biostudies-literatureChen XNICHD NIH HHSNHGRI NIH HHSWellcome Trust2340https://www.ebi.ac.uk/biostudies/studies/S-EPMC11890787biostudies-literatureUnknown16(1)Variant calling is hindered in segmental duplications by sequence homology. We developed Paraphase, a HiFi-based informatics method that resolves highly similar genes by phasing all haplotypes of paralogous genes together. We applied Paraphase to 160 long (>10 kb) segmental duplication regions across the human genome with high (>99%) sequence similarity, encoding 316 genes. Analysis across five ancestral populations revealed highly variable copy numbers of these regions. We identified 23 paralog groups with exceptionally low within-group diversity, where extensive gene conversion and unequal crossing over contribute to highly similar gene copies. Furthermore, our analysis of 36 trios identified 7 de novo SNVs and 4 de novo gene conversion events, 2 of which are non-allelic. Finally, we sumNature communicationsGenome-wide profiling of highly similar paralogous genes using HiFi sequencing.PMC11890787U01 HG011745R01 HD093450Belhadj SKo APitsava GKasperaviciute DBaker DDevaney JMKruszka PAlmalvez MDelaney MBluske KDelot EEberle MAHarting JBerlyoung ASFraser JLochovsky LChen XNewman SFusaro VLosic BDolzhenko EHruska KSBrandon RLoTempio JUCI Genomics Research to Elucidate the Genetics of Rare diseases (UCI GREGoR) Consortiumde Dios ILi WPastinen TCohen AKing CHHoischen AAuriga LThiffault IGilissen CVilain ECui YKaram RVissers LBoukas LFarrow ENoya JXiao CBerger SHsiao EYfalseGenome-wide profiling of highly similar paralogous genes using HiFi sequencing.Variant calling is hindered in segmental duplications by sequence homology. We developed Paraphase, a HiFi-based informatics method that resolves highly similar genes by phasing all haplotypes of paralogous genes together. We applied Paraphase to 160 long (>10 kb) segmental duplication regions across the human genome with high (>99%) sequence similarity, encoding 316 genes. Analysis across five ancestral populations revealed highly variable copy numbers of these regions. We identified 23 paralog groups with exceptionally low within-group diversity, where extensive gene conversion and unequal crossing over contribute to highly similar gene copies. Furthermore, our analysis of 36 trios identified 7 de novo SNVs and 4 de novo gene conversion events, 2 of which are non-allelic. Finally, we sum2025-01-01T00:00:00Z2025 Mar2026-06-01T20:13:50.107Z2025-04-04T08:22:44.085ZS-EPMC118907874005748510.1038/s41467-025-57505-2