Divergent evolutionary rates in vertebrate and mammalian specific conserved non-coding elements (CNEs) in echolocating mammals

abstract: ...Background The majority of DNA contained within vertebrate genomes is non-coding, with a certain proportion of this thought to play regulatory roles during development. Conserved Non-coding Elements (CNEs) are an abundant group of putative regulatory sequences that are highly conserved across divergent groups and thus assumed to be under strong selective constraint. Many CNEs may contain regulatory factor binding sites, and their frequent spatial association with key developmental genes such as those regulating sensory system development suggests crucial roles in regulating gene expression and cellular patterning. Yet surprisingly little is known about the molecular evolution of CNEs across diverse mammalian taxa or their role in specific phenotypic adaptations. We examined 3,110 vertebrate-specific and ~82,000 mammalian-specific CNEs across 19 and 9 mammalian orders respectively, and tested for changes in the rate of evolution of CNEs located in the proximity of genes underlying the development or functioning of auditory systems. As we focused on CNEs putatively associated with genes underlying the development/functioning of auditory systems, we incorporated echolocating taxa in our dataset because of their highly specialised and derived auditory systems. Results Phylogenetic reconstructions of concatenated CNEs broadly recovered accepted mammal relationships despite high levels of sequence conservation. We found that CNE substitution rates were highest in rodents and lowest in primates, consistent with previous findings. Comparisons of CNE substitution rates from several genomic regions containing genes linked to auditory system development and hearing revealed differences between echolocating and non-echolocating taxa. Wider taxonomic sampling of four CNEs associated with the homeobox genes Hmx2 and Hmx3 which are required for inner ear development revealed family-wise variation across diverse bat species. Specifically within one family of echolocating bats that utilise frequency-modulated echolocation calls varying widely in frequency and intensity high levels of sequence divergence were found. Conclusions Levels of selective constraint acting on CNEs differed both across genomic locations and taxa, with observed variation in substitution rates of CNEs among bat species. More work is needed to determine whether this variation can be linked to echolocation, and wider taxonomic sampling is necessary to fully document levels of conservation in CNEs across diverse taxa. Electronic supplementary material The online version of this article (doi:10.1186/s12862-014-0261-5) contains supplementary material, which is available to authorized users.

.... We found that CNE substitution rates were highest in rodents and lowest in primates, consistent with previous findings. Comparisons of CNE substitution rates from several genomic regions containing genes linked to auditory system development and hearing revealed differences between echolocating and non-echolocating taxa. Wider taxonomic sampling of four CNEs associated with the homeobox genes Hmx2 and Hmx3 which are required for inner ear development revealed family-wise variation across diverse

..., revealed a similar pattern to above (see Additional file 8 : Figure S7A). With the echolocating clades typically having a higher number of accelerated sites compared to the Old World fruit bats. In the case of Yangochiroptera this is particularly evident in elements CRCNE00009713, CRCNE00009716 and CRCNE00009717 which have 3.35, 2.29 and 1.68% of sites identified as significantly accelerated, these elements are some of the most proximally located to HMX2 and HMX3 based on the human annotation (see

... Plecotus auritus did not for the CRCNE00009716 element (Figure 6 C). For all four CNE datasets, all Yinpterochiroptera species showed similarly low substitution rates. Genomic alignments of human, mouse, rat and fugu suggested that, of the four CNEs amplified, CRCNE00009716 is the most proximally located to Hmx2 and Hmx3 . This was confirmed by examination of the recently completed Pteropus alecto genome [ 34 ]; this suggests ~4kb separates the 3 end of CRCNE00009716 and the start codon of Hmx2 . In CRCNE00009741, which is most distally located to either Hmx2 or Hmx3 , the Old World fruit bats Cynopterus brachyotis and C. sphinx had considerably longer branch lengths than the remaining Yinpterochiroptera species. Within this sample, again there was no consistent difference in branch lengths between the non-echolocating humpback whale, Megaptera novaeangliae , and the remaining echolocating toothed whales. Figure 6 Estimated lineage-specific nucleotide substitution rates across four CNE sequence

... location (in kilo-bases) of each of the four CNEs under study and the three proximate genes ( HMX3 , HMX2 and BUB3 ) based on the human genome. Discussion Previous studies attempting to link genetic variation and phenotypic adaptations in echolocating mammals have tended to focus on selection pressures acting on protein coding genes (e.g. [ 35 , 36 ]), thus often placing less emphasis on the molecular evolution of putative regulatory regions or transcription factors. However, given their role in the

... [ 50 ], but which showed approximately equal relative rates in all three bat clades, or lower in echolocating clades. Focusing on echolocating taxa specifically, the four laryngeal echolocating bat species and the bottlenose dolphin initially studied had significantly greater substitution rates, compared to the horse, in CNEs from the HMX2 and HMX3 genomic regions. This was confirmed by the addition of additional echolocating taxa. Wider family level bat comparisons revealed that four conserved

... raising the possibility that CNE may be truncated in these species. The CNEs examined in this region span across ~500 kilo-bases in the human genome, within this region based on Ensembl annotation there are three genes BUB3, HMX2 and HMX3 . The Bub3 protein is encoded by BUB3 which is an essential component of the mitotic spindle assembly complex during early development, disruptions to this gene prove lethal [ 53 ]. The two homeobox genes, Hmx2 and Hmx3 , are associated with nervous system

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Gene: HMX3 - H6 family homeobox 3 - (NCBI)

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