Λεπτομέρειες βιβλιογραφικής εγγραφής
| Τίτλος: |
Mismapping of sequencing reads from polymorphic duplications generates spurious trans-eQTLs. |
| Συγγραφείς: |
Aqil, Alber1 (AUTHOR), Huang, Betty Y.H.1,2 (AUTHOR), Pavlidis, Pavlos3,4 (AUTHOR), McCoy, Rajiv C.1,2 (AUTHOR) rajiv.mccoy@jhu.edu, Gokcumen, Omer1,5 (AUTHOR) gokcumen@gmail.com |
| Πηγή: |
American Journal of Human Genetics. Aug2026, Vol. 113 Issue 8, p1604-1617. 14p. |
| Θεματικοί όροι: |
*False positive error, *Linkage disequilibrium, *Genomics, *DNA copy number variations, *RNA sequencing, *Locus (Genetics) |
| Περίληψη: |
The discovery of trans -acting expression quantitative trait loci (trans -eQTLs) remains plagued by false positives. One unaddressed source of these false positives is polymorphic duplications absent in the reference genome. Specifically, RNA sequencing (RNA-seq) reads from a non-reference gene duplicate have the potential to erroneously map to the single reference copy of the gene. These mismapped RNA-seq reads could generate spurious trans -eQTLs that localize near the insertion site of the non-reference duplicate but appear to regulate the reference copy of the gene. In such scenarios, similarly mismapped DNA-seq reads would create apparent long-range linkage disequilibrium between the spurious trans -eQTL and its target gene's locus. We call this footprint "mismapping linkage disequilibrium" and use it to flag spurious trans -eQTLs. We applied this strategy to published trans -eQTLs from Genotype-Tissue Expression (GTEx) and newly generated trans -eQTLs from MAGE, both already filtered for calls attributable to cross-mappability of RNA-seq reads between reference duplicates. This strategy demonstrated that at least 15.4% and 6.1% of trans -eQTLs in GTEx and MAGE, respectively, are spurious due to non-reference polymorphic duplications. We find that spurious trans -eQTLs are more likely to have large effect sizes. Thus, we expect large-sample studies such as eQTLGen (n > 30,000), which are powered to detect many more small-effect trans -eQTLs, to harbor smaller proportions of spurious trans -eQTLs than smaller studies such as GTEx (n = 838) and MAGE (n = 731). The polymorphic duplication of DUSP22 demonstrates how mismapping linkage disequilibrium can uncover both false-positive trans -eQTLs and trans -acting splicing QTLs (trans -sQTLs). Overall, our study offers a practical metric to improve trans -eQTL filtering. Polymorphic gene duplications absent from the reference genome can generate spurious trans -eQTLs. Specifically, variants tagging the polymorphic duplicate may masquerade as trans -eQTLs regulating the reference gene copy. Here, we develop a method to identify these artifacts in trans -eQTL maps using apparent linkage disequilibrium between putative trans -eQTLs and their target genes. [ABSTRACT FROM AUTHOR] |
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