SUMMARY/ABSTRACT Structurally complex loci (SCLs) are hotspots of genome dynamism whose relationship to human phenotypic variation is unknown. SCLs have multiple segments of duplicated DNA sequence which can contain or flank genes, exons, or regulatory elements; these repeated sequences recombine with one another to generate new alleles by non-allelic homologous recombination and gene conversion, creating many functionally distinct alleles with different gene dosages and/or protein structures. Human genetics does not yet know the alleles that are present at most SCLs, nor their relationship to human phenotypic variation. Genetic variation at SCLs tends to arise from many alleles, to be hard to assemble, and to have complex relationships to nearby SNPs and SNP haplotypes. Yet SCLs provide a real opportunity to relate phenotypes to allelic series of functional alleles with interpretable effects on gene dosage or protein domain structure. In this work, we will develop ways to ascertain how SCLs at loci across the genome are comprised of allelic series and relate to a diverse set of human phenotypes. To do this, we will combine data from many forms of genome analysis – definitive long-read data (n ~102 and growing), whole-genome and whole-exome sequence data (104-105) and SNP array data (105-107) with companion phenotype data. In Aim 1, we will develop methods to reveal the full spectrum of variation at SCLs. We will (a) identify variable DNA features and the ways in which these features vary and co-distribute across thousands of people of diverse ancestries, and (b) find the underlying alleles and allele frequencies that explain this population-scale variation. In Aim 2, we will enable powerful genotype-phenotype analyses that leverage vast existing SNP data sets; we will do this by creating large panels of reference haplotypes of SCL alleles and surrounding SNPs, and advancing methods for imputing SCL alleles into SNP data. In Aim 3, we will advance approaches for genetic association analysis and fine-mapping at SCLs, and explore the functional consequences of SCLs on quantitative traits and disease risk. We aspire to make and enable many more discoveries about how allelic series at structurally complex loci shape human phenotypes.