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Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

Belinda Giardine et al. Nat Genet. .

Abstract

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.

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Figures

Figure 1
Figure 1. Graphical display of the HBB promoter variants recorded in HbVar, partitioned into unpublished variants contributed by investigators (blue) and published variants (purple)
The genomic position, sequence change and associated phenotype (β+ or β0 thalassemia) are given for each variant. Known protein-binding sites in the DNA sequence are boxed, with the name of the site and the binding protein above it. The transcription start site (+1) is in reverse type. The reverse complement of the genomic sequence is shown so that the gene is in the conventional left-to-right transcriptional orientation. The image was generated by displaying the results of a query on HbVar in the Pennsylvania State University genome browser followed by editing for clarity. Variants are given using the conventional nomenclature.
Figure 2
Figure 2. Functional role of HBG1 and HBG2 promoter variants
HBG1 promoter variants are confined to the upstream region and associated with HPFH. The top line gives a schematic view of previously described binding sites for transcription factors, including the TATA box, the stage-selector element (SSE), the CCAAT boxes, GATA motifs bound by GATA1, and an octamer motif (OCT), plus the response element (RE) defined by a cluster of HPFH mutations. Motifs in which variants have been found are colored gray. The transcription start site (+1) is in reverse type. The image was generated by displaying the results of a query on HbVar in the Pennsylvania State University genome browser followed by editing for clarity. Variants are given using the conventional nomenclature. (b) Flow cytometry analysis of γ-globin+ erythrocytes from adult HBG1 c.-248C>G HPFH β-YAC transgenic lines. A mouse monoclonal γ-globin antibody was used to determine the percentage of F cells. Line and individual numbers are indicated at the top of the panels. Percent γ-globin–positive cells are indicated within each plot (see also Online Methods). Wild-type (wt) β-YAC mice served as negative controls, and HBG1 c.-170G>A HPFH β-YAC mice13 were used as positive controls. In parallel experiments, human β-globin was expressed in 92–97% of the cells analyzed for all lines (data not shown). (c) Human γ-globin gene expression in HBG1 c.-248C>G HPFH β-YAC transgenic lines. Percent γ-globin gene expression, copy number-corrected and normalized to per-copy mouse α-globin gene expression, is shown on the y axis. β-YAC construct and line numbers, where appropriate, are indicated at the bottom of the plot. Error bars represent standard deviation of triplicate experiments.
Figure 3
Figure 3. Correlation of the different KLF1 gene variants deposited into HbVar (shown as blue and red squares, depicting unpublished and published information, respectively) and their corresponding HbF levels (median value in cases of three or more individuals) compared to wild-type individuals (shown as green squares)
KLF1 is not shown to scale. A simplified diagram depicting the KLF1 promoter and protein is shown underneath. The positions of the zinc fingers are indicated (F1, F2 and F3). For the exact HbF levels corresponding to each KLF1 gene variant, see Supplementary Table 2.
See this image and copyright information in PMC

Comment in

  • Crowdsourcing human mutations.
    [No authors listed] [No authors listed] Nat Genet. 2011 Mar 29;43(4):279. doi: 10.1038/ng0411-279. Nat Genet. 2011. PMID: 21445067

References

    1. Anonymous. Human variome microattribution reviews. Nat. Genet. 2008;40:1.
    1. Patrinos GP, Antonarakis SE. Human hemoglobin. In: Speicher M, Antonarakis SE, Motulsky A, editors. Human Genetics: Problems and Approaches. Heidelberg, Germany: Springer-Verlag; 2010. pp. 366–401.
    1. Gibbons RJ, Picketts DJ, Villard L, Higgs DR. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome) Cell. 1995;80:837–845. - PubMed
    1. Gibbons RJ, et al. Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the α-thalassemia myelodysplasia syndrome (ATMDS) Nat. Genet. 2003;34:446–449. - PubMed
    1. Viprakasit V, et al. Mutations in the general transcription factor TFIIH result in β-thalassaemia in individuals with trichothiodystrophy. Hum. Mol. Genet. 2001;10:2797–2802. - PubMed

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