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

doi:10.1111/ahg.12077

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

Twin Research & Genetic Epidemiology

Research output: Contribution to journal › Article › peer-review

21 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 language	English
Pages (from-to)	434-451
Number of pages	18
Journal	Annals of Human Genetics
Volume	78
Issue number	6
DOIs	https://doi.org/10.1111/ahg.12077
Publication status	Published - 1 Nov 2014

Keywords

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

UN SDGs

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10.1111/ahg.12077

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Menzel, S., Rooks, H., Zelenika, D., Mtatiro, S. N., 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, 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

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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.",

keywords = "CMYB, Gene enhancer variant, Malaria, Population genetics, Quantitative trait locus, Red blood cells, Sickle cell disease",

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

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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

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 - http://www.scopus.com/inward/record.url?scp=84908256845&partnerID=8YFLogxK

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 -

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

Abstract

Keywords

UN SDGs

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