Discovering the genetic causes of natural phenotypic variation in P. falciparum requires a combination of epidemiological and laboratory-based approaches. A powerful laboratory approach, which was instrumental in discovering the chloroquine resistance gene PfCRT, involves crossing two parasite strains with different phenotypic characteristics and then studying the resulting progeny.

Unfortunately, it is extremely laborious to perform genetic crosses for P. falciparum, and to date it has been accomplished only four times. The strains that have been crossed are 3D7 with HB3 (Walliker et al, 1987), HB3 with Dd2 (Wellems et al, 1990) and 7G8 with GB4 (Hayton et al, 2008). A fourth cross between clones 803 and GB4 was recently performed to study the genetic basis for artemisinin resistance. The parents and progeny of these genetic crosses represent a hugely valuable resource for the malaria research community to investigate a range of different phenotypes.

Assembling a complete and accurate picture of P. falciparum genome variation from short sequence reads presents many analytical challenges, particularly in regions of the genome that are highly polymorphic or made up of repetitive elements. To provide researchers with data resources to help overcome these challenges, the P. falciparum Genetic Crosses project has:

• Sequenced the parents and 78 progeny clones from the crosses 3D7xHB3, HB3xDd2 and 7G8xGB4
• Performed the first integrated analysis of single nucleotide polymorphisms (SNPs), INDELs and complex polymorphisms in P. falciparum, using Mendelian error rates as an indicator of genotypic accuracy
• Released sequence data and variant calls open access, and provided a dedicated web application to increase the usefulness of these data resources