Genome-wide profiling of highly similar paralogous genes using HiFi sequencing
Xiao Chen1, Daniel Baker2, Egor Dolzhenko2
1PacBio, Menlo Park, CA, USA. xchen@pacificbiosciences.com.
Nature Communications
|March 8, 2025
Summary
Paraphase, a new method, accurately phases highly similar genes in segmental duplications. This advances genetic variant calling and enables studies of previously inaccessible genes.
Area of Science:
- Genomics
- Bioinformatics
Background:
- Variant calling in segmental duplications is challenging due to high sequence homology.
- Highly similar paralogous genes complicate accurate genetic analysis.
Purpose of the Study:
- To develop and apply Paraphase, a HiFi-based method for resolving highly similar genes in segmental duplications.
- To analyze genetic diversity and identify novel variants within these complex genomic regions.
Main Methods:
- Developed Paraphase, a bioinformatics tool for phasing haplotypes of paralogous genes.
- Applied Paraphase to 160 long segmental duplication regions in the human genome.
- Analyzed data from five ancestral populations and 36 trios.
Main Results:
- Paraphase successfully resolved highly similar genes in segmental duplications.
- Identified highly variable copy numbers across ancestral populations.
- Discovered 23 paralog groups with low diversity due to gene conversion and unequal crossing over.
- Detected 7 de novo single nucleotide variants and 4 de novo gene conversion events.
Conclusions:
- Paraphase provides a robust framework for resolving gene paralogs.
- Enables accurate genetic testing in medically relevant genes and previously inaccessible genes.
- Facilitates population-wide genetic studies in complex genomic regions.
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