Reduced Detection of Human Orphan Gene Transcripts in Disease Tissue Relative to Expression- and Detection- Matched Controls

Abstract

Human orphan genes are poorly annotated and lowly expressed, which makes their behavior in disease difficult to establish. We analyzed paired normal and disease RNA-seq libraries from four cohorts, quantified against a combined reference in which 2190 of 198,507 transcripts are orphan. Cohorts were first screened for library-level differences between the two conditions, and one (GSE40419, lung adenocarcinoma) was excluded because sequencing depth, pseudoalignment rate, and submission provenance all differed by condition; it is retained throughout as a calibration. In the remaining three cohorts, comprising 151 matched pairs from psoriasis, laryngeal squamous cell carcinoma, and hepatocellular carcinoma, we measured the change in the fraction of transcripts with zero abundance, a quantity that does not depend on any transformation of expression. Orphan transcripts lose detection relative to non-orphan transcripts matched on abundance and on cross-patient detection frequency, by +0.0250±0.0178, +0.0553±0.0073, and +0.0659±0.0122 once the global shift in detection is held fixed. The three estimates are homogeneous (p=0.163) and pool to +0.0544±0.0059, whereas the same analysis applied to the excluded cohort returns thirteen times that value. We report the result at the level at which it is measured, and withdraw the patient-level and cohort-specific claims made in the first preprint version of this work.