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.

Keywords: 1000 genomes; Core promoter; Exome; GWAS; Variation; eQTL.

Fig. 1

Comparison of genome variation and core promoter variation in worldwide human populations. The variants in each population are divided into four groups, including Shared across all continents, Shared across the continent, Private to continent, and Private to population. The distribution of variants is compared in pair between core promoter and whole genome. In each pair, the left circle is from core promoter variants and the right circle is from whole genome referred from Fig. 1a (1000 Genomes Project Consortium, 2015). See actual rates and p values in Supplementary Table 3). The original world map was downloaded from Free world maps (http://www.free-world-maps.com). The figure was generated by using Adobe Photoshop version CS6

Fig. 2

Features of core promoter variation in human populations. a core promoter variants and their hosting genes across human populations. It shows the highly diversified core promoter among human populations, with YRI having the highest variation frequency whereas KHV the lowest. b. Variant distribution across core promoter region. It shows that variation downstream of TSS site was higher than the variation upstream TSS. c. Variation frequencies in the core promoters of 12,509 genes containing core promoter variants

Fig. 3

Variants distributed in the four core promoter motifs. It shows that DPE had the highest number of variants and TATA box had the lowest across all 25 populations

Fig. 4

Core promoter variation in DNA damage repair genes and their effects in gene expression. a. Variant distribution in core promoters of DNA damage repair genes. Of the 177 genes involved with DNA damage repair, 94 genes had variants in their core promoters with the highest in YRI and the lowest in KHV. b. Variants in MSH3 core promoter. Six variants were distributed 53 times in MSH3 core promoter in 19 populations, of which 5 variants were present in 18 populations. c. Variants in MSH3 core promoter alter MSH3 expression. eQTL test showed that the variant rs151182735 at − 76 can decrease MSH3 expression level in thyroid (p = 2.1 × 10^− 28), and the variant rs1105525 at + 42 can increase MSH3 expression level in transformed fibroblast cells (p = 4.0 × 10^− 9)

Fig. 5

Core promoter variants associated with diseases. a. Venn demonstration of multiple diseases identified by core promoter variants matched with GWAS traits in different populations. Of the 163 diseases or phenotypes, 31 were shared in populations across all continents, 44 were shared in populations across the continents of Africa, American, Europe, and South Asia but not in East Asia. The rests were private to population or private to continental. b. Variant rs1883832 in CD40 core promoter. CD40 is a member of the TNF-receptor superfamily involving in immune and inflammatory responses. A variant rs1883832 is located at the core promoter of CD40 (+ 90). This variant was determined by GWAS study as being associated with high susceptibility to chronic hepatitis B infection in Chinese population. c. eQTL analysis showed rs1883832 can increase CD40 expression in lung (p = 5.5 × 10^− 18)