Hardy-Weinberg Equilibrium (HWE) is used to estimate the number of homozygous and heterozygous variant carriers based on its allele frequency in populations that are not evolving. Previously, deviation from HWE in large population databases were investigated to detect genotyping errors, which can result in extreme heterozygote excess (HetExc). However, HetExc might also be a sign of natural selection since recessive disease causing variants are expected to occur less frequently in a homozygous

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... tate in the general population, but might reach high allele frequency, especially if they are advantageous, in a heterozygote state. We developed a filtering strategy to detect these variants and applied it on genome data from 137,842 individuals. We found that the main limitations of this approach were quality of genotype calls and insufficient population sizes, whereas population structure and high level of inbreeding could reduce sensitivity, but not precision, in certain populations. Nevertheless, we identified 365 HetExc variants in 326 genes, most of which were specific to African/African American populations (~84.7%). Although the majority of them were not associated with known diseases, or were classified as "benign", they were enriched in genes associated with autosomal recessive diseases. The resulting dataset also contained two known recessive disease causing variants with evidence of heterozygote advantage in the genes and . Finally, we provide evidence of a novel heterozygote advantageous variant in the gene (involved in influenza virus replication). We anticipate that our approach will allow the detection of rare recessive disease causing variants in the future.