Oxygen association-dissociation and stability analysis on mouse hemoglobins with mutant alpha- and beta-globins.

D'Surney, Stephen J.; Popp, Raymond A.

doi:10.1093/genetics/132.2.545

Genetics

1992

DOI: 10.1093/genetics/132.2.545

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Oxygen association-dissociation and stability analysis on mouse hemoglobins with mutant alpha- and beta-globins.

Stephen J. D'Surney¹,

Raymond A. Popp²

Abstract: Oxygen association-dissociation and hemoglobin stability analysis were performed on mouse hemoglobins with amino acid substitutions in an alpha-globin (alpha 89, His to Leu) and a beta-globin (beta 59, Lys to Ile). The variant alpha-globin, designated chain 5m in the Hbag2 haplotype, had an high oxygen affinity and was stable. The variant beta-globin, (beta s2) of the Hbbs2 haplotype, also had an elevated oxygen affinity and in addition was moderately unstable in 19% isopropanol. Hemoglobins from the expected … Show more

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Cited by 6 publications

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“…The various aand b-chain hemoglobin isoforms of house mice are characterized by different oxygen-binding affinities (Newton and Peters 1983;D'surney and Popp 1992), and allelic variation in b-chain cysteine content exerts a strong influence on intraerythrocyte glutathione and nitric oxide (NO) metabolism (Giustarini et al 2006;Hempe et al 2007). Despite the well-documented functional differences between the s-and d-type b-globin alleles and the suggestive evidence for balancing selection, a mechanistic link between allelic variation in hemoglobin function and fitness-related physiological performance has yet to be established.…”

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Complex Signatures of Selection and Gene Conversion in the Duplicated Globin Genes of House Mice

et al. 2007

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Results of electrophoretic surveys have suggested that hemoglobin polymorphism may be maintained by balancing selection in natural populations of house mice, Mus musculus. Here we report a survey of nucleotide variation in the adult globin genes of house mice from South America. We surveyed nucleotide polymorphism in two closely linked alpha-globin paralogs and two closely linked beta-globin paralogs to test whether patterns of variation are consistent with a model of long-term balancing selection. Surprisingly high levels of nucleotide polymorphism at the two beta-globin paralogs were attributable to the segregation of two highly divergent haplotypes, Hbbs (which carries two identical beta-globin paralogs) and Hbbd (which carries two functionally divergent beta-globin paralogs). Interparalog gene conversion on the Hbbs haplotype has produced a highly unusual situation in which the two paralogs are more similar to one another than either one is to its allelic counterpart on the Hbbd haplotype. Levels of nucleotide polymorphism and linkage disequilibrium at the two beta-globin paralogs suggest a complex history of diversity-enhancing selection that may be responsible for long-term maintenance of alternative protein alleles. The alternative two-locus beta-globin haplotypes are associated with pronounced differences in intraerythrocyte glutathione and nitric oxide metabolism, suggesting a possible mechanism for selection on hemoglobin function.

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confidence: 99%

Complex Signatures of Selection and Gene Conversion in the Duplicated Globin Genes of House Mice

et al. 2007

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Globin gene transfer for treatment of the β-thalassemias and sickle cell disease

Sadelain

Rivella

Lisowski

et al. 2004

Best Practice & Research Clinical Haematology

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Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb β ^s -globin yeast artificial chromosome: A mouse model of sickle cell anemia

Chang

Lin

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Sickle cell anemia (SCA) and thalassemia are among the most common genetic diseases worldwide. Current approaches to the development of murine models of SCA involve the elimination of functional murine ␣-and ␤-globin genes and substitution with human ␣ and ␤ s transgenes. Recently, two groups have produced mice that exclusively express human HbS. The transgenic lines used in these studies were produced by coinjection of human ␣-, ␥-, and ␤-globin constructs. Thus, all of the transgenes are integrated at a single chromosomal site. Studies in transgenic mice have demonstrated that the normal gene order and spatial organization of the members of the human ␤-globin gene family are required for appropriate developmental and stage-restricted expression of the genes. As the cis-acting sequences that participate in activation and silencing of the ␥-and ␤-globin genes are not fully defined, murine models that preserve the normal structure of the locus are likely to have significant advantages for validating future therapies for SCA. To produce a model of SCA that recapitulates not only the phenotype, but also the genotype of patients with SCA, we have generated mice that exclusively express HbS after transfer of a 240-kb ␤ The biochemical basis for sickle cell anemia (SCA) was described more than 30 years ago (1, 2); however, advances in the treatment of SCA have in part been hampered by the lack of an animal model that accurately reproduces the pathophysiology and genetics of this disorder. The strategies for making a murine model of SCA have evolved as the limitations of each approach became apparent. Thus, initial efforts focused on the transfer of human ␤ s -globin genes to generate transgenic lines. Heterotetramers of murine ␣-globin and human ␤ s -globin do not polymerize efficiently; even with the addition of human ␣-globin transgenes only a small fraction of the cells sickled in vivo because of the disruption of HbS by murine ␣-and ␤-globins (3-11). Under hypoxic conditions there is more extensive deoxygenation of murine hemoglobin than HbS, as mouse hemoglobin has a lower O 2 affinity than does HbS (12). To produce a hemoglobin that would polymerize more readily, two additional mutations were introduced into ␤ s transgenes; a second mutation in codon 23 to reproduce the ␤ s Antilles allele, and a third mutation to yield ␤ s AntillesD Punjab or HbSAD (6,7,13). While the SAD mice exhibited a greater propensity for red cell sickling under hypoxic conditions, this model did not fully recapitulate the features of sickle cell disease. Hence, recent efforts have been directed toward reducing or eliminating endogenous mouse globin gene expression and the production of mice that exclusively express human HbS as adults.Two such models have been reported recently (15, 16). Expression of the adult murine ␣-and ␤-globin genes was eliminated by targeted disruption of these loci in embryonic stem (ES) cells. Mice exclusively expressing human HbS were identified after successive cycles of crossbreeding knockout lines wi...

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Oxygen association-dissociation and stability analysis on mouse hemoglobins with mutant alpha- and beta-globins.

Cited by 6 publications

References 18 publications

Complex Signatures of Selection and Gene Conversion in the Duplicated Globin Genes of House Mice

Complex Signatures of Selection and Gene Conversion in the Duplicated Globin Genes of House Mice

Globin gene transfer for treatment of the β-thalassemias and sickle cell disease

Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb β ^s -globin yeast artificial chromosome: A mouse model of sickle cell anemia

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Oxygen association-dissociation and stability analysis on mouse hemoglobins with mutant alpha- and beta-globins.

Cited by 6 publications

References 18 publications

Complex Signatures of Selection and Gene Conversion in the Duplicated Globin Genes of House Mice

Complex Signatures of Selection and Gene Conversion in the Duplicated Globin Genes of House Mice

Globin gene transfer for treatment of the β-thalassemias and sickle cell disease

Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb β s -globin yeast artificial chromosome: A mouse model of sickle cell anemia

Contact Info

Product

Resources

About

Transgenic knockout mice exclusively expressing human hemoglobin S after transfer of a 240-kb β ^s -globin yeast artificial chromosome: A mouse model of sickle cell anemia