Abstract
BackgroundCommon human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment’s influence on the epigenome, and therefore genome function, as well as conversely the genome’s facilitative effect on the epigenome, analysis of this level of regulation may increase our knowledge of disease pathogenesis.MethodsIn order to identify human-specific epigenetic influences, we have performed a novel genome-wide DNA methylation analysis comparing human, chimpanzee and rhesus macaque.ResultsWe have identified that the immunological Leukotriene B4 receptor (LTB4R, BLT1 receptor) is the most epigenetically divergent human gene in peripheral blood in comparison with other primates. This difference is due to the co-ordinated active state of human-specific hypomethylation in the promoter and human-specific increased gene body methylation. This gene is significant in innate immunity and the LTB4/LTB4R pathway is involved in the pathogenesis of the spectrum of human inflammatory diseases. This finding was confirmed by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Additionally we show through functional analysis that this receptor has increased expression and a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. Genome-wide we also find human species-specific differentially methylated regions (human s-DMRs) are more prevalent in CpG island shores than within the islands themselves, and within the latter are associated with the CTCF motif.ConclusionsThis result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from very closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness.
Highlights
Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors
The DNA methylomes are displayable in the individual genomes, human (GRCh37), chimpanzee (CGCS 2.1/PanTrog2) and rhesus macaque (MGSC Merged 1.0/rheMac2) in the University of California Santa Cruz (UCSC) genome browser in the context of existing annotation and are available at [61]
We identified all human peaks where no chimpanzee or rhesus macaque peak was present in the orthologous location to define hypermethylated human s-differentially methylated region (DMR), and hypomethylated human species-specific DMR (s-DMR) where no human peak was present but where both chimpanzee and macaque peaks were located in common
Summary
Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. In the past half century there has been a dramatic increase in chronic inflammatory and metabolic common human diseases [1,2] This is too rapid a time frame to be due to changes in common genetic allele frequency; the environment of this increasingly urbanized. Comparative epigenomics has only recently started to be explored in a number of tissues [18,19,20,21,22] This regulatory level has a plausible role as a rapid adaptive response mechanism to external change. It is hypothesized to hold insights into recent environmental effects impacting on genomic activity [23,24] This regulatory change can occur gradually, minimizing effects on viability
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