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Gene turnover in the avian globin gene families and evolutionary changes in hemoglobin isoform expression.

ABSTRACT: The apparent stasis in the evolution of avian chromosomes suggests that birds may have experienced relatively low rates of gene gain and loss in multigene families. To investigate this possibility and to explore the phenotypic consequences of variation in gene copy number, we examined evolutionary changes in the families of genes that encode the ?- and ?-type subunits of hemoglobin (Hb), the tetrameric ?2?2 protein responsible for blood-O2 transport. A comparative genomic analysis of 52 bird species revealed that the size and membership composition of the ?- and ?-globin gene families have remained remarkably constant during approximately 100 My of avian evolution. Most interspecific variation in gene content is attributable to multiple independent inactivations of the ?(D)-globin gene, which encodes the ?-chain subunit of a functionally distinct Hb isoform (HbD) that is expressed in both embryonic and definitive erythrocytes. Due to consistent differences in O2-binding properties between HbD and the major adult-expressed Hb isoform, HbA (which incorporates products of the ?(A)-globin gene), recurrent losses of ?(D)-globin contribute to among-species variation in blood-O2 affinity. Analysis of HbA/HbD expression levels in the red blood cells of 122 bird species revealed high variability among lineages and strong phylogenetic signal. In comparison with the homologous gene clusters in mammals, the low retention rate for lineage-specific gene duplicates in the avian globin gene clusters suggests that the developmental regulation of Hb synthesis in birds may be more highly conserved, with orthologous genes having similar stage-specific expression profiles and similar functional properties in disparate taxa.

SUBMITTER: Opazo JC

PROVIDER: S-EPMC4379397 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Gene turnover in the avian globin gene families and evolutionary changes in hemoglobin isoform expression.

Opazo Juan C JC Hoffmann Federico G FG Natarajan Chandrasekhar C Witt Christopher C CC Berenbrink Michael M Storz Jay F JF

Molecular biology and evolution 20141209 4

The apparent stasis in the evolution of avian chromosomes suggests that birds may have experienced relatively low rates of gene gain and loss in multigene families. To investigate this possibility and to explore the phenotypic consequences of variation in gene copy number, we examined evolutionary changes in the families of genes that encode the α- and β-type subunits of hemoglobin (Hb), the tetrameric α2β2 protein responsible for blood-O2 transport. A comparative genomic analysis of 52 bird spe ...[more]

PMID: 25502940

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Project description:The functional diversification of multigene families may be strongly influenced by mechanisms of concerted evolution such as interparalog gene conversion. The beta-globin gene family of house mice (genus Mus) represents an especially promising system for evaluating the effects of gene conversion on the functional divergence of duplicated genes. Whereas the majority of mammalian species possess tandemly duplicated copies of the adult beta-globin gene that are identical in sequence, natural populations of house mice are often polymorphic for distinct two-locus haplotypes that differ in levels of functional divergence between duplicated beta-globin genes, HBB-T1 and HBB-T2. Here, we use a phylogenetic approach to unravel the complex evolutionary history of the HBB-T1 and HBB-T2 paralogs in a taxonomically diverse set of species in the genus Mus. The main objectives of this study were 1) to reconstruct the evolutionary history of the different HBB haplotypes of house mice, 2) to assess the role of recombinational exchange between HBB-T1 and HBB-T2 in promoting concerted evolution, 3) to assess the role of recombinational exchange between HBB-T1 and HBB-T2 in creating chimeric genes, and 4) to assess the structural basis of hemoglobin isoform differentiation in species that possess distinct HBB paralogs. Results of our phylogenetic survey revealed that the HBB-T1 and HBB-T2 genes in different species of Mus exhibit the full range of evolutionary outcomes with respect to levels of interparalog divergence. At one end of the spectrum, the two identical HBB paralogs on the Hbb(s) haplotype (shared by Mus domesticus, Mus musculus, and Mus spretus) represent a classic example of concerted evolution. At the other end of the spectrum, the two distinct HBB paralogs on the Hbb(d), Hbb(p), Hbb(w1), and Hbb(w2) haplotypes (shared by multiple species in the subgenus Mus) show no trace of gene conversion and are distinguished by a number of functionally important amino acid substitutions. Because the possession of distinct HBB paralogs expands the repertoire of functionally distinct hemoglobin isoforms that can be synthesized during fetal development and postnatal life, variation in the level of functional divergence between HBB-T1 and HBB-T2 may underlie important physiological variation within and among species.

Project description:Increase of the expression of ?-globin gene and high production of fetal hemoglobin (HbF) in ?-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF-associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify ?-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea).A?-globin gene sequencing was performed on genomic DNA isolated from a total of 75 ?-thalassemia patients, including 31 ?039/?039, 33 ?039/?+IVSI-110, 9 ?+IVSI-110/?+IVSI-110, one ?0IVSI-1/?+IVSI-6 and one ?039/?+IVSI-6.The results show that the rs368698783 polymorphism is present in ?-thalassemia patients in the 5'UTR sequence (+25) of the A?-globin gene, known to affect the LYAR (human homologue of mouse Ly-1 antibody reactive clone) binding site 5'-GGTTAT-3'. This A?(+25 G->A) polymorphism is associated with the G?-globin-XmnI polymorphism and both are linked with the ?039-globin gene, but not with the ?+IVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the A?(+25 G->A) and G?-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from ?039/?039 thalassemia patients.As a potential explanation of our findings, we hypothesize that in ?-thalassemia the G?-globin-XmnI/A?-globin-(G->A) genotype is frequently under genetic linkage with ?0-thalassemia mutations, but not with the ?+-thalassemia mutation here studied (i.e. ?+IVSI-110) and that this genetic combination has been selected within the population of ?0-thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the A?-globin gene associated in ?039 thalassemia patients with high HbF in erythroid precursor cells.

Dataset Information

Gene turnover in the avian globin gene families and evolutionary changes in hemoglobin isoform expression.

Publications

Gene turnover in the avian globin gene families and evolutionary changes in hemoglobin isoform expression.

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