Evolutionary and functional properties of a two-locus β-globin polymorphism in Indian house mice

Amy M. Runck, Roy E. Weber, Angela Fago, Jay F Storz

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Electrophoretic surveys of hemoglobin (Hb) polymorphism in house mice from South Asia and the Middle East have revealed that two alternative β-globin haplotypes, Hbbd and Hbbp, are often present at intermediate frequencies in geographically disparate populations. Both haplotypes harbor two functionally distinct β-globin paralogs, HBB-T1 (which encodes the β-chain subunits of the major Hb isoform) and HBB-T2 (which encodes the β-chains of the minor Hb isoform). The Hbbd and Hbbp haplotypes share identical HBB-T1 alleles, but products of the alternative HBB-T2 alleles (dminor and pminor) are distinguished by two amino acid substitutions. To investigate the possible adaptive significance of the Hbbd/Hbbp polymorphism we conducted a population genetic analysis of the duplicated β-globin genes of Indian house mice (Mus castaneus) in conjunction with experimental studies of Hb function in inbred strains of mice that carry the alternative Hbbd and Hbbp haplotypes. The main objectives of this study were (i) to characterize patterns of nucleotide polymorphism and linkage disequilibrium in the duplicated β-globin genes of M. castaneus, (ii) to test the hypothesis that the Hbbd and Hbbp haplotypes are maintained as a balanced polymorphism, and (iii) to assess whether allelic differences in the alternative minor Hb isoforms (dminor and pminor) are associated with different O2-binding properties. A multilocus analysis of polymorphism and divergence revealed that levels of diversity at the HBB-T2 gene exceeded neutral expectations, and reconstructed haplotype networks for both β-globin paralogs revealed extensive allele sharing with several other closely related species of Mus. However, despite this suggestive evidence for balancing selection, O2-equilibrium curves revealed no discernible functional differences between red cell lysates containing the dminor and pminor Hb isoforms. If the dminor and pminor alleles are maintained as a balanced polymorphism, our results indicate that the associated fitness variance is not directly related to respiratory functions of Hb.

Original languageEnglish (US)
Pages (from-to)1121-1131
Number of pages11
JournalGenetics
Volume184
Issue number4
DOIs
StatePublished - Apr 1 2010

Fingerprint

Globins
Haplotypes
Hemoglobins
Protein Isoforms
Alleles
Hemoglobin Subunits
Genes
Inbred Strains Mice
Middle East
Linkage Disequilibrium
Population Genetics
Amino Acid Substitution
Nucleotides
Population

ASJC Scopus subject areas

  • Genetics

Cite this

Evolutionary and functional properties of a two-locus β-globin polymorphism in Indian house mice. / Runck, Amy M.; Weber, Roy E.; Fago, Angela; Storz, Jay F.

In: Genetics, Vol. 184, No. 4, 01.04.2010, p. 1121-1131.

Research output: Contribution to journalArticle

Runck, Amy M. ; Weber, Roy E. ; Fago, Angela ; Storz, Jay F. / Evolutionary and functional properties of a two-locus β-globin polymorphism in Indian house mice. In: Genetics. 2010 ; Vol. 184, No. 4. pp. 1121-1131.
@article{6521f9c26c9c4b9cb0175a2f1472ecfc,
title = "Evolutionary and functional properties of a two-locus β-globin polymorphism in Indian house mice",
abstract = "Electrophoretic surveys of hemoglobin (Hb) polymorphism in house mice from South Asia and the Middle East have revealed that two alternative β-globin haplotypes, Hbbd and Hbbp, are often present at intermediate frequencies in geographically disparate populations. Both haplotypes harbor two functionally distinct β-globin paralogs, HBB-T1 (which encodes the β-chain subunits of the major Hb isoform) and HBB-T2 (which encodes the β-chains of the minor Hb isoform). The Hbbd and Hbbp haplotypes share identical HBB-T1 alleles, but products of the alternative HBB-T2 alleles (dminor and pminor) are distinguished by two amino acid substitutions. To investigate the possible adaptive significance of the Hbbd/Hbbp polymorphism we conducted a population genetic analysis of the duplicated β-globin genes of Indian house mice (Mus castaneus) in conjunction with experimental studies of Hb function in inbred strains of mice that carry the alternative Hbbd and Hbbp haplotypes. The main objectives of this study were (i) to characterize patterns of nucleotide polymorphism and linkage disequilibrium in the duplicated β-globin genes of M. castaneus, (ii) to test the hypothesis that the Hbbd and Hbbp haplotypes are maintained as a balanced polymorphism, and (iii) to assess whether allelic differences in the alternative minor Hb isoforms (dminor and pminor) are associated with different O2-binding properties. A multilocus analysis of polymorphism and divergence revealed that levels of diversity at the HBB-T2 gene exceeded neutral expectations, and reconstructed haplotype networks for both β-globin paralogs revealed extensive allele sharing with several other closely related species of Mus. However, despite this suggestive evidence for balancing selection, O2-equilibrium curves revealed no discernible functional differences between red cell lysates containing the dminor and pminor Hb isoforms. If the dminor and pminor alleles are maintained as a balanced polymorphism, our results indicate that the associated fitness variance is not directly related to respiratory functions of Hb.",
author = "Runck, {Amy M.} and Weber, {Roy E.} and Angela Fago and Storz, {Jay F}",
year = "2010",
month = "4",
day = "1",
doi = "10.1534/genetics.109.113506",
language = "English (US)",
volume = "184",
pages = "1121--1131",
journal = "Genetics",
issn = "0016-6731",
publisher = "Genetics Society of America",
number = "4",

}

TY - JOUR

T1 - Evolutionary and functional properties of a two-locus β-globin polymorphism in Indian house mice

AU - Runck, Amy M.

AU - Weber, Roy E.

AU - Fago, Angela

AU - Storz, Jay F

PY - 2010/4/1

Y1 - 2010/4/1

N2 - Electrophoretic surveys of hemoglobin (Hb) polymorphism in house mice from South Asia and the Middle East have revealed that two alternative β-globin haplotypes, Hbbd and Hbbp, are often present at intermediate frequencies in geographically disparate populations. Both haplotypes harbor two functionally distinct β-globin paralogs, HBB-T1 (which encodes the β-chain subunits of the major Hb isoform) and HBB-T2 (which encodes the β-chains of the minor Hb isoform). The Hbbd and Hbbp haplotypes share identical HBB-T1 alleles, but products of the alternative HBB-T2 alleles (dminor and pminor) are distinguished by two amino acid substitutions. To investigate the possible adaptive significance of the Hbbd/Hbbp polymorphism we conducted a population genetic analysis of the duplicated β-globin genes of Indian house mice (Mus castaneus) in conjunction with experimental studies of Hb function in inbred strains of mice that carry the alternative Hbbd and Hbbp haplotypes. The main objectives of this study were (i) to characterize patterns of nucleotide polymorphism and linkage disequilibrium in the duplicated β-globin genes of M. castaneus, (ii) to test the hypothesis that the Hbbd and Hbbp haplotypes are maintained as a balanced polymorphism, and (iii) to assess whether allelic differences in the alternative minor Hb isoforms (dminor and pminor) are associated with different O2-binding properties. A multilocus analysis of polymorphism and divergence revealed that levels of diversity at the HBB-T2 gene exceeded neutral expectations, and reconstructed haplotype networks for both β-globin paralogs revealed extensive allele sharing with several other closely related species of Mus. However, despite this suggestive evidence for balancing selection, O2-equilibrium curves revealed no discernible functional differences between red cell lysates containing the dminor and pminor Hb isoforms. If the dminor and pminor alleles are maintained as a balanced polymorphism, our results indicate that the associated fitness variance is not directly related to respiratory functions of Hb.

AB - Electrophoretic surveys of hemoglobin (Hb) polymorphism in house mice from South Asia and the Middle East have revealed that two alternative β-globin haplotypes, Hbbd and Hbbp, are often present at intermediate frequencies in geographically disparate populations. Both haplotypes harbor two functionally distinct β-globin paralogs, HBB-T1 (which encodes the β-chain subunits of the major Hb isoform) and HBB-T2 (which encodes the β-chains of the minor Hb isoform). The Hbbd and Hbbp haplotypes share identical HBB-T1 alleles, but products of the alternative HBB-T2 alleles (dminor and pminor) are distinguished by two amino acid substitutions. To investigate the possible adaptive significance of the Hbbd/Hbbp polymorphism we conducted a population genetic analysis of the duplicated β-globin genes of Indian house mice (Mus castaneus) in conjunction with experimental studies of Hb function in inbred strains of mice that carry the alternative Hbbd and Hbbp haplotypes. The main objectives of this study were (i) to characterize patterns of nucleotide polymorphism and linkage disequilibrium in the duplicated β-globin genes of M. castaneus, (ii) to test the hypothesis that the Hbbd and Hbbp haplotypes are maintained as a balanced polymorphism, and (iii) to assess whether allelic differences in the alternative minor Hb isoforms (dminor and pminor) are associated with different O2-binding properties. A multilocus analysis of polymorphism and divergence revealed that levels of diversity at the HBB-T2 gene exceeded neutral expectations, and reconstructed haplotype networks for both β-globin paralogs revealed extensive allele sharing with several other closely related species of Mus. However, despite this suggestive evidence for balancing selection, O2-equilibrium curves revealed no discernible functional differences between red cell lysates containing the dminor and pminor Hb isoforms. If the dminor and pminor alleles are maintained as a balanced polymorphism, our results indicate that the associated fitness variance is not directly related to respiratory functions of Hb.

UR - http://www.scopus.com/inward/record.url?scp=77954856208&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954856208&partnerID=8YFLogxK

U2 - 10.1534/genetics.109.113506

DO - 10.1534/genetics.109.113506

M3 - Article

VL - 184

SP - 1121

EP - 1131

JO - Genetics

JF - Genetics

SN - 0016-6731

IS - 4

ER -