title: Global genetic architecture of an erythroid quantitative trait locus, HMIP-2.
abstract: HMIP-2 is a human quantitative trait locus affecting peripheral numbers, size and hemoglobin composition of red blood cells, with a marked effect on the persistence of the fetal form of hemoglobin, HbF, in adults. The locus consists of multiple common variants in an enhancer region for MYB (chr 6q23.3), which encodes the hematopoietic transcription factor cMYB. Studying a European population cohort and four African-descended groups of patients with sickle cell anemia, we found that all share a set of two spatially separate HbF-promoting alleles at HMIP-2, termed "A" and "B." These typically occurred together ("A-B") on European chromosomes, but existed on separate homologous chromosomes in Africans. Using haplotype signatures for "A" and "B," we interrogated public population datasets. Haplotypes carrying only "A" or "B" were typical for populations in Sub-Saharan Africa. The "A-B" combination was frequent in European, Asian, and Amerindian populations. Both alleles were infrequent in tropical regions, possibly undergoing negative selection by geographical factors, as has been reported for malaria with other hematological traits. We propose that the ascertainment of worldwide distribution patterns for common, HbF-promoting alleles can aid their further genetic characterization, including the investigation of gene-environment interaction during human migration and adaptation.
authors: King's College London, London, UK.
authors: Stephan
authors: S
authors: Menzel
authors: King's College London, London, UK.
authors: Helen
authors: H
authors: Rooks
authors: Centre National de Génotypage, Evry, France.
authors: Diana
authors: D
authors: Zelenika
authors: King's College London, London, UK.|Muhimbili University, Dar es Salaam, Tanzania.
authors: Siana N
authors: SN
authors: Mtatiro
authors: King's College London, London, UK.
authors: Akshala
authors: A
authors: Gnanakulasekaran
authors: King's College London, London, UK.|King's College Hospital NHS Foundation Trust, London, UK.
authors: Emma
authors: E
authors: Drasar
authors: Muhimbili University, Dar es Salaam, Tanzania.
authors: Sharon
authors: S
authors: Cox
authors: University of Texas at Dallas, Richardson, TX, USA.
authors: Li
authors: L
authors: Liu
authors: King's College London, London, UK.
authors: Mariam
authors: M
authors: Masood
authors: King's College London, London, UK.
authors: Nicholas
authors: N
authors: Silver
authors: University of California Irvine School of Medicine, Irvine, CA, USA.
authors: Chad
authors: C
authors: Garner
authors: King's College London, London, UK.
authors: Nisha
authors: N
authors: Vasavda
authors: King's College London, London, UK.|Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK.
authors: Jo
authors: J
authors: Howard
authors: Muhimbili University, Dar es Salaam, Tanzania.
authors: Julie
authors: J
authors: Makani
authors: Faculty of Medicine, Kuwait University, Kuwait.
authors: Adekunle
authors: A
authors: Adekile
authors: Georgia Regents University, Augusta, GA, USA.
authors: Betty
authors: B
authors: Pace
authors: King's College London, London, UK.
authors: Tim
authors: T
authors: Spector
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors: Martin
authors: M
authors: Farrall
authors: McGill University, Montreal, Canada.
authors: Mark
authors: M
authors: Lathrop
authors: King's College London, London, UK.|King's College Hospital NHS Foundation Trust, London, UK.
authors: Swee Lay
authors: SL
authors: Thein
mesh_terms: D000483:Alleles; D000755:Anemia, Sickle Cell / Q000235:genetics*; D044383:Black People / Q000235:genetics; D004742:Enhancer Elements, Genetic; D004912:Erythrocytes / Q000166:cytology*; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D005828:Genetics, Population; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
chemical_list: D020598:Proto-Oncogene Proteins c-myb
keywords: Red blood cells; cMYB; gene enhancer variant; malaria; population genetics; quantitative trait locus; sickle cell disease