α-Globin gene organisation in blacks precludes the severe form of α-thalassaemia

Dozy, Andrée M.; Kan, Yuet Wai; Embury, Stephen H.; Mentzer, William C.; Wang, W. C.; Lubin, Bertram H.; Davis, Julian; Koenig, Harold M.

doi:10.1038/280605a0

Cited by 218 publications

(76 citation statements)

References 19 publications

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“…Chromosomes bearing these ␣-globin gene deletions are very common, particularly in Asia and Africa, where they can attain population frequencies as high as 90% (28,36,37), and are most likely maintained by malaria selection in favor of Ϫ␣ chromosomes (27,28). In contrast, nonmalarial populations show a much lower incidence of deletion chromosomes (Ϸ0.6% in northern Europeans; see Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Lam

Jeffreys²

2006

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

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Ectopic recombination between locally repeated DNA sequences is of fundamental importance in the evolution of gene families, generating copy-number variation in human DNA and often leading to pathological rearrangements. Despite its importance, little is known about the dynamics and processes of these unequal crossovers and the degree to which meiotic recombination plays a role in instability. We address this issue by using as a highly informative system the duplicated ␣-globin genes in which ectopic recombination can lead to gene deletions, often very prevalent in populations affected by malaria, as well as reduplications. Here we show that spontaneous deletions can be accessed directly in genomic DNA by using single-DNA-molecule methods. These deletions proved to be remarkably common in both blood and sperm. Somatic deletions arise by a strictly intrachromosomal pathway of homologous exchange that also operates in the germ line and can generate mutational mosaicism, whereas sperm deletions frequently involve recombinational interactions between homologous chromosomes that most likely occur at meiosis. Ectopic recombination frequencies show surprisingly little requirement for long, identical homology blocks shared by paralogous sequences, and exchanges can occur even between short regions of sequence identity. Finally, direct knowledge of germ-line deletion rates can give insights into the fitness of individuals with these ␣-globin gene deletions, providing a new approach to investigating historical levels of selection operating in human populations.ectopic ͉ recombination ͉ selection ͉ mutation ͉ mosaicism

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Section: Resultsmentioning

confidence: 99%

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Lam

Jeffreys²

2006

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

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“…10 The laboratory methods used to define the hemoglobin phenotype and the haplotypes of the b-like and a -globin gene cluster were described previously. 11,38,39 SNP selection and genotyping The selection of genes was based on previously reported linkage peaks (6q22-q23, 8q11-q12 and Xp22.2-p22. 3) 16,19,40 genes involved in metabolism of HU and genes related to erythroid progenitor proliferation.…”

Section: Laboratory Studiesmentioning

confidence: 99%

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

et al. 2007

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The increase in fetal hemoglobin (HbF) in response to hydroxyurea (HU) varies among patients with sickle cell anemia. Twenty-nine candidate genes within loci previously reported to be linked to HbF level (6q22.3-q23.2, 8q11-q12 and Xp22.2-p22.3), involved in metabolism of HU and related to erythroid progenitor proliferation were studied in 137 sickle cell anemia patients treated with HU. Three-hundred and twenty tagging single nucleotide polymorphisms (SNPs) for genotyping were selected based on HapMap data. Multiple linear regression and the nonlinear regression Random Forest method were used to investigate the association between SNPs and the change in HbF level after 2 years of treatment with HU. Both methods revealed that SNPs in genes within the 6q22.3-23.2 and 8q11-q12 linkage peaks, and also the ARG2, FLT1, HAO2 and NOS1 genes were associated with the HbF response to HU. Polymorphisms in genes regulating HbF expression, HU metabolism and erythroid progenitor proliferation might modulate the patient response to HU.

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“…Laboratory methods used to define the hemoglobin phenotype and the haplotypes of the b-like and a-globin gene cluster were described in detail elsewhere [26][27][28].…”

Section: Laboratorymentioning

confidence: 99%

Estimated glomerular filtration rate in sickle cell anemia is associated with polymorphisms of bone morphogenetic protein receptor 1B

Nolan

Cohen

et al. 2006

American J Hematol

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Renal disease is common in sickle cell anemia. In this exploratory work, we used data from a longitudinal study of the natural history of sickle cell disease to examine the hypothesis that polymorphisms (SNPs) in selected candidate genes are associated with glomerular filtration rate (GFR). DNA samples and clinical and laboratory data were available for 1,140 patients with sickle cell anemia. GFR was estimated using the Cockcroft-Gault and Schwartz formulas for adults and children, respectively. We examined *175 haplotype tagging (ht) SNPs in about 70 genes of the TGFb/BMP pathway for their association with GFR using linear regression. Four SNPs in BMPR1B, a bone morphogenetic protein (BMP) receptor gene, yielded statistically significant associations (P values ranging from 0.015 to 0.046). Three haplotypes in this gene were also associated with GFR. The TGF-b/BMP pathway has been associated with the development of diabetic nephropathy, which has some features in common with sickle cell nephropathy. Our results suggest that, as with other subphenotypes of sickle cell disease, renal function may be genetically modulated. Am. J. Hematol. 82:179-184, 2007. V V C 2006 Wiley-Liss, Inc.

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α-Globin gene organisation in blacks precludes the severe form of α-thalassaemia

Cited by 218 publications

References 19 publications

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

Estimated glomerular filtration rate in sickle cell anemia is associated with polymorphisms of bone morphogenetic protein receptor 1B

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