Non-random mating due to geographical location might be a common cause of deviations from HWE due to heterozygous deficiency in large populations of different ethnicities ( Garnier-Géré and Chikhi, 2013). Positive and negative assertive mating might result in deviations from HWE due to heterozygote deficiency or excess respectively, although the latter is more rarely observed in humans ( Thiessen and Gregg, 1980). However, various factors, including mutation, natural selection, non-random mating, genetic drift, and gene flow can cause deviations from HWE ( Graffelman et al., 2017). According to HWE, for a locus with two alleles A and a with corresponding frequencies p and q, three genotypes are possible AA, Aa, and aa with expected frequencies p 2, 2pq, q 2, respectively ( Graffelman et al., 2017). The Hardy-Weinberg Equilibrium (HWE) is an important fundamental principal of population genetics, which states that “genotype frequencies in a population remain constant between generations in the absence of disturbance by outside factors” ( Edwards, 2008). We anticipate that our approach will aid the detection of rare recessive disease causing variants in the future. Finally, we provide supporting in silico evidence of a novel heterozygote advantageous variant in the chromodomain helicase DNA binding protein 6 gene ( CHD6 involved in influenza virus replication).

The resulting dataset also contained two known recessive disease causing variants with evidence of heterozygote advantage in the sickle-cell anemia (HBB) and cystic fibrosis (CFTR). Although the majority of them were not associated with known diseases, or were classified as clinically “benign,” they were enriched in genes associated with autosomal recessive diseases. Nevertheless, we identified 161 HetExc variants in 149 genes, most of which were specific to African/African American populations (∼79.5%). The main limitations of this approach were quality of genotype calls and insufficient population sizes, whereas population structure and inbreeding can reduce sensitivity, but not precision, in certain populations. We developed a filtering strategy to detect these variants and applied it on genome data from 137,842 individuals. However, HetExc might also be a sign of natural selection since recessive disease causing variants should occur less frequently in a homozygous state in the population, but may reach high allele frequency in a heterozygous state, especially if they are advantageous. Deviations from HWE in large population databases have been used to detect genotyping errors, which can result in extreme heterozygote excess (HetExc). 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.

Hardy weinberg principle