title: Sequence variation at multiple loci influences red cell hemoglobin concentration.
abstract: A substantial genetic contribution underlies variation in baseline peripheral blood counts. We performed quantitative trait locus/loci analyses to identify chromosome regions harboring genes influencing red cell hemoglobin concentration using the cell hemoglobin concentration mean (CHCM), a directly measured parameter analogous to the mean cell hemoglobin concentration. Fourteen significant loci (gene symbols Chcmq1-Chcmq14) were detected. Seven of these influenced CHCM in a sex-specific fashion, and 2 showed significant interactive effects (epistasis). For quantitative trait locus/loci detected in multiple crosses, confidence intervals were narrowed using statistical and bioinformatic approaches. Two strong candidate genes emerged and were further analyzed: adult β-globin (Hbb) for Chcmq3 on Chr 7, and transferrin (Trf) for Chcmq2 on Chr 9. High and low allele parental strains in crosses detecting Chcmq3 segregate 100% with the known ancestral haplotype blocks, hemoglobin (Hb) diffuse (Hbb(d)) and Hb single (Hbb(s)), respectively. Hbb(d) consists of nonidentical major and minor polypeptides and exhibits an increased positive charge relative to Hbb(s) due to the net loss of 2 negative residues in the Hbb(dminor) polypeptide, resulting in a pI of 7.85 versus 7.13. Thus, as shown in human erythrocytes, positively charged Hbs are associated with cell dehydration and increased CHCM in mouse erythrocytes.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA. luanne.peters@jax.org
authors.forename: Luanne L
authors.initials: LL
authors.lastname: Peters
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Shavit
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Lambert
authors.forename: Shirng-Wern
authors.initials: SW
authors.lastname: Tsaih
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Su
authors.forename: Magalie S
authors.initials: MS
authors.lastname: Leduc
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
authors.forename: Carlo
authors.initials: C
authors.lastname: Brugnara
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003433:Crosses, Genetic; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006454:Hemoglobins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D040641:Quantitative Trait Loci; D055544:beta-Globins / Q000235:genetics*
chemical_list: D006454:Hemoglobins; D055544:beta-Globins