Cloning genes that underlie complex traits is one of the most difficult challenges faced by geneticists, many of whom will be fascinated by the recent report published in Nature Genetics on the identification of a single locus that underlies both a simple monogenic and a complex trait.

Min-Oo et al. identified the pyruvate kinase gene ( Pklr ) as the locus that causes reticulocytosis — an increase in the proportion of immature red blood cells in the blood — and confers malaria resistance in mice.

The discovery that Pklr also underlies resistance to malaria came when the authors tried to find the genetic basis of malaria resistance in two mouse congenic strains, AcB55 and AcB61. Linkage analysis showed that one locus (dubbed Char4 ) that influences parasite load in the blood of these strains mapped to chromosome 3.

The two resistant mouse strains had many more immature red blood cells than susceptible mice. To understand the relationship between this phenomenon, which is a simple trait, and resistance to malaria, which is a complex trait, the authors mapped the reticulocytosis locus. It mapped to the Char4 region on chromosome 3 and a search of public databases for candidates that are specifically expressed in red blood cells led Min-Oo and colleagues to Pklr — a locus that encodes pyruvate kinase, which is essential for ATP production in red blood cells. Sure enough, the two resistant strains carried the same substitution mutation in Pklr. In humans, the homologous mutation in PKLR leads to pyruvate kinase deficiency and anaemia.

Although the mechanism by which a mutation in Pklr confers resistance to malaria is unclear, the authors established that higher numbers of immature red blood cells correlated with lower numbers of parasites in the blood and that homozygosity for mutant Pklr was associated with reduced mortality owing to malaria.

The formal proof that Pklr and Char4 are allelic is yet to come. Nonetheless, several facts strongly indicate that the two loci are allelic: they both map to the same interval on chromosome 3, they have the same mode of inheritance, Pklr acts in the cell type that is the primary site of replication of the malaria parasite in vivo and parasite load and mortality are reduced in Pklr mutants.

One of many intriguing aspects of this story is associated with the human mutation in PKLR, which causes the most common type of hereditary haemolytic anaemia. Could it be that the high prevalence of this anaemia in human populations is explained by the advantage that it confers on carriers owing to decreased malaria susceptibility, much in the way that mutations in haemoglobin C or α-thalassaemia do? Min-Oo and colleagues are investigating.