RESUMO
Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.
Assuntos
Metilação de DNA , Epigenoma/genética , Desnutrição Aguda Grave/genética , Adolescente , Adulto , Estudos de Casos e Controles , Pré-Escolar , Ilhas de CpG/genética , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Jamaica/epidemiologia , Malaui/epidemiologia , Masculino , Mucosa Bucal , Estudos Prospectivos , Estudos Retrospectivos , Desnutrição Aguda Grave/mortalidade , Sobreviventes , Adulto JovemRESUMO
Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (n = 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (n = 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (n = 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.
RESUMO
We investigated 67 breakpoint junctions of gene copy number gains in 31 unrelated subjects. We observed a strikingly high frequency of small deletions and insertions (29%) apparently originating from polymerase slippage events, in addition to frameshifts and point mutations in homonucleotide runs (13%), at or flanking the breakpoint junctions of complex copy number variants. These single-nucleotide variants were generated concomitantly with the de novo complex genomic rearrangement (CGR) event. Our findings implicate low-fidelity, error-prone DNA polymerase activity in synthesis associated with DNA repair mechanisms as the cause of local increase in point mutation burden associated with human CGR.
Assuntos
Quebras de DNA , Variações do Número de Cópias de DNA/genética , Reparo do DNA/genética , Replicação do DNA/genética , Rearranjo Gênico/genética , Sequência de Bases , Mutação da Fase de Leitura , Variação Genética , Genótipo , Humanos , Análise de Sequência de DNA , Deleção de SequênciaRESUMO
For admixture mapping studies in Mexican Americans (MAM), we define a genomewide single-nucleotide-polymorphism (SNP) panel that can distinguish between chromosomal segments of Amerindian (AMI) or European (EUR) ancestry. These studies used genotypes for >400,000 SNPs, defined in EUR and both Pima and Mayan AMI, to define a set of ancestry-informative markers (AIMs). The use of two AMI populations was necessary to remove a subset of SNPs that distinguished genotypes of only one AMI subgroup from EUR genotypes. The AIMs set contained 8,144 SNPs separated by a minimum of 50 kb with only three intermarker intervals >1 Mb and had EUR/AMI FST values >0.30 (mean FST = 0.48) and Mayan/Pima FST values <0.05 (mean FST < 0.01). Analysis of a subset of these SNP AIMs suggested that this panel may also distinguish ancestry between EUR and other disparate AMI groups, including Quechuan from South America. We show, using realistic simulation parameters that are based on our analyses of MAM genotyping results, that this panel of SNP AIMs provides good power for detecting disease-associated chromosomal segments for genes with modest ethnicity risk ratios. A reduced set of 5,287 SNP AIMs captured almost the same admixture mapping information, but smaller SNP sets showed substantial drop-off in admixture mapping information and power. The results will enable studies of type 2 diabetes, rheumatoid arthritis, and other diseases among which epidemiological studies suggest differences in the distribution of ancestry-associated susceptibility.
Assuntos
Mapeamento Cromossômico , Genoma Humano , Americanos Mexicanos/genética , Polimorfismo de Nucleotídeo Único , Algoritmos , Cromossomos Humanos , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos , Genética Populacional , Genótipo , Humanos , Indígenas Norte-Americanos/genética , Indígenas Sul-Americanos/genética , Cadeias de Markov , Método de Monte Carlo , População BrancaRESUMO
Argentine population genetic structure was examined using a set of 78 ancestry informative markers (AIMs) to assess the contributions of European, Amerindian, and African ancestry in 94 individuals members of this population. Using the Bayesian clustering algorithm STRUCTURE, the mean European contribution was 78%, the Amerindian contribution was 19.4%, and the African contribution was 2.5%. Similar results were found using weighted least mean square method: European, 80.2%; Amerindian, 18.1%; and African, 1.7%. Consistent with previous studies the current results showed very few individuals (four of 94) with greater than 10% African admixture. Notably, when individual admixture was examined, the Amerindian and European admixture showed a very large variance and individual Amerindian contribution ranged from 1.5 to 84.5% in the 94 individual Argentine subjects. These results indicate that admixture must be considered when clinical epidemiology or case control genetic analyses are studied in this population. Moreover, the current study provides a set of informative SNPs that can be used to ascertain or control for this potentially hidden stratification. In addition, the large variance in admixture proportions in individual Argentine subjects shown by this study suggests that this population is appropriate for future admixture mapping studies.
Assuntos
Indígenas Sul-Americanos/genética , Povo Asiático/genética , Teorema de Bayes , População Negra/genética , Frequência do Gene , Marcadores Genéticos , Variação Genética , Genética Populacional , Humanos , Americanos Mexicanos/genética , População Branca/genéticaRESUMO
BACKGROUND: The left ventricular outflow tract (LVOT) malformations aortic valve stenosis (AVS), coarctation of the aorta (CoA), and hypoplastic left heart syndrome (HLHS) contribute significantly to infant mortality due to birth defects. Previous epidemiology data showed rate differences between male and female and white and black ethnic groups. The Texas Birth Defects Registry, an active surveillance program, enables study in a large, diverse population including Hispanics. METHODS: Records of children up to 1 year old with AVS, CoA, and HLHS born in Texas from 1999 to 2001, were collected from the registry. Those including additional heart defects or a chromosomal anomaly were excluded. Multivariate analysis included: infant sex; United States-Mexico border county residence; and maternal age, race/ethnicity, birthplace, and education. RESULTS: There were 910 cases among 1.08 million live births, of which 499 met inclusion criteria. Multivariate modeling of all LVOT malformations combined demonstrated lower prevalence rate ratios (PRRs) for black males (0.26) and Hispanic males (0.70). Similar results were found for CoA but not AVS or HLHS. Higher PRRs were noted for increased maternal age for LVOT (1.3 for 24-34 years; 1.7 for >34 years), AVS, and HLHS, but not CoA, and higher PRRs across all diagnoses for males (LVOT PRR, 2.4) were noted. CoA PRRs were higher in border county vs. non-border county residents (PRR, 2.1). Maternal education and birthplace were not significant factors. CONCLUSIONS: There are rate differences for males among all 3 ethnic groups. Sex and ethnic differences suggest genetic etiologies, where the ethnic differences could be used to find susceptibility loci with mapping by admixture linkage disequilibrium. Increased CoA rates along the U.S.-Mexico border suggest environmental causes that will require further monitoring.
Assuntos
Coartação Aórtica/epidemiologia , Estenose da Valva Aórtica/epidemiologia , Síndrome do Coração Esquerdo Hipoplásico/epidemiologia , Coartação Aórtica/etnologia , Coartação Aórtica/mortalidade , Estenose da Valva Aórtica/etnologia , Estenose da Valva Aórtica/mortalidade , Feminino , Humanos , Síndrome do Coração Esquerdo Hipoplásico/etnologia , Síndrome do Coração Esquerdo Hipoplásico/mortalidade , Lactente , Recém-Nascido , Masculino , Idade Materna , México , Análise Multivariada , Gravidez , Prevalência , Grupos Raciais , Fatores Sexuais , Texas , Obstrução do Fluxo Ventricular Externo/congênito , Obstrução do Fluxo Ventricular Externo/epidemiologiaRESUMO
Markers with large differences in allele frequencies between ethnicities provide ancestry information that can be applied to genetic studies. We identified over 100 biallelic ancestry informative markers (AIMs) with large allele frequency differences between European Americans (EA) and Pima Amerindians from laboratory and database screens. For 35 of these markers, Mayan, Yavapai and Quechuan Amerindians were genotyped and compared with EA and Pima allele frequencies. Markers with large allele frequency differences between EA and one Amerindian tribe showed only small differences between the Amerindian tribes. Examination of structure in individuals demonstrated a clear separation of subjects of European from those of Amerindian ancestry, and similarity between individuals from disparate Amerindian populations. The AIMs demonstrated the variation in ancestral composition of individual Mexican Americans, providing evidence of applicability in admixture mapping and in controlling for structure in association tests. In addition, a high percentage of single-nucleotide polymorphisms (SNPs) selected on the basis of large frequency differences between EA and Asian populations had large allele frequency differences between EA and Amerindians, suggesting an efficient method for greatly expanding AIMs for use in admixture mapping/structure analysis in Mexican Americans. Together, these data provide additional support for the practical application of admixture mapping in the Mexican American population.