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This study investigated whether genetic regulatory variations (cis-eQTLs) explain why some genes on chromosome 21 deviate from the expected 1.5-fold overexpression in people with Down syndrome. Analyzing RNA sequencing data from 274 individuals with trisomy 21 and 80 euploid controls, researchers identified 13 genes that differed significantly from expected expression levels. While common cis-eQTLs were found for many of these genes, the same regulatory variants were present at similar frequencies in both Down syndrome participants and the general population, indicating that these variants do not explain why certain genes deviate from the expected dosage effect in trisomy 21.
Why it matters
Understanding why some chromosome 21 genes escape the typical dosage effect in Down syndrome could reveal compensatory mechanisms and identify therapeutic targets. The finding that common genetic variants do not explain these deviations suggests that other regulatory mechanisms, such as epigenetic factors or trans-acting elements, may be responsible for dosage compensation.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Down syndrome (DS) results from trisomy 21 (T21), the triplication of human chromosome 21 (HSA21). On average, genes on HSA21 are overexpressed at the expected 1.5-fold increase. A small subset of HSA21 genes is expressed closer to euploid levels. Could local genetic regulatory variation explain deviations from the expected dosage? Using the largest DS-specific transcriptomic dataset to date from the Human Trisome Project (HTP) and GTEx expression quantitative trait loci (eQTLs), we tested whether local genetic regulatory variation contributes to gene-specific buffering or amplification of HSA21 dosage effects in DS. We compared the bulk RNA-seq profiles of protein-coding genes, lncRNAs, and pseudogenes from whole-blood samples of 274 participants with T21 and 80 euploid (D21) participants. We filtered out genes with low read counts or high genomic repeat content and applied ploidy correction to the differential expression analysis. We found 13 genes that differed significantly from the expected fold change. We cross-referenced GTEx whole-blood eQTLs (cis window 1 {+/-} Mb) with the 13 deviating genes. A common cis-eQTL was detected for 8 of the 10 testable genes. However, 59 of 99 HSA21 genes that had the expected fold change had significant cis-eQTLs. Additionally, T21 participants carry the eQTL alleles at similar frequencies to GTEx donors. Therefore, cis-eQTLs explain differences between people with T21, not the difference between T21 and D21. Overall, common cis-regulatory variation acts on HSA21 genes in T21 as it does in euploid blood, but it does not explain which genes deviate from the ploidy expectation.