Genome-wide profiling of highly similar paralogous genes using HiFi sequencing

Chen, X.; Baker, D.; Dolzhenko, E.; Devaney, J. M.; Noya, J.; Berlyoung, A. S.; Brandon, R.; Hruska, K. S.; Lochovsky, L.; Kruszka, P.; Newman, S.; Farrow, E.; Thiffault, I.; Pastinen, T.; Kasperaviciute, D.; Gilissen, C.; Vissers, L.; Hoischen, A.; Berger, S.; Vilain, E.; Delot, E.; Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium,; Eberle, M. A.

doi:10.1101/2024.04.19.590294

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bioRxiv · 10.1101/2024.04.19.590294

Genome-wide profiling of highly similar paralogous genes using HiFi sequencing

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Abstract

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 a gene family. 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 families with exceptionally low within-family diversity, where extensive gene conversion and unequal-crossing over have resulted in 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 summarized extensive genetic diversity in 9 medically relevant genes previously considered challenging to genotype. Paraphase provides a framework for resolving gene paralogs, enabling accurate testing in medically relevant genes and population-wide studies of previously inaccessible genes.

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Chen, X., Baker, D., Dolzhenko, E., Devaney, J. M., Noya, J., Berlyoung, A. S., Brandon, R., Hruska, K. S., Lochovsky, L., Kruszka, P., Newman, S., Farrow, E., Thiffault, I., Pastinen, T., Kasperaviciute, D., Gilissen, C., Vissers, L., Hoischen, A., Berger, S., Vilain, E., Delot, E., Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium,, Eberle, M. A.. 2024-04-24. Genome-wide profiling of highly similar paralogous genes using HiFi sequencing. https://doi.org/10.1101/2024.04.19.590294

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