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Haemoglobin disorders

Haemoglobin disorders are amongst the commonest human genetic diseases worldwide. They represent a unique and fascinating example of balancing selection because of the resistance conferred against malaria by some variants of these disorders. Moreover, it is expected that they will represent an increasing public health and economic burden, both in low-/middle- and high-income countries, due to the epidemiological transition and to migrations respectively. Our research combines mapping and modelling methodologies to study a range of basic and applied questions.

Sickle haemoglobin (HbS) is a structural variant of normal adult haemoglobin (HbA), resulting from a single amino acid substitution at position 6 of the beta globin molecule (β 6Glu→Val). HbS is the most common pathological haemoglobin variant worldwide. Through the spatial validation of the malaria hypothesis and modelling epistatic interactions between sickle haemoglobin and alpha-thalassaemia, we are working on the evolutionary processes involved in the selection of the sickle cell gene. We are also interested in refining our knowledge about its contemporary distribution, as well as the present and future burden of sickle haemoglobin.

Alpha-thalassaemia (αTh) affects the normal production of the alpha-globin genes. The severity of the disorder is usually related to number of functional copies of the alpha-globin genes (from 4: normal to 0: lethal). In humans, we are currently looking at i) the distribution of this disorder and its different variants, ii) the phenotype-genotype relationship, iii) epistatic interactions with other haemoglobin disorders (e.g. sickle haemoglobin or beta-thalassaemia) and iv) the burden associated with this disorder. We are also exploring the presence of similar polymorphisms in the alpha-globin gene in non-human primates (NHPs).


  1. Williams, T.N., Mwangi, T.W., Wambua, S., Peto, T.E.A., Weatherall, D.J., Gupta, S., Recker, M., Penman, B.S., Uyoga, S., Macharia, A., Mwacharo, J.K., Snow, R.W. and Marsh, K. (2005) Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait. Nature Genetics, 37(11): 1253-7. PDF
  2. Penman, B.S., Pybus, O.G., Weatherall, D.J. & Gupta, S. (2009) Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean. Proceedings of the National Academy of Sciences USA: 106(50): 21242-21246. PDF
  3. Piel, F.B., Patil, A.P., Howes, R.H., Nyangiri, O.A., Gething, P.W., Williams, T.N., Weatherall, D.J. and Hay, S.I. (2010) Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nature Communications. 2: 104. PDF
  4. Penman B.S., Habib S., Kanchan, K. and Gupta, S. (2011) Negative epistasis between α+-thalassaemia and sickle cell trait can explain interpopulation variation in South Asia. Evolution. 65(12): 3625-3632. PDF
  5. Piel, F.B., Patil, A.P., Howes, R.H., Nyangiri, O.A., Gething, P.W., Dewi, M., Temperley, W.H., Williams, T.N., Weatherall, D.J. and Hay, S.I. (2012) Global epidemiology of sickle haemoglobin in neonates: a contemporay geostatistical model-based map and population estimates. The Lancet 381(9861): 142-151. PDF