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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)434-451
Number of pages18
JournalAnnals of Human Genetics
Volume78
Issue number6
DOIs
StatePublished - Nov 1 2014

Fingerprint

Quantitative Trait Loci
Alleles
Haplotypes
Population
Human Migration
Chromosomes
Fetal Hemoglobin
Gene-Environment Interaction
Africa South of the Sahara
Sickle Cell Anemia
Malaria
Hemoglobins
Transcription Factors
Erythrocytes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Menzel, S., Rooks, H., Zelenika, D., Mtatiro, S. N., Gnanakulasekaran, A., Drasar, E., ... Thein, S. L. (2014). Global Genetic Architecture of an Erythroid Quantitative Trait Locus, HMIP-2. Annals of Human Genetics, 78(6), 434-451. https://doi.org/10.1111/ahg.12077

Global Genetic Architecture of an Erythroid Quantitative Trait Locus, HMIP-2. / Menzel, Stephan; Rooks, Helen; Zelenika, Diana; Mtatiro, Siana N.; Gnanakulasekaran, Akshala; Drasar, Emma; Cox, Sharon; Liu, Li; Masood, Mariam; Silver, Nicholas; Garner, Chad; Vasavda, Nisha; Howard, Jo; Makani, Julie; Adekile, Adekunle; Pace, Betty; Spector, Tim; Farrall, Martin; Lathrop, Mark; Thein, Swee Lay.

In: Annals of Human Genetics, Vol. 78, No. 6, 01.11.2014, p. 434-451.

Research output: Contribution to journalArticle

Menzel, S, Rooks, H, Zelenika, D, Mtatiro, SN, Gnanakulasekaran, A, Drasar, E, Cox, S, Liu, L, Masood, M, Silver, N, Garner, C, Vasavda, N, Howard, J, Makani, J, Adekile, A, Pace, B, Spector, T, Farrall, M, Lathrop, M & Thein, SL 2014, 'Global Genetic Architecture of an Erythroid Quantitative Trait Locus, HMIP-2', Annals of Human Genetics, vol. 78, no. 6, pp. 434-451. https://doi.org/10.1111/ahg.12077
Menzel S, Rooks H, Zelenika D, Mtatiro SN, Gnanakulasekaran A, Drasar E et al. Global Genetic Architecture of an Erythroid Quantitative Trait Locus, HMIP-2. Annals of Human Genetics. 2014 Nov 1;78(6):434-451. https://doi.org/10.1111/ahg.12077
Menzel, Stephan ; Rooks, Helen ; Zelenika, Diana ; Mtatiro, Siana N. ; Gnanakulasekaran, Akshala ; Drasar, Emma ; Cox, Sharon ; Liu, Li ; Masood, Mariam ; Silver, Nicholas ; Garner, Chad ; Vasavda, Nisha ; Howard, Jo ; Makani, Julie ; Adekile, Adekunle ; Pace, Betty ; Spector, Tim ; Farrall, Martin ; Lathrop, Mark ; Thein, Swee Lay. / Global Genetic Architecture of an Erythroid Quantitative Trait Locus, HMIP-2. In: Annals of Human Genetics. 2014 ; Vol. 78, No. 6. pp. 434-451.
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