Lineage-associated Human Divergently-paired Genes Exhibit Structural and Regulatory Characteristics

Divergently-paired genes (DPGs) are minimal co-transcriptional units of clustered genes, representing over 10% of human genes. Our previous studies have shown that vertebrate DPGs are highly conserved compared to those from invertebrates. Three critical questions remain: (1) which DPGs are conserved across vertebrates, especially among mammals and primates? (2) to what extent and precision do these paired promoters share their sequences mechanistically and stringently? and (3) how are human DPGs distributed over selected primate lineages, and what are their possible biological functional consequences? There are 1399 human DPGs (approximately 12% of all human protein-coding genes), of which 1136, 1118, 925, and 830 human DPGs show conservation when compared to selected primates, mammals, avians, and fish, respectively. DPGs are not only functionally enriched toward direct protein-DNA interactions and cell cycle synchronization, but also exhibit lineage association, narrow in principle toward synchronization of certain core molecular mechanisms and cellular processes. Second, the inter-transcription start site (inter-TSS) distances affect both co-expression strength and disparity between the two genes of a DPG. Finally, among primates, human-associated DPGs exhibit diversification in their co-expression patterns and gene duplication events, and are obviously involved in neural development. Comparing high-quality human reference genomes from European (T2T-CHM13) and Chinese (T2T-YAO) populations, we identified 55 and 357 DPGs unique to the former and the latter, respectively. Our findings offer novel insights into the regulatory characteristics between neighboring genes and their structure-function selection among functionally conserved gene clusters.