RESUMO
OBJECTIVES: This investigation was performed to examine genetic variation at the ß-globin locus in a sample of 30 healthy individuals from native populations in South America. The patterns of haplotypic variation were compared with those of previous studies including samples for various worldwide populations in an attempt to make inferences about the occupation of the Americas from a deeper temporal perspective than is typically available with haploid markers. METHODS: A 2.67-kb segment containing the ß-globin gene and its flanking regions was examined for genetic variation in a sample of 60 chromosomes from native populations in South America. The fragment was PCR-amplified and directly sequenced. To determine linkage relationships in compound heterozygotes, we used the amplification refractory mutation system. In addition, we assessed genetic variability and differentiation among populations, and we performed tests of selective neutrality. These analyses were performed for Brazilian Amerindian group and other worldwide populations previously studied. RESULTS: Eleven polymorphic sites were found in the studied fragment, which distinguished eight different haplotypes, three recombinants haplotypes (present as single copies) and five previously described haplotypes, including some of those most highly differentiated. Genetic variation found in the pooled sample is substantial. CONCLUSIONS: Although only five known haplotypes are observed in Amazonia, some of these are highly divergent, resulting in patterns of molecular polymorphism equal to or higher than those from other world regions.
Assuntos
Haplótipos , Indígenas Sul-Americanos/genética , Polimorfismo Genético , Globinas beta/genética , Brasil/etnologia , Núcleo Celular/genética , Frequência do Gene , Heterozigoto , Humanos , Reação em Cadeia da Polimerase , Análise de Sequência de DNARESUMO
We have studied the interaction of the OOO/OO gene arrangements with various á globin genotypes (AA, AS, AC, SS and SC). Whereas this interaction has no detectable clinical or haematological effects in subjects with AA, SS or SC genotypes it is associated with a significantly increased level of Hb S or Hb C in heterozygotes for these variants. These findings indicate that the additional O globin gene in the OOO gene arrangement is functional (Summary)
Assuntos
Humanos , Criança , Adolescente , Adulto , Masculino , Feminino , Globinas/genética , Hemoglobina Falciforme , Anemia Falciforme/sangue , Anemia Falciforme/genética , Mapeamento Cromossômico , Enzimas de Restrição do DNA , Genótipo , Hemoglobina C/análise , Doença da Hemoglobina SC/sangue , Doença da Hemoglobina SC/genética , Hemoglobina Falciforme/análise , Heterozigoto , HomozigotoRESUMO
Patients with homozygous sickle-cell disease may be homozygous for alpha-thalassemia 2 (O-/O-), may be heterozygous for alpha-thalessemia 2 (O-/OO), or may have a normal alpha-globin-gene complement (OO/OO). We compared the clinical and hematologic features of 44 patients who had sickle-cell disease and homozygous alpha-thalassemia 2 with those of controls with the two hematologic conditions. The patients with homozygous alpha-thalassemia 2 had significantly higher red-cell counts and levels of hemoglobin and hemoglobin Aý, as well as significantly lower hemoglobin F, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, reticulocyte counts, irreversibly-sickled-cell counts, and serum total billirubin levels, than those with a normal alpha-globin-gene complement. Heterozygotes (O-/OO) had intermediate values. In the group with homozygous alpha-thalassemia 2, fewer patients had episodes of acute chest syndrome and chronic leg ulceration and more patients had splenomegaly, as compared with patients in the other two subgroups. These data confirmed previous suggestions that alpha-thalassemia inhibits in vivo sickling in homozygous sickle-cell disease and may be an important genetic determinant of its hematologic severity.
Assuntos
Humanos , Adolescente , Adulto , Masculino , Feminino , Anemia Falciforme/complicações , Talassemia/complicações , Anemia Falciforme/sangue , Anemia Falciforme/genética , Bilirrubina/análise , Contagem de Eritrócitos , Índices de Eritrócitos , Hemoglobina Fetal/análise , Hemoglobina A2/análise , Hemoglobinas/análise , Hematócrito , Globinas/genética , Heterozigoto , Homozigoto , Esplenomegalia/complicações , Talassemia/sangue , Talassemia/genéticaRESUMO
We have studied seven Jamaican Negro families in whom the genes for O thalassaemia and the sickle cell mutation (ás) were independently segretated. Using a combination of techniques we identified two O thalassaemia phenotypes which resemble the reserve (O thalassaemia 1) and mild (O thalassaemia 2) determinants previously described in Orientals. This study has enabled us to clearly correlate the phenotype of O thalassaemia with the genotype in this population. Furthermore, since in each family O thalassaemia was present in association with the gene for the sickle cell mutation we have determined the proportion of Hb S in the peripheral blood of individuals with the OO/OO, -O/-O genotype who are also heterozygous for the ás mutation. Genetic analysis in these families shows that in each case subjects with the O thalassaemia 1 phenotype are homozygous for the O thalassaemia 2 defect (-O/-O). We have found no instances of the genotype --/OO in this population which may explain the rarity of the severe O thalassaemia 2 homozygotes from this population shows that the (-O/) haplotype results from a deletion of one of the linked pair of O globin and that this had probably arisen by an unequal crossover between non-homologous O genes (AU)
Assuntos
Humanos , Masculino , Feminino , Hemoglobina Falciforme/análise , Talassemia/sangue , Talassemia/genética , Mapeamento Cromossômico , DNA/sangue , Heterozigoto , Homozigoto , Linhagem , Fenótipo , Genótipo , JamaicaAssuntos
Humanos , Recém-Nascido , Lactente , Masculino , Feminino , Hemoglobinas Anormais/genética , Talassemia/epidemiologia , Talassemia/genética , Genótipo , América do Norte , Linhagem , Fenótipo , JamaicaRESUMO
A prospective study of 2191 Negro infants in Jamaica showed that approximately 7 percent of them had detectable levels of Hb Bart's (Y4) in the neonatal period. The red cell indices, globin chain biosynthesis and restriction endonuclease mapping of DNA from these infants were used to determine the significance of Hb Bart's at birth. The results indicate that the genotypes OO/OO, - O/OO and - O/-O are associated with 0 percent, 0.1-2 percent, and greater than 2 percent Hb Bart's respectively. Although trace amounts of Hb Bart's may be associated with the genotype - O/OO this is not always the case and therefore haemoglobin analysis in the neonatal period cannot be used to diagnose this genotype with any certainty (AU)
Assuntos
Humanos , Recém-Nascido , Lactente , Talassemia/diagnóstico , DNA , Índices de Eritrócitos , Genótipo , Globinas/biossíntese , Hemoglobinas Anormais/análise , Jamaica , Estudos Prospectivos , Talassemia/sangue , Talassemia/genéticaRESUMO
Five families are described in which there have been matings between individuals doubly heterozygous for beta thalassaemia and the delta-chain variant haemoglobin A2' to normal persons. In all there were 24 informative offspring. There were no crossovers between the beta-thalassaemia and delta-chain loci; in three of the families the genes were linked in cis and in two families the genes were found in trans.Together with previously reported families there have now been 58 opportunities for crossing over between the beta-thalassaemia and delta-chain loci and there have been two possible and one highly probable crossovers. Of the total of 9 families reported to date 4 have had the genes for beta thalassaemia and Hb A2' in cis and 5 in trans. These findings are contrasted with the findings in families where a beta-chain structural variant and Hb A2' have been observed together and these genes have always been found in trans and never in cis. The reasons for linkage disequilibrium of this type are discussed. It is concluded tentatively that the distance between the delta-structural and beta-thalassaemia loci is greater than that between the delta-structural and beta-structural loci. To date this conclusion can only be applied to the beta+ -thalassaemia and beta-thalassaemia genes as found in the African population, since this is the only population with a high incidence of delta-chain mutants which allow linkage analysis of this type to be carried out. (AU)
Assuntos
Humanos , Masculino , Feminino , Genes , Hemoglobinas Anormais , Ligação Genética , Talassemia/genética , África , Eletroforese em Gel de Amido , Hemoglobinas/análise , Heterozigoto , Linhagem , Talassemia/sangueRESUMO
Clinical, hmatological, genetic, chemical, and oxygen-affinity studies have been carried out on a group of 18 Shiite Saudi Arabians with sickle-cell anmia. Apart from occasional attacks of mild musculo-skeletal pain they are well and have few of the complications which are usual in the sickling disorders. The unusually mild course of the illness is attributable, at least in part, to a genetically determined ability to produce large amounts of fetal hmoglobin (Summary)
Assuntos
Humanos , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Feminino , Anemia Falciforme , Fatores Etários , Anemia Falciforme/diagnóstico , Anemia Falciforme/genética , Arábia , Estatura , Peso Corporal , Hemoglobina Fetal/análise , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Homozigoto , Jamaica , Fatores SexuaisAssuntos
Humanos , Lactente , Masculino , Sequência de Aminoácidos , Hemoglobinas Anormais/análise , Alanina/análise , Anemia Falciforme/sangue , Anemia Falciforme/genética , Ácido Aspártico/análise , Eletroforese das Proteínas Sanguíneas , Cromatografia , Eletroforese em Gel de Amido , Métodos , Peptídeos/análise , Tripsina , HeterozigotoRESUMO
Of the 120 or so variants of human haemoglobin polypeptide chains so far described, nearly all are the result of the substitution of a single amino acid residue for another, or a deletion of one or more residues in the chain, caused by a point mutation in the codens of the chromosomal DNA. Hb H disease is also a genetically determined haemolytic anaemia, common in Orientals, but is caused by a reduced rate of synthesis of the O-chain of normal haemoglobin, resulting in an excess of á-chains (Hb H). A study of a Chinese family in Jamaica has revealed a slow moving haemoglobin in three children who have clinical haemoglobin H disease and in their fathers and siblings who have no haematological abnormality. The mothers have classical O-thalassaemia trait, as do some of the other siblings. Detailed biochemical analysis of this variant has shown that the O-chain is abnormal and is elongated by the addition of 31 residues to the 141 of the normal OA-chain. The extra residues are continuous with the normal C-terminal (O-141 Arg.) Biosynthetic studies, incorporating H(to 3rd power) leucine have indicated a low rate of synthesis for this abnormal chain. Interest lies in the nature of the genetic defect which could produce this abnormalty. While considering several hypotheses, the authors favour the theory that the genetic codon for 'end of chain' is the site of a mutation. This hypothesis is strengthened by finding Glutamine to be the next residue after the C-terminal Arginine. This extra piece of chain bears no resemblance to any known human globin chain sequence, so that it is unlikely that it has resulted from an unequal crossing over in a similar way to the Lepore haemoglobins. It may be that the messenge RNA for the normal OA-chain is longer than is required to direct synthesis of the chain. Further studies are in progress to try and define the nature of this genetic defect (AU)
Assuntos
Humanos , Talassemia alfa , Hemoglobinas Anormais , JamaicaAssuntos
Humanos , Criança , Masculino , Feminino , Hemoglobinas Anormais/isolamento & purificação , Mutação , Sequência de Aminoácidos , Aminoácidos/análise , Anemia Hemolítica/genética , Eletroforese das Proteínas Sanguíneas , Cromatografia , Brometo de Cianogênio , Hemoglobinopatias/genética , Hemoglobinas Anormais/análise , Hemoglobinas Anormais/biossíntese , Jamaica , Peptídeos/análise , Relação Estrutura-Atividade , Talassemia/genética , Trítio , TripsinaRESUMO
The clinical and genetic properties of an unusual O-chain variant of human haemoglobin are described. It constitutes less than 1 percent of the total haemoglobin in heterozygotes and, when inherited together with an O-thalassaemia gene, produces the clinical picture of haemoglobin-H disease. Preliminary structural studies indicatge that, in addition to the 141 aminoacid residues which constitute the normal O-chain, this variant has about 31 extra residues attached to the C-terminal end.(SUMMARY)