied a five-generation family, in which a CACNA1C variant c.2573G>A p.Arg858His co-segregates with syncope and cardiac arrest, documenting electrocardiographic data and cardiac symptomatology. The reported patients/families from the literature with CACNA1C gene variants were reviewed, and genotype-phenotype correlations are drawn. RESULTS: The range of phenotype in the studied family is wide, from no apparent effect, through an asymptomatic QT interval prolongation on electrocardiography, to episodes of presyncope and syncope, ventricular fibrillation, and sudden death. QT prolongation showed inconsistent correlation with functional cardiology. Based upon analysis of 28 heterozygous family members, estimates of penetrance and expressivity are derived. CONCLUSIONS: These estimates of penetrance and expressivity, for this specific variant, may be useful in clinical practice. Review of the literature indicates that individual CACNA1C variants have their own particular genotype-phenotype correlations. We suggest that, at least in respect of the particular variant reported here, "arrhythmogenic channelopathy" may be a more fitting nomenclature than long QT syndrome.


Assuntos
Arritmias Cardíacas/genética , Canais de Cálcio Tipo L/genética , Canalopatias/genética , Mutação de Sentido Incorreto , Penetrância , Adulto , Idoso , Arritmias Cardíacas/patologia , Canalopatias/patologia , Criança , Eletrocardiografia , Feminino , Genótipo , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
6.
Dis Model Mech ; 11(11)2018 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-30266839

RESUMO

Brain dopamine-serotonin vesicular transport disease is a rare disease caused by autosomal recessive mutations in the SLC18A2 gene, which encodes the VMAT2 protein. VMAT2 is a membrane protein responsible for vesicular transport of monoamines, and its disruption negatively affects neurotransmission. This results in a severe neurodevelopmental disorder affecting motor skills and development, and causes muscular hypotonia. The condition was initially described in a consanguineous Saudi Arabian family with affected siblings homozygous for a P387L mutation. We subsequently found a second mutation in a New Zealand family (homozygous P237H), which was later also identified in an Iraqi family. Pramipexole has been shown to have some therapeutic benefit. Transgenic Caenorhabditis elegans were developed to model the P237H and P387L mutations. Investigations into dopamine- and serotonin-related C. elegans phenotypes, including pharyngeal pumping and grazing, showed that both mutations cause significant impairment of these processes when compared with a non-transgenic N2 strain and a transgenic containing the wild-type human SLC18A2 gene. Preliminary experiments investigating the therapeutic effects of serotonin and pramipexole demonstrated that serotonin could successfully restore the pharyngeal pumping phenotype. These analyses provide further support for the role of these mutations in this disease.


Assuntos
Encéfalo/metabolismo , Caenorhabditis elegans/metabolismo , Dopamina/metabolismo , Modelos Biológicos , Serotonina/metabolismo , Vesículas Transportadoras/patologia , Animais , Animais Geneticamente Modificados , Sequência de Bases , Transporte Biológico , Humanos , Faringe/patologia , Fenótipo , Vesículas Transportadoras/metabolismo
7.
Expert Rev Clin Immunol ; 14(7): 549-556, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29806948

RESUMO

INTRODUCTION: Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune defect in adults. Within the broad spectrum of CVID, a proportion of patients present with a predominant T cell phenotype associated with increased mortality. These patients are termed late-onset combined immunodeficiency (LOCID) and are currently separated from patients suffering from CVID. Areas covered: We have recently codiscovered a new CVID-like disorder caused by mutations of the NFKB1 gene. Members of this non-consanguineous New Zealand kindred have a very diverse spectrum of phenotypes in spite of carrying the identical mutation. The proband appears to have the autoimmune variant. The proband's recently deceased sister best matched LOCID while other family members are less severely affected, including one asymptomatic adult brother, who has an affected daughter. Differences in genetics was one of the main arguments for separating these disorders in the past. Expert commentary: Given the recent advances in the understanding of the genetic basis of these conditions, we present the case that LOCID should now be considered a subset of CVID, rather than a separate disorder. At a clinical level, this distinction is less important but it is imperative these patients are carefully evaluated, the relevant complications are treated, and they are offered prognostic information.


Assuntos
Imunodeficiência de Variável Comum/genética , Genótipo , Mutação/genética , Subunidade p50 de NF-kappa B/genética , Imunodeficiência Combinada Severa/genética , Linfócitos T/fisiologia , Adolescente , Idade de Início , Idoso , Autoimunidade , Imunodeficiência de Variável Comum/imunologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Linhagem , Fenótipo , Imunodeficiência Combinada Severa/imunologia
8.
Sci Rep ; 8(1): 7548, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29765130

RESUMO

The pathophysiology of stress cardiomyopathy (SCM), also known as takotsubo syndrome, is poorly understood. SCM usually occurs sporadically, often in association with a stressful event, but clusters of cases are reported after major natural disasters. There is some evidence that this is a familial condition. We have examined three possible models for an underlying genetic predisposition to SCM. Our primary study cohort consists of 28 women who suffered SCM as a result of two devastating earthquakes that struck the city of Christchurch, New Zealand, in 2010 and 2011. To seek possible underlying genetic factors we carried out exome analysis, genotyping array analysis, and array comparative genomic hybridization on these subjects. The most striking finding was the observation of a markedly elevated rate of rare, heterogeneous copy number variants (CNV) of uncertain clinical significance (in 12/28 subjects). Several of these CNVs impacted on genes of cardiac relevance including RBFOX1, GPC5, KCNRG, CHODL, and GPBP1L1. There is no physical overlap between the CNVs, and the genes they impact do not appear to be functionally related. The recognition that SCM predisposition may be associated with a high rate of rare CNVs offers a novel perspective on this enigmatic condition.


Assuntos
Variações do Número de Cópias de DNA , Redes Reguladoras de Genes , Técnicas de Genotipagem/métodos , Cardiomiopatia de Takotsubo/genética , Hibridização Genômica Comparativa , Terremotos , Feminino , Predisposição Genética para Doença , Glipicanas/genética , Humanos , Lectinas Tipo C/genética , Proteínas de Membrana/genética , Nova Zelândia , Análise de Sequência com Séries de Oligonucleotídeos , Canais de Potássio/genética , Fatores de Processamento de RNA/genética , Sequenciamento Completo do Exoma
9.
Clin Rev Allergy Immunol ; 54(2): 261-268, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29030829

RESUMO

Common variable immunodeficiency disorders (CVID) are an enigmatic group of often heritable conditions, which may manifest for the first time in early childhood or as late as the eighth decade of life. In the last 5 years, next generation sequencing (NGS) has revolutionised identification of genetic disorders. However, despite the best efforts of researchers around the globe, CVID conditions have been slow to yield their molecular secrets. We have previously described the many clinical advantages of identifying the genetic basis of primary immunodeficiency disorders (PIDs). In a minority of CVID patients, monogenic defects have now been identified. If a causative mutation is identified, these conditions are reclassified as CVID-like disorders. Here we discuss recent advances in the genetics of CVID and discuss how NGS can be optimally deployed to identify the causal mutations responsible for the protean clinical manifestations of these conditions. Diagnostic criteria such as the Ameratunga et al. criteria will continue to play an important role in patient management as well as case selection and sequencing strategy design until the genetic conundrum of CVID is solved.


Assuntos
Imunodeficiência de Variável Comum/genética , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Imunodeficiência de Variável Comum/diagnóstico , Predisposição Genética para Doença , Humanos , Mutação/genética , Sequenciamento Completo do Genoma
10.
JIMD Rep ; 42: 31-36, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29159460

RESUMO

Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ10, and the siblings were subsequently established on a therapeutic dose of CoQ10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.

11.
Clin Transl Immunology ; 6(10): e159, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29114388

RESUMO

Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of TCF3 impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband.

12.
Artigo em Inglês | MEDLINE | ID: mdl-28696212

RESUMO

Mutations in the gene SLC19A3 result in thiamine metabolism dysfunction syndrome 2, also known as biotin-thiamine-responsive basal ganglia disease (BTBGD). This neurometabolic disease typically presents in early childhood with progressive neurodegeneration, including confusion, seizures, and dysphagia, advancing to coma and death. Treatment is possible via supplement of biotin and/or thiamine, with early treatment resulting in significant lifelong improvements. Here we report two siblings who received a refined diagnosis of BTBGD following whole-genome sequencing. Both children inherited compound heterozygous mutations from unaffected parents; a missense single-nucleotide variant (p.G23V) in the first transmembrane domain of the protein, and a 4808-bp deletion in exon 1 encompassing the 5' UTR and minimal promoter region. This deletion is the smallest promoter deletion reported to date, further defining the minimal promoter region of SLC19A3 Unfortunately, one of the siblings died prior to diagnosis, but the other is showing significant improvement after commencement of therapy. This case demonstrates the power of whole-genome sequencing for the identification of structural variants and subsequent diagnosis of rare neurodevelopmental disorders.


Assuntos
Doenças dos Gânglios da Base/genética , Proteínas de Membrana Transportadoras/genética , Regiões 5' não Traduzidas/genética , Gânglios da Base/metabolismo , Doenças dos Gânglios da Base/diagnóstico , Biotina/genética , Biotina/metabolismo , Encéfalo/metabolismo , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Mutação , Regiões Promotoras Genéticas/genética , Irmãos , Tiamina/metabolismo , Adulto Jovem
13.
Front Immunol ; 8: 1965, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29434582

RESUMO

The existence of epistasis in humans was first predicted by Bateson in 1909. Epistasis describes the non-linear, synergistic interaction of two or more genetic loci, which can substantially modify disease severity or result in entirely new phenotypes. The concept has remained controversial in human genetics because of the lack of well-characterized examples. In humans, it is only possible to demonstrate epistasis if two or more genes are mutated. In most cases of epistasis, the mutated gene products are likely to be constituents of the same physiological pathway leading to severe disruption of a cellular function such as antibody production. We have recently described a digenic family, who carry mutations of TNFRSF13B/TACI as well as TCF3 genes. Both genes lie in tandem along the immunoglobulin isotype switching and secretion pathway. We have shown they interact in an epistatic way causing severe immunodeficiency and autoimmunity in the digenic proband. With the advent of next generation sequencing, it is likely other families with digenic inheritance will be identified. Since digenic inheritance does not always cause epistasis, we propose an epistasis index which may help quantify the effects of the two mutations. We also discuss the clinical implications of digenic inheritance and epistasis in humans with primary immunodeficiency disorders.

14.
Sci Rep ; 6: 25376, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27146958

RESUMO

The mammary gland is a prolific lipogenic organ, synthesising copious amounts of triglycerides for secretion into milk. The fat content of milk varies widely both between and within species, and recent independent genome-wide association studies have highlighted a milk fat percentage quantitative trait locus (QTL) of large effect on bovine chromosome 5. Although both EPS8 and MGST1 have been proposed to underlie these signals, the causative status of these genes has not been functionally confirmed. To investigate this QTL in detail, we report genome sequence-based imputation and association mapping in a population of 64,244 taurine cattle. This analysis reveals a cluster of 17 non-coding variants spanning MGST1 that are highly associated with milk fat percentage, and a range of other milk composition traits. Further, we exploit a high-depth mammary RNA sequence dataset to conduct expression QTL (eQTL) mapping in 375 lactating cows, revealing a strong MGST1 eQTL underpinning these effects. These data demonstrate the utility of DNA and RNA sequence-based association mapping, and implicate MGST1, a gene with no obvious mechanistic relationship to milk composition regulation, as causally involved in these processes.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Glutationa Transferase/genética , Leite/química , Locos de Características Quantitativas , Animais , Teorema de Bayes , Bovinos , Mapeamento Cromossômico/veterinária , Cromossomos de Mamíferos/genética , Estudo de Associação Genômica Ampla/veterinária , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/veterinária , Análise de Sequência de RNA/veterinária
15.
Front Pharmacol ; 7: 1, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26858644

RESUMO

Whole-exome sequencing (WES) has been widely used for analysis of human genetic diseases, but its value for the pharmacogenomic profiling of individuals is not well studied. Initially, we performed an in-depth evaluation of the accuracy of WES variant calling in the pharmacogenes CYP2D6 and CYP2C19 by comparison with MiSeq(®) amplicon sequencing data (n = 36). This analysis revealed that the concordance rate between WES and MiSeq(®) was high, achieving 99.60% for variants that were called without exceeding the truth-sensitivity threshold (99%), defined during variant quality score recalibration (VQSR). Beyond this threshold, the proportion of discordant calls increased markedly. Subsequently, we expanded our findings beyond CYP2D6 and CYP2C19 to include more genes genotyped by the iPLEX(®) ADME PGx Panel in the subset of twelve samples. WES performed well, agreeing with the genotyping panel in approximately 99% of the selected pass-filter variant calls. Overall, our results have demonstrated WES to be a promising approach for pharmacogenomic profiling, with an estimated error rate of lower than 1%. Quality filters, particularly VQSR, are important for reducing the number of false variants. Future studies may benefit from examining the role of WES in the clinical setting for guiding drug therapy.

16.
J Inherit Metab Dis ; 39(2): 305-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26497564

RESUMO

Two male siblings from a consanguineous union presented in early infancy with marked truncal hypotonia, a general paucity of movement, extrapyramidal signs and cognitive delay. By mid-childhood they had made little developmental progress and remained severely hypotonic and bradykinetic. They developed epilepsy and had problems with autonomic dysfunction and oculogyric crises. They had a number of orthopaedic problems secondary to their hypotonia. Cerebrospinal fluid (CSF) neurotransmitters were initially normal, apart from mildly elevated 5-hydroxyindolacetic acid, and the children did not respond favourably to a trial of levodopa-carbidopa. The youngest died from respiratory complications at 10 years of age. Repeat CSF neurotransmitters in the older sibling at eight years of age showed slightly low homovanillic acid and 5-hydroxyindoleacetic acid levels. Whole-exome sequencing revealed a novel mutation homozygous in both children in the monoamine transporter gene SLC18A2 (p.Pro237His), resulting in brain dopamine-serotonin vesicular transport disease. This is the second family to be described with a mutation in this gene. Treatment with the dopamine agonist pramipexole in the surviving child resulted in mild improvements in alertness, communication, and eye movements. This case supports the identification of the causal mutation in the original case, expands the clinical phenotype of brain dopamine-serotonin vesicular transport disease and confirms that pramipexole treatment may lead to symptomatic improvement in affected individuals.


Assuntos
Encefalopatias/genética , Encefalopatias/metabolismo , Encéfalo/metabolismo , Dopamina/metabolismo , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , Serotonina/metabolismo , Encéfalo/efeitos dos fármacos , Encefalopatias/tratamento farmacológico , Carbidopa/uso terapêutico , Criança , Humanos , Levodopa/uso terapêutico , Masculino , Transtornos Parkinsonianos/tratamento farmacológico , Polimorfismo de Nucleotídeo Único/genética
17.
Case Rep Genet ; 2015: 454526, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26587300

RESUMO

We describe two brothers who presented at birth with bone growth abnormalities, followed by development of increasingly severe intellectual and physical disability, growth restriction, epilepsy, and cerebellar and brain stem atrophy, but normal ocular phenotypes. Case 1 died at 19 years of age due to chronic respiratory illnesses without a unifying diagnosis. The brother remains alive but severely disabled at 19 years of age. Whole exome sequencing identified compound heterozygous stop mutations in the peroxisome biogenesis factor 7 gene in both individuals. Mutations in this gene cause rhizomelic chondrodysplasia punctata, type 1 (RCDP1). One mutation, p.Arg232 (∗) , has only been documented once before in a Japanese family, which is of interest given these two boys are of European descent. The other mutation, p.Leu292 (∗) , is found in approximately 50% of RCDP1 patients. These are the first cases of RCDP1 that describe the coinheritance of the p.Arg232 (∗) and p.Leu292 (∗) mutations and demonstrate the utility of WES in cases with unclear diagnoses.

18.
Am J Hum Genet ; 97(3): 389-403, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26279205

RESUMO

Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50­translated from the non-mutated alleles­were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.


Assuntos
Imunodeficiência de Variável Comum/genética , Haploinsuficiência/genética , Subunidade p50 de NF-kappa B/genética , Austrália , Sequência de Bases , Western Blotting , Primers do DNA/genética , Exoma/genética , Humanos , Microscopia de Fluorescência , Dados de Sequência Molecular , Países Baixos , Nova Zelândia , Análise de Sequência de DNA
19.
Sci Rep ; 5: 8484, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25719731

RESUMO

Selective breeding has strongly reduced the genetic diversity in livestock species, and contemporary breeding practices exclude potentially beneficial rare genetic variation from the future gene pool. Here we test whether important traits arising by new mutations can be identified and rescued in highly selected populations. We screened milks from 2.5 million cows to identify an exceptional individual which produced milk with reduced saturated fat content, and improved unsaturated and omega-3 fatty acid concentrations. The milk traits were transmitted dominantly to her offspring, and genetic mapping and genome sequencing revealed a new mutation in a previously unknown splice enhancer of the DGAT1 gene. Homozygous carriers show features of human diarrheal disorders, and may be useful for the development of therapeutic strategies. Our study demonstrates that high-throughput phenotypic screening can uncover rich genetic diversity even in inbred populations, and introduces a novel strategy to develop novel milks with improved nutritional properties.


Assuntos
Diacilglicerol O-Aciltransferase/genética , Leite/metabolismo , Mutação de Sentido Incorreto , Animais , Sequência de Bases , Bovinos/genética , Ácidos Graxos/biossíntese , Feminino , Estudos de Associação Genética , Metabolismo dos Lipídeos/genética , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único
20.
J Dairy Res ; 81(3): 340-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25052435

RESUMO

The objective of this study was to estimate heritability and crossbreeding parameters (breed and heterosis effects) of various fatty acid (FA) concentrations in milk fat of New Zealand dairy cattle. For this purpose, calibration equations to predict concentration of each of the most common FAs were derived with partial least squares (PLS) using mid-infrared (MIR) spectral data from milk samples (n=850) collected in the 2003-04 season from 348 second-parity crossbred cows during peak, mid and late lactation. The milk samples produced both, MIR spectral data and concentration of the most common FAs determined using gas chromatography (GC). The concordance correlation coefficients (CCC) between the concentration of a FA determined by GC and the PLS equation ranged from 0.63 to 0.94, suggesting that some prediction equations can be considered to have substantial predictive ability. The PLS calibration equations were then used to predict the concentration of each of the fatty acids in 26,769 milk samples from 7385 cows that were herd-tested during the 2007-08 season. Data were analysed using a single-trait repeatability animal model. Shorter chain FA (16:0 and below) were significantly higher (P<0.05) in Jersey cows, while longer chain, including unsaturated longer chain FA were higher in Holstein-Friesian cows. The estimates of heritabilities ranged from 0.17 to 0.41 suggesting that selective breeding could be used to ensure milk fat composition stays aligned to consumer, market and manufacturing needs.


Assuntos
Bovinos/genética , Ácidos Graxos/análise , Leite/química , Animais , Cromatografia Gasosa/veterinária , Feminino , Hibridização Genética/genética , Característica Quantitativa Herdável , Espectrofotometria Infravermelho/veterinária
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