Aggregate variant calling using short reads enables population and disease studies for paralogous genes

= 0.9998). Using sequence data from population and disease cohorts, we utilized aggregate variant calls to perform population-genetic analysis, case-control association analysis, and haplotype phasing in specific disease-relevant paralogous genes that are inaccessible to standard diploid variant calling. Specifically, in the SMN1 gene, we identified tag-SNPs for two-copy SMN1 haplotypes and showed that specific low-frequency missense variants in African populations occurred exclusively on such haplotypes. For the CFC1 gene-previously implicated in heterotaxy syndrome-association analysis using exome data indicated that loss-of-function variants are unlikely to be associated with heterotaxy in individuals with congenital heart disease. Finally, we utilized aggregate genotypes to perform haplotype phasing for the X-linked gene IKBKG, achieving 99.2% concordance between trio-based and statistical phasing approaches.