Origins and impacts of new mammalian exons.
Ontology highlight
ABSTRACT:
SUBMITTER: Merkin JJ
PROVIDER: S-EPMC4715653 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
Publications
Origins and impacts of new mammalian exons.
Merkin Jason J JJ Chen Ping P Alexis Maria S MS Hautaniemi Sampsa K SK Burge Christopher B CB
Cell reports 20150319 12
Mammalian genes are composed of exons, but the evolutionary origins and functions of new internal exons are poorly understood. Here, we analyzed patterns of exon gain using deep cDNA sequencing data from five mammals and one bird, identifying thousands of species- and lineage-specific exons. Most new exons derived from unique rather than repetitive intronic sequence. Unlike exons conserved across mammals, species-specific internal exons were mostly located in 5' UTRs and alternatively spliced. T ...[more]
Similar Datasets
Project description:Alternative splicing of messenger RNA can generate a wide variety of mature RNA transcripts, and these transcripts may produce protein isoforms with diverse cellular functions. While there is much supporting evidence for the expression of alternative transcripts, the same is not true for the alternatively spliced protein products. Large-scale mass spectroscopy experiments have identified evidence of alternative splicing at the protein level, but with conflicting results. Here we carried out a rigorous analysis of the peptide evidence from eight large-scale proteomics experiments to assess the scale of alternative splicing that is detectable by high-resolution mass spectroscopy. We find fewer splice events than would be expected: we identified peptides for almost 64% of human protein coding genes, but detected just 282 splice events. This data suggests that most genes have a single dominant isoform at the protein level. Many of the alternative isoforms that we could identify were only subtly different from the main splice isoform. Very few of the splice events identified at the protein level disrupted functional domains, in stark contrast to the two thirds of splice events annotated in the human genome that would lead to the loss or damage of functional domains. The most striking result was that more than 20% of the splice isoforms we identified were generated by substituting one homologous exon for another. This is significantly more than would be expected from the frequency of these events in the genome. These homologous exon substitution events were remarkably conserved--all the homologous exons we identified evolved over 460 million years ago--and eight of the fourteen tissue-specific splice isoforms we identified were generated from homologous exons. The combination of proteomics evidence, ancient origin and tissue-specific splicing indicates that isoforms generated from homologous exons may have important cellular roles.
| S-EPMC4465641 | biostudies-literature
Project description:Gene number difference among organisms demonstrates that new gene origination is a fundamental biological process in evolution. Exon shuffling has been universally observed in the formation of new genes. Yet to be learned are the ways new exons originate and evolve, and how often new exons appear. To address these questions, we identified 2695 newly evolved exons in the mouse and rat by comparing the expressed sequences of 12,419 orthologous genes between human and mouse, using 743,856 pig ESTs as the outgroup. The new exon origination rate is about 2.71 x 10(-3) per gene per million years. These new exons have markedly accelerated rates both of nonsynonymous substitutions and of insertions/deletions (indels). A much higher proportion of new exons have K(a)/K(s) ratios >1 (where K(a) is the nonsynonymous substitution rate and K(s) is the synonymous substitution rate) than do the old exons shared by human and mouse, implying a role of positive selection in the rapid evolution. The majority of these new exons have sequences unique in the genome, suggesting that most new exons might originate through "exonization" of intronic sequences. Most of the new exons appear to be alternative exons that are expressed at low levels.
| S-EPMC1199540 | biostudies-literature
Project description:BACKGROUND: Functional diversification of genes in mammalian genomes is engendered by a number of processes, e.g., gene duplication and alternative splicing. Gene duplication is classically discussed as leading to neofunctionalization (generation of new functions), subfunctionalization (generation of a varied function), or pseudogenization (loss of the gene and its function). RESULTS: Here, we focus on the process of pseudogenization, but specifically for individual exons from genes. It is at present unclear to what extent pseudogenization of individual exon duplications affects gene evolution, i.e., is it a random phenomenon, or is it associated with specific types of genes and encoded proteins, and positions in gene structures? We gathered genomic evidence for pseudogenic exons (PsiEs, i.e., exons disabled by frameshifts and premature stop codons), to examine for significant trends in their distribution across four mammalian genomes (specifically human, cow, mouse and rat). Across these four genomes, we observed a consistent population of PsiEs, associated with 0.4-1.0% of genes. These PsiE populations exhibit codon substitution patterns that are typical of an endemic population of decaying sequences. In human, PsiEs have significant over-representation for functional categories related to 'ion binding' and 'nucleic-acid binding', compared to duplicated exons in general. Also, PsiEs tend to be associated with some protein domains that are abundant generally, e.g., Zinc-finger and immunoglobulin protein domains, but not others, e.g., EGF-like domains. Positionally, PsiEs are also significantly associated with the 5' end of genes, but despite this, individual stop codons are positioned so that there is significant avoidance of potential targeting to nonsense-mediated decay. In human, PsiEs are often associated with alternative splicing (in 22 out of 284 genes with PsiEs in their milieu), and can have different parts of their sequence differentially spliced in alternative transcripts. Some unusual cases of PsiEs embedded within 5' and 3' non-coding exons are observed. CONCLUSION: Our results indicate the types of genes that harbour PsiEs, and demonstrate that PsiEs have non-random distribution within gene structures. These PsiEs may function in gene regulation through generation of transcribed pseudogenes, or regulatory alternate transcripts.
| S-EPMC2718932 | biostudies-literature
Project description:Cognitive decline is common in Parkinson's disease (PD), and precise cognitive assessment is important for diagnosis, prognosis, and treatment. To date, there are no studies in PD investigating cultural bias on neuropsychological tests. Clinical practice in multicultural societies such as, Toronto Canada where nearly half of the population is comprised of first generation immigrants, presents important challenges as most neuropsychological tools were developed in Anglosphere cultures (e.g., USA, UK) and normed in more homogeneous groups. We examine total scores and rates of deficits on tests of visuoperceptual/visuospatial, attention, memory, and executive functions in Canadians with PD born in Anglosphere countries (n = 248) vs. in Canadians with PD born in other regions (International group; n = 167). The International group shows lower scores and greater rates of deficits on all visuoperceptual and some executive function tasks, but not on attention or memory measures. These biases are not explained by demographic and clinical variables as groups were comparable. Age at immigration, years in Canada, and English proficiency also do not account for the observed biases. In contrast, group differences are strongly mediated by the Historical Index of Human Development of the participants' country of birth, which reflects economic, health, and educational potential of a country at the time of birth. In sum, our findings demonstrate lasting biases on neuropsychological tests despite significant exposure to, and participation in, Canadian culture. These biases are most striking on visuoperceptual measures and non-verbal executive tasks which many clinicians still considered to be "culture-fair" despite the growing evidence from the field of cross-cultural neuropsychology to the contrary. Our findings also illustrate that socio-development context captures important aspects of culture that relate to cognition, and have important implications for clinical practice.
| S-EPMC6694800 | biostudies-literature
Project description:Mitral/tufted (M/T) cells of the main olfactory bulb transmit odorant information to higher brain structures. The relative timing of action potentials across M/T cells has been proposed to encode this information and to be critical for the activation of downstream neurons. Using ensemble recordings from the mouse olfactory bulb in vivo, we measured how correlations between cells are shaped by stimulus (odor) identity, common respiratory drive, and other cells' activity. The shared respiration cycle is the largest source of correlated firing, but even after accounting for all observable factors a residual positive noise correlation was observed. Noise correlation was maximal on a ∼100-ms timescale and was seen only in cells separated by <200 µm. This correlation is explained primarily by common activity in groups of nearby cells. Thus, M/T-cell correlation principally reflects respiratory modulation and sparse, local network connectivity, with odor identity accounting for a minor component.
| S-EPMC3800994 | biostudies-literature
Project description:Observations made with Escherichia coli have suggested that a lag between replication and methylation regulates initiation of replication. To address the question of whether a similar mechanism operates in mammalian cells, we have determined the temporal relationship between initiation of replication and methylation in mammalian cells both at a comprehensive level and at specific sites. First, newly synthesized DNA containing origins of replication was isolated from primate-transformed and primary cell lines (HeLa cells, primary human fibroblasts, African green monkey kidney fibroblasts [CV-1], and primary African green monkey kidney cells) by the nascent-strand extrusion method followed by sucrose gradient sedimentation. By a modified nearest-neighbor analysis, the levels of cytosine methylation residing in all four possible dinucleotide sequences of both nascent and genomic DNAs were determined. The levels of cytosine methylation observed in the nascent and genomic DNAs were equivalent, suggesting that DNA replication and methylation are concomitant events. Okazaki fragments were also demonstrated to be methylated, suggesting that the rapid kinetics of methylation is a feature of both the leading and the lagging strands of nascent DNA. However, in contrast to previous observations, neither nascent nor genomic DNA contained detectable levels of methylated cytosines at dinucleotide contexts other than CpG (i.e., CpA, CpC, and CpT are not methylated). The nearest-neighbor analysis also shows that cancer cell lines are hypermethylated in both nascent and genomic DNAs relative to the primary cell lines. The extent of methylation in nascent and genomic DNAs at specific sites was determined as well by bisulfite mapping of CpG sites at the lamin B2, c-myc, and beta-globin origins of replication. The methylation patterns of genomic and nascent clones are the same, confirming the hypothesis that methylation occurs concurrently with replication. Interestingly, the c-myc origin was found to be unmethylated in all clones tested. These results show that, like genes, different origins of replication exhibit different patterns of methylation. In summary, our results demonstrate tight coordination of DNA methylation and replication, which is consistent with recent observations showing that DNA methyltransferase is associated with proliferating cell nuclear antigen in the replication fork.
| S-EPMC108928 | biostudies-literature
Project description:DNA cytosine methylation is a central epigenetic marker that is usually mutagenic and may increase the level of sequence divergence. However, methylated genes have been reported to evolve more slowly than unmethylated genes. Hence, there is a controversy on whether DNA methylation is correlated with increased or decreased protein evolutionary rates. We hypothesize that this controversy has resulted from the differential correlations between DNA methylation and the evolutionary rates of coding exons in different genic positions. To test this hypothesis, we compare human-mouse and human-macaque exonic evolutionary rates against experimentally determined single-base resolution DNA methylation data derived from multiple human cell types. We show that DNA methylation is significantly related to within-gene variations in evolutionary rates. First, DNA methylation level is more strongly correlated with C-to-T mutations at CpG dinucleotides in the first coding exons than in the internal and last exons, although it is positively correlated with the synonymous substitution rate in all exon positions. Second, for the first exons, DNA methylation level is negatively correlated with exonic expression level, but positively correlated with both nonsynonymous substitution rate and the sample specificity of DNA methylation level. For the internal and last exons, however, we observe the opposite correlations. Our results imply that DNA methylation level is differentially correlated with the biological (and evolutionary) features of coding exons in different genic positions. The first exons appear more prone to the mutagenic effects, whereas the other exons are more influenced by the regulatory effects of DNA methylation.
| S-EPMC3465446 | biostudies-literature
Project description:The mechanisms that control the location and timing of firing of replication origins are poorly understood. Using a novel functional genomic approach based on the analysis of SNPs and indels in phased human genomes, we observe that replication asynchrony is associated with small cumulative variations in the initiation efficiency of multiple origins between the chromosome homologues, rather than with the activation of dormant origins. Allele-specific measurements demonstrate that the presence of G-quadruplex-forming sequences does not correlate with the efficiency of initiation. Sequence analysis reveals that the origins are highly enriched in sequences with profoundly asymmetric G/C and A/T nucleotide distributions and are almost completely depleted of antiparallel triplex-forming sequences. We therefore propose that although G4-forming sequences are abundant in replication origins, an asymmetry in nucleotide distribution, which increases the propensity of origins to unwind and adopt non-B DNA structure, rather than the ability to form G4, is directly associated with origin activity.
| S-EPMC4479011 | biostudies-literature
Project description:In the male germ cells of placental mammals, 26-30-nt-long PIWI-interacting RNAs (piRNAs) emerge when spermatocytes enter the pachytene phase of meiosis. In mice, pachytene piRNAs derive from ~100 discrete autosomal loci that produce canonical RNA polymerase II transcripts. These piRNA clusters bear 5' caps and 3' poly(A) tails, and often contain introns that are removed before nuclear export and processing into piRNAs. What marks pachytene piRNA clusters to produce piRNAs, and what confines their expression to the germline? We report that an unusually long first exon (≥ 10 kb) or a long, unspliced transcript correlates with germline-specific transcription and piRNA production. Our integrative analysis of transcriptome, piRNA, and epigenome datasets across multiple species reveals that a long first exon is an evolutionarily conserved feature of pachytene piRNA clusters. Furthermore, a highly methylated promoter, often containing a low or intermediate level of CG dinucleotides, correlates with germline expression and somatic silencing of pachytene piRNA clusters. Pachytene piRNA precursor transcripts bind THOC1 and THOC2, THO complex subunits known to promote transcriptional elongation and mRNA nuclear export. Together, these features may explain why the major sources of pachytene piRNA clusters specifically generate these unique small RNAs in the male germline of placental mammals.
| S-EPMC7782496 | biostudies-literature
Project description:Extreme ecosystem modification by humans has caused drastic reductions in populations and ranges of top mammalian predators, while simultaneously allowing synanthropic mesopredator species to expand. These conditions often result in inflated local densities of highly adaptable mesopredators that disrupt trophic dynamics and place unsustainable predation pressure on native prey populations. Colonization of a dominant predator may lead to top-down control of mesopredators and restore trophic balance. Coyotes are a novel colonizer of some coastal barrier islands of eastern North America, offering an opportunity to test how the addition of an apex predator impacts an established guild of mesopredators. To assess their trophic impact, we conducted 75,576 camera trapping hours over an 18-month study period, capturing > 1.5 million images across 108 coastal camera sites. Using two-species occupancy and habitat use models, we found sizeable effects of coyote habitat use on that of red foxes and free-ranging domestic cats, suggesting that coyotes function as apex predators in barrier island ecosystems. In fact, the only factor that determined the spatial pattern of highly ubiquitous red foxes was the sympatric habitat use of the largest carnivore in the food web-coyotes. That 'novel' apex predators can become established in coastal food webs illustrates the highly dynamic nature of conservation challenges for habitats and species at the edge of the sea.
| S-EPMC11294349 | biostudies-literature