Highly diversified core promoters in the human genome and their effects on gene expression and disease predisposition

Abstract

Background Core promoter controls transcription initiation. However, little is known for core promoter diversity in the human genome and its relationship with diseases. We hypothesized that as a functional important component in the genome, the core promoter in the human genome could be under evolutionary selection, as reflected by its highly diversification in order to adjust gene expression for better adaptation to the different environment. Results Applying the “Exome-based Variant Detection in Core-promoters” method, we analyzed human core-promoter diversity by using the 2682 exome data sets of 25 worldwide human populations sequenced by the 1000 Genome Project. Collectively, we identified 31,996 variants in the core promoter region (− 100 to + 100) of 12,509 human genes (https://dbhcpd.fhs.um.edu.mo). Analyzing the rich variation data identified highly ethnic-specific patterns of core promoter variation between different ethnic populations, the genes with highly variable core promoters, the motifs affected by the variants, and their involved functional pathways. eQTL test revealed that 12% of core promoter variants can significantly alter gene expression level. Comparison with GWAS data we located 163 variants as the GWAS identified traits associated with multiple diseases, half of these variants can alter gene expression. Conclusion Data from our study reals the highly diversified nature of core promoter in the human genome, and highlights that core promoter variation could play important roles not only in gene expression regulation but also in disease predisposition.

Core promoter in TNBC is highly mutated with rich ethnic signature

“…Consistent with its highly stable nature [ 22 ], only one somatic and two germline mutations were located in the TATA box. For the 114 single-base germline substitutions, the transition (Ts)/ transversion (Tv) ratio was 2.43 ( Table 1C ), significantly lower than the 3.25–3.81 in CHB (Han Chinese in Beijing), 3.65; in CHS (Southern Han Chinese), 3.28; in CDX (Chinese Dai in Xishuangbanna), 3.25; in JPT (Japanese in Tokyo), 3.81; in KHV (Kinh in Ho Chi Minh City), 3.37 in EAS (East Asian) populations from the 1000 Genome data [ 11 ]. We compared the distribution of mutations in motif and non-motif regions in the core promoter.…”

“…We then investigated the core promoter polymorphism in 25 human ethnic populations using the exome data generated by the 1000 Genome project. We observed the highly diversified core promoter architecture in humans in reflecting its evolution and environmental adaptation [ 11 ]. Using the normal polymorphism data as the control, we further investigated the core promoter mutation in the Chinese TNBC cohort and the Spanish bladder cancer cohort.…”

“…This can be partly explained by the technical difficulty to study the core promoter due to its compact structure highly conserved between different genes [ 10 ]. To understand the potential biological roles of core promoter variation, we characterized the core promoter in worldwide human populations [ 11 ]. The results revealed a highly polymorphic nature of core promoter in the human population highlighting the importance of the core promoter variation in human evolution adaptation.…”

Core promoter mutation contributes to abnormal gene expression in bladder cancer

“…We hypothesized that core promoter mutation contributes to the abnormal gene expression in bladder cancer. Previously, we developed the Exome-based Variant Detection in Core-promoters (EVDC) method [ 13 ] for genome-wide core promoter mutation study, and used it in mapping the core promoter polymorphism in global human populations [ 14 ]. In this study, we applied this method to systematically analyze core promoter mutation in bladder cancer by using the exome data from bladder cancer patients.…”