Functionality of Intergenic Transcription: An Evolutionary Comparison

Abstract

Although a large proportion of human transcription occurs outside the boundaries of known genes, the functional significance of this transcription remains unknown. We have compared the expression patterns of known genes as well as intergenic transcripts within the ENCODE regions between humans and chimpanzees in brain, heart, testis, and lymphoblastoid cell lines. We find that intergenic transcripts show patterns of tissue-specific conservation of their expression, which are comparable to exonic transcripts of known genes. This suggests that intergenic transcripts are subject to functional constraints that restrict their rate of evolutionary change as well as putative positive selection to an extent comparable to that of classical protein-coding genes. In brain and testis, we find that part of this intergenic transcription is caused by widespread use of alternative promoters. Further, we find that about half of the expression differences between humans and chimpanzees are due to intergenic transcripts.

Long non‐coding RNAs in corticogenesis: deciphering the non‐coding code of the brain

“…These specific expression patterns are reminiscent of genes with regulatory functions and have been considered as one indication of lncRNAs having roles in development and cell identity (Mercer et al , ; Mattick & Dinger, ). However, expression patterns alone are not sufficient to validate function since lncRNAs may theoretically be the result of unspecific transcription from cryptic promoters or intergenic sequences that happen to have high affinity for the transcription machinery (Khaitovich et al , ; Ravasi et al , ; Struhl, ; Ulitsky & Bartel, ). Accordingly, lncRNAs' specific expression patterns would result from cell type, tissue or developmental changes in the chromatin accessibility of the corresponding loci and/or from transcriptional regulatory activity proximal to their loci (Khaitovich et al , ; Ravasi et al , ; Struhl, ).…”

“…Another tissue with widespread expression of lncRNAs with conserved tissue specificity is the testis (Necsulea et al , ; Washietl et al , ). Testis‐specific lncRNAs are enriched in young lncRNAs (Necsulea et al , ) showing greater variability among species than those expressed in other tissues (Khaitovich et al , ). These results are indicative of positive selection (Khaitovich et al , ) and consistent with testis permissive expression leading to new gene origination (Necsulea et al , ).…”

“…Testis‐specific lncRNAs are enriched in young lncRNAs (Necsulea et al , ) showing greater variability among species than those expressed in other tissues (Khaitovich et al , ). These results are indicative of positive selection (Khaitovich et al , ) and consistent with testis permissive expression leading to new gene origination (Necsulea et al , ). However, those lncRNAs expressed in the brain present lower variability between species than those expressed in other tissues, pointing to negative selection and conserved functions of brain‐specific lncRNAs (Khaitovich et al , ).…”

“…Independently from sequence similarity, evolutionary conservation can be investigated at the level of transcription by assessing whether or not ortholog loci exist and whether they present similar transcriptional regulation and display similar expression patterns across species. In this context, lncRNAs have also evolved rapidly (Khaitovich et al, 2006) with the proportion of human lncRNAs with orthologous transcripts increasing from one-third among placental mammals to 63-72% in primates and 80-92% in hominids. This is much lower than the 90-98% observed for primates' protein-coding genes but still higher than expected by chance (Necsulea et al, 2014;Washietl et al, 2014).…”

Noncoding RNAs in development and teratology, with focus on effects of cannabis, cocaine, nicotine, and ethanol

“…These intergenic TSSs may either be useless, generating junk RNA transcripts, or useful, that is, as loci‐encoding nonprotein‐coding RNA (ncRNA) transcripts. It has been shown that intergenic‐encoded ncRNAs contribute to functional differences between closely related species, such as humans and chimpanzees (Khaitovich et al, ), pointing to the importance of ncRNA in speciation and in biological processes.…”