Global Genetic Architecture of an Erythroid Quantitative Trait Locus, HMIP-2

TY - JOUR

T1 - Global Genetic Architecture of an Erythroid Quantitative Trait Locus, HMIP-2

AU - Menzel, Stephan

AU - Rooks, Helen

AU - Zelenika, Diana

AU - Mtatiro, Siana N.

AU - Gnanakulasekaran, Akshala

AU - Drasar, Emma

AU - Cox, Sharon

AU - Liu, Li

AU - Masood, Mariam

AU - Silver, Nicholas

AU - Garner, Chad

AU - Vasavda, Nisha

AU - Howard, Jo

AU - Makani, Julie

AU - Adekile, Adekunle

AU - Pace, Betty

AU - Spector, Tim

AU - Farrall, Martin

AU - Lathrop, Mark

AU - Thein, Swee Lay

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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.

AB - 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.

KW - CMYB

KW - Gene enhancer variant

KW - Malaria

KW - Population genetics

KW - Quantitative trait locus

KW - Red blood cells

KW - Sickle cell disease

UR - https://www.scopus.com/pages/publications/84908256845

U2 - 10.1111/ahg.12077

DO - 10.1111/ahg.12077

M3 - Article

AN - SCOPUS:84908256845

SN - 0003-4800

VL - 78

SP - 434

EP - 451

JO - Annals of Human Genetics

JF - Annals of Human Genetics

IS - 6

ER -