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

Stephan Menzel*, Helen Rooks, Diana Zelenika, Siana N. Mtatiro, Akshala Gnanakulasekaran, Emma Drasar, Sharon Cox, Li Liu, Mariam Masood, Nicholas Silver, Chad Garner, Nisha Vasavda, Jo Howard, Julie Makani, Adekunle Adekile, Betty Pace, Tim Spector, Martin Farrall, Mark Lathrop, Swee Lay Thein

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)434-451
Number of pages18
JournalAnnals of Human Genetics
Issue number6
Publication statusPublished - 1 Nov 2014


  • CMYB
  • Gene enhancer variant
  • Malaria
  • Population genetics
  • Quantitative trait locus
  • Red blood cells
  • Sickle cell disease


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