Long-read sequencing with targeted assembly of the opsin locus accurately evaluates genes in expressed positions
Anderson, Z. B.; Prall, T.; Damaraju, N.; Storz, S. H.; Goffena, J.; Miller, A. L.; Carroll, J.; Neitz, M.; Miller, D. E.
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The human opsin gene cluster at Xq28 contains highly similar OPN1LW and OPN1MW genes essential for red-green color vision. Current molecular methods cannot accurately analyze this complex locus, limiting diagnosis of color vision deficiencies (CVD) and detection of carrier status. We performed Nanopore long-read sequencing of 206 individuals, comparing alignment-based analysis with targeted de novo assembly. Alignment-based methods performed poorly, whereas targeted assembly achieved 99% concordance for OPN1LW and 92% for OPN1MW copy numbers and resolved gene order in all XY individuals and 87% of XX individuals. This approach detected CVD in 3.2% of XY individuals and identified 8% of XX individuals as carriers, consistent with population estimates. Moreover, it molecularly explained the phenotypic severity in a family with Bornholm eye disease and clarified carrier status in an XX individual suspected of carrying two CVD haplotypes. Our approach provides a comprehensive, reference-free method for accurate analysis of expressed opsin genes and reliable CVD carrier detection.
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