In some cases variation is maintained because the heterozygote has the highest fitness. Sickle-cell anemia is a genetic disease caused by a mutant form of hemoglobin. Individuals who are homozygous for this recessive allele have the disease and die at an early age. One would expect the sickle-cell allele to be reduced to very low levels by natural selection. Surprisingly, the frequency of the allele is quite high in certain parts of the world. The clue to solving this mystery came from the discovery that the areas with high sickle-cell frequency coincided with areas where malaria, a blood disease, was common. What is the connection between malaria and sickle-cell? Individuals that had one or two sickle-cell alleles were found to be more resistant to malaria.