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Evolutionary Loss of Genomic Proximity to Conserved Noncoding Elements Impacted the Gene Expression Dynamics During Mammalian Brain Development.

ABSTRACT: Conserved noncoding elements (CNEs) have a significant regulatory influence on their neighboring genes. Loss of proximity to CNEs through genomic rearrangements can, therefore, impact the transcriptional states of the cognate genes. Yet, the evolutionary implications of such chromosomal alterations have not been studied. Through genome-wide analysis of CNEs and the cognate genes of representative species from five different mammalian orders, we observed a significant loss of genes' linear proximity to CNEs in the rat lineage. The CNEs and the genes losing proximity had a significant association with fetal, but not postnatal, brain development as assessed through ontology terms, developmental gene expression, chromatin marks, and genetic mutations. The loss of proximity to CNEs correlated with the independent evolutionary loss of fetus-specific upregulation of nearby genes in the rat brain. DNA breakpoints implicated in brain abnormalities of germline origin had significant representation between a CNE and the gene that exhibited loss of proximity, signifying the underlying developmental tolerance of genomic rearrangements that allowed the evolutionary splits of CNEs and the cognate genes in the rodent lineage. Our observations highlighted a nontrivial impact of chromosomal rearrangements in shaping the evolutionary dynamics of mammalian brain development and might explain the loss of brain traits, like cerebral folding of the cortex, in the rodent lineage.

SUBMITTER: Bagadia M

PROVIDER: S-EPMC6456320 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Evolutionary Loss of Genomic Proximity to Conserved Noncoding Elements Impacted the Gene Expression Dynamics During Mammalian Brain Development.

Bagadia Meenakshi M Chandradoss Keerthivasan Raanin KR Jain Yachna Y Singh Harpreet H Lal Mohan M Sandhu Kuljeet Singh KS

Genetics 20190222 4

Conserved noncoding elements (CNEs) have a significant regulatory influence on their neighboring genes. Loss of proximity to CNEs through genomic rearrangements can, therefore, impact the transcriptional states of the cognate genes. Yet, the evolutionary implications of such chromosomal alterations have not been studied. Through genome-wide analysis of CNEs and the cognate genes of representative species from five different mammalian orders, we observed a significant loss of genes' linear proxim ...[more]

PMID: 30796012

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Project description:BackgroundThe 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.ResultsPhylogenetic 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.ConclusionsLevels 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.

Project description:BACKGROUND: The mariner family of transposable elements is one of the most widespread in the Metazoa. It is subdivided into several subfamilies that do not mirror the phylogeny of these species, suggesting an ancient diversification. Previous hybridization and PCR studies allowed a partial survey of mariner diversity in the Metazoa. In this work, we used a comparative genomics approach to access the genus-wide diversity and evolution of mariner transposable elements in twenty Drosophila sequenced genomes. RESULTS: We identified 36 different mariner lineages belonging to six distinct subfamilies, including a subfamily not described previously. Wide variation in lineage abundance and copy number were observed among species and among mariner lineages, suggesting continuous turn-over. Most mariner lineages are inactive and contain a high proportion of damaged copies. We showed that, in addition to substitutions that rapidly inactivate copies, internal deletion is a major mechanism contributing to element decay and the generation of non-autonomous sublineages. Hence, 23% of copies correspond to several Miniature Inverted-repeat Transposable Elements (MITE) sublineages, the first ever described in Drosophila for mariner. In the most successful MITEs, internal deletion is often associated with internal rearrangement, which sheds light on the process of MITE origin. The estimation of the transposition rates over time revealed that all lineages followed a similar progression consisting of a rapid amplification burst followed by a rapid decrease in transposition. We detected some instances of multiple or ongoing transposition bursts. Different amplification times were observed for mariner lineages shared by different species, a finding best explained by either horizontal transmission or a reactivation process. Different lineages within one species have also amplified at different times, corresponding to successive invasions. Finally, we detected a preference for insertion into short TA-rich regions, which appears to be specific to some subfamilies. CONCLUSIONS: This analysis is the first comprehensive survey of this family of transposable elements at a genus scale. It provides precise measures of the different evolutionary processes that were hypothesized previously for this family based on PCR data analysis. mariner lineages were observed at almost all "life cycle" stages: recent amplification, subsequent decay and potential (re)-invasion or invasion of genomes.

Dataset Information

Evolutionary Loss of Genomic Proximity to Conserved Noncoding Elements Impacted the Gene Expression Dynamics During Mammalian Brain Development.

Publications

Evolutionary Loss of Genomic Proximity to Conserved Noncoding Elements Impacted the Gene Expression Dynamics During Mammalian Brain Development.

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