RNAScope-Ancestry: A Cross-Modality Framework for Inferring Genetic Ancestry from RNA-Seq with Application to MECA

Genetic ancestry inference traditionally relies on genotyping arrays or whole-genome sequencing. We present RNAScope-Ancestry, a computational pipeline that leverages short-read RNA-seq for dual-purpose ancestry and transcriptomic analysis. Using RNA-seq from 490 MECA participants and 1000 Genomes reference populations, we performed variant calling, quality filtering, principal component analysis and retained 230 high-frequency SNPs for ancestry estimation via Rye algorithm for ancestry inferences. MECA participants aligned with African and admixed populations, predominantly West African. Correlation with gene expression identified the top 50 ancestry-associated transcripts. Validation in 109 longitudinal samples confirmed reproducibility. The pipeline is open-source and generalizable: https://github.com/rob-meller/; https://github.com/Vermarashi/.