The Evolution of Bony Vertebrate Enhancers at Odds with Their Coding Sequence Landscape

Abstract

Enhancers lie at the heart of transcriptional and developmental gene regulation. Therefore, changes in enhancer sequences usually disrupt the target gene expression and result in disease phenotypes. Despite the well-established role of enhancers in development and disease, evolutionary sequence studies are lacking. The current study attempts to unravel the puzzle of bony vertebrates’ conserved noncoding elements (CNE) enhancer evolution. Bayesian phylogenetics of enhancer sequences spotlights promising interordinal relationships among placental mammals, proposing a closer relationship between humans and laurasiatherians while placing rodents at the basal position. Clock-based estimates of enhancer evolution provided a dynamic picture of interspecific rate changes across the bony vertebrate lineage. Moreover, coelacanth in the study augmented our appreciation of the vertebrate cis-regulatory evolution during water–land transition. Intriguingly, we observed a pronounced upsurge in enhancer evolution in land-dwelling vertebrates. These novel findings triggered us to further investigate the evolutionary trend of coding as well as CNE nonenhancer repertoires, to highlight the relative evolutionary dynamics of diverse genomic landscapes. Surprisingly, the evolutionary rates of enhancer sequences were clearly at odds with those of the coding and the CNE nonenhancer sequences during vertebrate adaptation to land, with land vertebrates exhibiting significantly reduced rates of coding sequence evolution in comparison to their fast evolving regulatory landscape. The observed variation in tetrapod cis-regulatory elements caused the fine-tuning of associated gene regulatory networks. Therefore, the increased evolutionary rate of tetrapods’ enhancer sequences might be responsible for the variation in developmental regulatory circuits during the process of vertebrate adaptation to land.

Nucleotide diversity analysis highlights functionally important genomic regions

“…In general, DNA sequences in promoters, enhancers and other regulatory elements in eukaryotes are less variable than the rest the genome 74 75 76 77 . However, the patterns of variability may be organism specific and are not well studied in plants.…”

Molecular evolutionary and structural analysis of human UCHL1 gene demonstrates the relevant role of intragenic epistasis in Parkinson’s disease and other neurological disorders

“…In order to analyze evolutionary rate differences of the UCHL1 gene within different groups of sarcopterygians lineage, key animals were selected from four groups like hominoids (human, chimpanzee, gorilla and orangutan), non-hominoids (macaque, squirrel monkey, marmoset and Otolemur), non-primate placental mammals (cow, cat, elephant and mouse) and non-mammalian tetrapods (chicken, zebra finch, turtle and coelacanth). The rationale behind choosing only sarcopterygians for evolutionary rate analysis is that animals of this lineage are known to be more closely related or show more homology to humans as compare to teleost and cartilaginous fishes [ 24 ]. To evaluate the selection constraints on selected subgroups of animals, the rates of non-synonymous (Ka/dN) and synonymous (Ks/dS) substitutions were estimated and their difference was calculated using z-test [ 25 ].…”

“…Three protein kinase C (PKC) phosphorylation sites (76-78, 121-123, 205-207) and four casein kinase II (CK2) phosphorylation sites (119-122, 125-128, 188-191, 205-208) are also found to be highly conserved in mammals (human, mouse and cat), whereas in chicken a PKC phosphorylation site appears to have been translocated from Cterminal to N-terminal of UCHL1 and an additional PKC phosphorylation site (198-200) is detected. Furthermore, both in chicken and coelacanth one N-myristoylation site appears to have been translocated from C-terminal to Nterminal of UCHL1 (at position [21][22][23][24][25][26]. In both chicken and coelacanth, a CK2 phosphorylation site (119-122) is not detected and some translocations of PKC phosphorylation sites are also observed ( Fig.…”

“…Numbers on branches represent bootstrap values (based on 1000 replications) supporting that branch; only the values ≥50% are presented here. Scale bar shows amino acid substitution per site behind choosing only sarcopterygians for evolutionary rate analysis is that animals of this lineage are known to be more closely related or show more homology to humans as compare to teleost and cartilaginous fishes [24]. To evaluate the selection constraints on selected subgroups of animals, the rates of non-synonymous (Ka/dN) and synonymous (Ks/dS) substitutions were estimated and their difference was calculated using z-test [25].…”

Homo sapiens-Specific Binding Site Variants within Brain Exclusive Enhancers Are Subject to Accelerated Divergence across Human Population

“…2012 ; Hubisz and Pollard 2014 ). Evolutionary studies have also endorsed acceleration in enhancer sequences compared with coding and noncoding/nonenhancer genomic blocks in vertebrates during land adaptation ( Yousaf et al. 2015 ).…”