Global genetic architecture of an erythroid quantitative trait locus, HMIP-2.

Stephan Menzel,Martin Farrall,Swee Lay Thein,Nicholas Silver,Helen Rooks,Jo Howard,Siana N Mtatiro,Mark Lathrop,Chad Garner,Mariam Masood,Adekunle Adekile,Akshala Gnanakulasekaran,Nisha Vasavda,Julie Makani,Sharon E Cox ,L I Liu ,Emma Drašar ,Tim D Spector ,Diana Zélénika ,Betty S Pace

doi:10.1111/ahg.12077

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.

Highlights

Human red blood cells have long appealed to geneticists because of their significant contribution to genetic disease, their exceptional accessibility and their relatively simple biology
One such quantitative trait locus (QTL) is HBS1L-MYB intergenic polymorphism (HMIP) on Chromosome 6q23.3, which was first detected in a large Asian Indian family (“Family D”) of Gujarati/North Indian descent (Thein & Weatherall, 1989; Craig et al, 1996), where it causes autosomal-dominant inheritance of hereditary persistence of fetal hemoglobin (HPFH)
To evaluate the biological significance of the “HPFH+” variants, we tested for association with HbF persistence in our cohort of healthy European twins

Summary

Introduction

Human red blood cells have long appealed to geneticists because of their significant contribution to genetic disease, their exceptional accessibility and their relatively simple biology. HMIP-2 Global Architecture become accessible to systematic genetic dissection, leading to the discovery of a large number of common genetic variants influencing red blood cell function and appearance (Sankaran & Orkin, 2013) One such quantitative trait locus (QTL) is HBS1L-MYB intergenic polymorphism (HMIP) on Chromosome 6q23.3, which was first detected in a large Asian Indian family (“Family D”) of Gujarati/North Indian descent (Thein & Weatherall, 1989; Craig et al, 1996), where it causes autosomal-dominant inheritance of hereditary persistence of fetal hemoglobin (HPFH). It was shown that variants at this locus contribute to a limited, but variable, HbF persistence that exists in the general European population This finding enabled its subsequent fine-mapping to a 75-kb interval between HBS1L and MYB and its partitioning into three independent linkage disequilibrium (LD) blocks of common genetic variants associated with the trait (Thein et al, 2007). In the general European population, these blocks were found to predominantly exist in different combinations (Thein et al, 2007), leading to the appearance of HBS1L-MYB as a more conventional QTL that contributes to the complex genetic determination of HbF persistence

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