Limits...
Mutations in the paralogous human alpha-globin genes yielding identical hemoglobin variants.

Moradkhani K, Préhu C, Old J, Henderson S, Balamitsa V, Luo HY, Poon MC, Chui DH, Wajcman H, Patrinos GP - Ann. Hematol. (2008)

Bottom Line: There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes.We identified 14 different Hb variants resulting from identical mutations on either one of the two human alpha-globin paralogue genes.Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category.

View Article: PubMed Central - PubMed

Affiliation: Biochimie Génétique, AP-HP, Hôpital Henri Mondor, Créteil, France.

ABSTRACT
The human alpha-globin genes are paralogues, sharing a high degree of DNA sequence similarity and producing an identical alpha-globin chain. Over half of the alpha-globin structural variants reported to date are only characterized at the amino acid level. It is likely that a fraction of these variants, with phenotypes differing from one observation to another, may be due to the same mutation but on a different alpha-globin gene. There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes. Here, we report the results of a systematic multicenter study in a large multiethnic population to identify such variants and to analyze their differences from a functional and evolutionary perspective. We identified 14 different Hb variants resulting from identical mutations on either one of the two human alpha-globin paralogue genes. We also showed that the average percentage of hemoglobin variants due to a HBA2 gene mutation (alpha2) is higher than the percentage of hemoglobin variants due to the same HBA1 gene mutation (alpha1) and that the alpha2/alpha1 ratio varied between variants. These alpha-globin chain variants have most likely occurred via recurrent mutations, gene conversion events, or both. Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category.

Show MeSH

Related in: MedlinePlus

Schematic drawing of the 14 α-globin chain variants resulting from an identical mutation in either the HBA1 or HBA2 genes. Original graphs have been automatically generated by HbVar graphical display [8]. Thick lines under each coding sequence (CDS) represent the position of each substitution deposited in HbVar. Asterisk 3′ end of the human α-globin gene conversion tract [6], caret PSVs in the promoter and coding sequences of the human α-globin genes (c.300+55G/T, c.301-35_29GGCCCTCdel, c.301-24C/G, c.*+15G/A, c.*+19A/G) deducted from sequence comparison between the HBA2 and HBA1 reference sequences (NG_000006.1; see also Supplementary data)
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2690850&req=5

Fig3: Schematic drawing of the 14 α-globin chain variants resulting from an identical mutation in either the HBA1 or HBA2 genes. Original graphs have been automatically generated by HbVar graphical display [8]. Thick lines under each coding sequence (CDS) represent the position of each substitution deposited in HbVar. Asterisk 3′ end of the human α-globin gene conversion tract [6], caret PSVs in the promoter and coding sequences of the human α-globin genes (c.300+55G/T, c.301-35_29GGCCCTCdel, c.301-24C/G, c.*+15G/A, c.*+19A/G) deducted from sequence comparison between the HBA2 and HBA1 reference sequences (NG_000006.1; see also Supplementary data)

Mentions: How do these variants occur? Although recurrent mutational events can be a likely cause for some of them, interallelic gene conversion event is the most plausible cause that might have resulted in the same mutation being “transferred” into different genomic contexts. A handful of examples also exist in the human β-like globin genes (reviewed in [15]), as well as in other human multigene families [16]. In favor for this assumption is the fact that 13 out of 14 Hb variants described herein are within exons 1 and 2. These exons, and not exon 3, have been shown to be involved in gene conversion events, as the 3′ end of the human α-globin gene conversion tract is located in intron II (Fig. 3).Fig. 3


Mutations in the paralogous human alpha-globin genes yielding identical hemoglobin variants.

Moradkhani K, Préhu C, Old J, Henderson S, Balamitsa V, Luo HY, Poon MC, Chui DH, Wajcman H, Patrinos GP - Ann. Hematol. (2008)

Schematic drawing of the 14 α-globin chain variants resulting from an identical mutation in either the HBA1 or HBA2 genes. Original graphs have been automatically generated by HbVar graphical display [8]. Thick lines under each coding sequence (CDS) represent the position of each substitution deposited in HbVar. Asterisk 3′ end of the human α-globin gene conversion tract [6], caret PSVs in the promoter and coding sequences of the human α-globin genes (c.300+55G/T, c.301-35_29GGCCCTCdel, c.301-24C/G, c.*+15G/A, c.*+19A/G) deducted from sequence comparison between the HBA2 and HBA1 reference sequences (NG_000006.1; see also Supplementary data)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690850&req=5

Fig3: Schematic drawing of the 14 α-globin chain variants resulting from an identical mutation in either the HBA1 or HBA2 genes. Original graphs have been automatically generated by HbVar graphical display [8]. Thick lines under each coding sequence (CDS) represent the position of each substitution deposited in HbVar. Asterisk 3′ end of the human α-globin gene conversion tract [6], caret PSVs in the promoter and coding sequences of the human α-globin genes (c.300+55G/T, c.301-35_29GGCCCTCdel, c.301-24C/G, c.*+15G/A, c.*+19A/G) deducted from sequence comparison between the HBA2 and HBA1 reference sequences (NG_000006.1; see also Supplementary data)
Mentions: How do these variants occur? Although recurrent mutational events can be a likely cause for some of them, interallelic gene conversion event is the most plausible cause that might have resulted in the same mutation being “transferred” into different genomic contexts. A handful of examples also exist in the human β-like globin genes (reviewed in [15]), as well as in other human multigene families [16]. In favor for this assumption is the fact that 13 out of 14 Hb variants described herein are within exons 1 and 2. These exons, and not exon 3, have been shown to be involved in gene conversion events, as the 3′ end of the human α-globin gene conversion tract is located in intron II (Fig. 3).Fig. 3

Bottom Line: There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes.We identified 14 different Hb variants resulting from identical mutations on either one of the two human alpha-globin paralogue genes.Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category.

View Article: PubMed Central - PubMed

Affiliation: Biochimie Génétique, AP-HP, Hôpital Henri Mondor, Créteil, France.

ABSTRACT
The human alpha-globin genes are paralogues, sharing a high degree of DNA sequence similarity and producing an identical alpha-globin chain. Over half of the alpha-globin structural variants reported to date are only characterized at the amino acid level. It is likely that a fraction of these variants, with phenotypes differing from one observation to another, may be due to the same mutation but on a different alpha-globin gene. There have been very few previous examples of hemoglobin variants that can be found at both HBA1 and HBA2 genes. Here, we report the results of a systematic multicenter study in a large multiethnic population to identify such variants and to analyze their differences from a functional and evolutionary perspective. We identified 14 different Hb variants resulting from identical mutations on either one of the two human alpha-globin paralogue genes. We also showed that the average percentage of hemoglobin variants due to a HBA2 gene mutation (alpha2) is higher than the percentage of hemoglobin variants due to the same HBA1 gene mutation (alpha1) and that the alpha2/alpha1 ratio varied between variants. These alpha-globin chain variants have most likely occurred via recurrent mutations, gene conversion events, or both. Based on these data, we propose a nomenclature for hemoglobin variants that fall into this category.

Show MeSH
Related in: MedlinePlus