Haplotype Signatures At HBS1L-MYB In Global Populations
Authors: Thein Swee Lay , Rooks Helen , Drasar Emma , Gnanakulasekaran Akshala , Silver Nicholas , Spector Tim D , Lathrop Mark , Menzel Stephan 
Published: October 2019

Abstract
Common genetic variation has been found to significantly affect quantitative biological traits of red blood cells. One such locus in the intergenic region between HBS1L and MYB genes on chromosome 6q (HMIP-2), occupies upstream regulatory sequences for MYB1, which is a key erythroid transcription factor. HMIP-2 variation affects a series of erythroid traits2, with especially pronounced effects on variable persistence of fetal hemoglobin3.
In studying a large European population sample and an African-descended cohort of patients with sickle cell anemia (Hb SS), we found that both population groups share a set of two spatially separate alleles (HMIP-2 alleles ‘A’ and ‘B’) that increase HbF levels, but that these typically occur in tandem (‘A - B’) on European chromosomes, while they exist on separate chromosomes (either ‘A’ or ‘B’) in African populations. Surprisingly, ‘A’, ‘B’ and ‘A - B’ chromosomes exert similar effects on HbF persistence, suggesting a negative genetic interaction of these alleles when in cis configuration.
We extended our investigation to public data from the 1000Genomes4 and Human Genome Diversity5 projects, using characteristic haplotype signatures for ‘A’ and ‘B’ to investigate the prevalence of these alleles in global populations, without the need for phenotype data.
HMIP-2 variants exist in four characteristic principal haplotypes around the world: a haplotype clade without HbF-increasing variants (‘ancestral clade’), one clade each carrying only ‘A’ or ‘B’ (typical for African populations) and a fourth clade carrying both high-HbF alleles (‘A - B’). The latter was characteristic for all non-African populations studied and therefore termed the ‘Eurasian clade’. This clade is likely to have arisen in East Africa and to have been carried with the original migration of modern humans out of Africa. ‘A’ and ‘B’ alleles in either form are infrequent in malaria-endemic regions and might have unfavourable effects on malaria-protective genetic factors such as the sickle mutation. Phenotypic effects leading to the positive selection of these alleles in other populations might be related to their influence on general erythroid traits and on the kinetics of erythropoiesis in the bone marrow.
1. Stadhouders, R. et al. Dynamic long-range chromatin interactions control Myb proto-oncogene transcription during erythroid development. Embo J31, 986-99 (2012).
2. Menzel, S. et al. The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. Blood110, 3624-6 (2007).
3. Thein, S.L. et al. Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc Natl Acad Sci U S A104, 11346–11351 (2007).
4. Abecasis, G.R. et al. A map of human genome variation from population-scale sequencing. Nature467, 1061-73 (2010).
5. Li, J.Z. et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science319, 1100-4 (2008).

Disclosures:
Thein: Sangart: Consultancy; Shire: Consultancy, Research Funding; Novartis: Speakers Bureau.