Selective constraint on noncoding regions of hominid genomes.
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ABSTRACT:
SUBMITTER: Bush EC
PROVIDER: S-EPMC1314883 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Retroelements (REs) are mobile DNA sequences that multiply and spread throughout genomes by a copy-and-paste mechanism. These parasitic elements are active in diverse genomes, from yeast to humans, where they promote diversity, cause disease, and accelerate evolution. Because of their high copy number and sequence similarity, studying their activity and tracking their proliferation dynamics is a challenge. It is particularly difficult to pinpoint the few REs in a genome that are still active in the haystack of degenerate and suppressed elements. We develop a computational framework based on network theory that tracks the path of RE proliferation throughout evolution. We analyze SVA (SINE-VNTR-Alu), the youngest RE family in human genomes, to understand RE dynamics across hominids. Integrating comparative genomics and network tools enables us to track the course of SVA proliferation, identify yet unknown active communities, and detect tentative "master REs" that played key roles in SVA propagation, providing strong support for the fundamental "master gene" model of RE proliferation. The method is generic and thus can be applied to REs of any of the thousands of available genomes to identify active RE communities and master REs that were pivotal in the evolution of their host genomes.
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Project description:BACKGROUND: Small insertions and deletions ("indels" with size >/= 100 bp) whose lengths are not multiples of three (non-3n) are strongly constrained and depleted in protein-coding sequences. Such a constraint has never been reported in noncoding genomic regions. In 5'untranslated regions (5'UTRs) in mammalian genomes, upstream start codons (uAUGs) and upstream open reading frames (uORFs) can regulate protein translation. The presence of non-3n indels in uORFs can potentially disrupt the functions of these regulatory elements. We thus hypothesize that natural selection disfavors non-3n indels in 5'UTRs when these regulatory elements are present. RESULTS: We design the Indel Selection Index to measure the selective constraint on non-3n indels in 5'UTRs. The index controls for the genomic compositions of the analyzed 5'UTRs and measures the probability of non-3n indel depletion downstream of uAUGs. By comparing the experimentally supported transcripts of human-mouse orthologous genes, we demonstrate that non-3n indels downstream of two types of uAUGs (alternative translation initiation sites and the uAUGs of coding sequence-overlapping uORFs) are underrepresented. The results hold well regardless of differences in alignment tool, gene structures between human and mouse, or the criteria in selecting alternatively spliced isoforms used for the analysis. CONCLUSIONS: To our knowledge, this is the first study to demonstrate selective constraints on non-3n indels in 5'UTRs. Such constraints may be associated with the regulatory functions of uAUGs/uORFs in translational regulation or the generation of protein isoforms. Our study thus brings a new perspective to the evolution of 5'UTRs in mammals.
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Project description:SummaryViral genes, that are frequently small genes and/or with large overlaps, are still difficult to predict accurately. To help predict all genes in viral genomes, we provide CodingDiv that detects SNP-level microdiversity of all potential coding regions, using metagenomic reads and/or similar sequences from external databases. Protein coding regions can then be identified as the ones containing more synonymous SNPs than unfavorable nonsynonymous substitutions SNPs.Availability and implementationCodingDiv is released under the GPL license. Source code is available at https://github.com/ericolo/codingDiv. The software can be installed and used through a docker container.
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Project description:Protein kinases play an important role in the incidence of neurodegenerative diseases. However their incidence in non-human primates is found to be very low. Small differences among the genomes might influence the disease susceptibilities. The present study deals with finding the genetic differences of protein kinases in humans and their three closest evolutionary partners chimpanzee, gorilla and orangutan for three neurodegenerative diseases namely, Alzheimer's, Parkinson's and Huntington's diseases. In total 47 human protein kinases associated with three neurodegenerative diseases and their orthologs from other three non-human primates were identified and analyzed for any possible susceptibility factors in humans. Multiple sequence alignment and pairwise sequence alignment revealed that, 18 human protein kinases including DYRK1A, RPS6KB1, and GRK6 contained significant indels and substitutions. Further phosphorylation site analysis revealed that eight kinases including MARK2 and LTK contained sites of phosphorylation exclusive to human genomes which could be particular candidates in determining disease susceptibility between human and non-human primates. Final pathway analysis of these eight kinases and their targets revealed that these kinases could have long range consequences in important signaling pathways which are associated with neurodegenerative diseases.
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Project description:Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%-40% of pathogenic variants in noncanonical splice site positions are missing from public databases.
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Project description:Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression. Here, we explore the effects of stabilizing selection on cis-regulatory genetic variation in humans. We analyze patterns of expression variation at copy number variants and find evidence for selection against large increases in gene expression. Using allele-specific expression (ASE) data, we further show evidence of selection against smaller-effect variants. We estimate that, across all genes, singletons in a sample of 122 individuals have ∼2.2× greater effects on expression variation than the average variant across allele frequencies. Despite their increased effect size relative to common variants, we estimate that singletons in the sample studied explain, on average, only 5% of the heritability of gene expression from cis-regulatory variants. Finally, we show that genes depleted for loss-of-function variants are also depleted for cis-eQTLs and have low levels of allelic imbalance, confirming tighter constraint on the expression levels of these genes. We conclude that constraint on gene expression is present, but has relatively weak effects on most cis-regulatory variants, thus permitting high levels of gene-regulatory genetic variation.
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Project description:Viruses, far from being just parasites affecting hosts' fitness, are major players in any microbial ecosystem. In spite of their broad abundance, viruses, in particular bacteriophages, remain largely unknown since only about 20% of sequences obtained from viral community DNA surveys could be annotated by comparison with public databases. In order to shed some light into this genetic dark matter we expanded the search of orthologous groups as potential markers to viral taxonomy from bacteriophages and included eukaryotic viruses, establishing a set of 31,150 ViPhOGs (Eukaryotic Viruses and Phages Orthologous Groups). To do this, we examine the non-redundant viral diversity stored in public databases, predict proteins in genomes lacking such information, and used all annotated and predicted proteins to identify potential protein domains. The clustering of domains and unannotated regions into orthologous groups was done using cogSoft. Finally, we employed a random forest implementation to classify genomes into their taxonomy and found that the presence or absence of ViPhOGs is significantly associated with their taxonomy. Furthermore, we established a set of 1457 ViPhOGs that given their importance for the classification could be considered as markers or signatures for the different taxonomic groups defined by the ICTV at the order, family, and genus levels.
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Project description:Conservation of function can be accompanied by obvious similarity of homologous sequences which may persist for billions of years (Iyer LM, Leipe DD, Koonin EV, Aravind L. 2004. Evolutionary history and higher order classification of AAA+ ATPases. J Struct Biol. 146:11-31.). However, presumably homologous segments of noncoding DNA can also retain their ancestral function even after their sequences diverge beyond recognition (Fisher S, Grice EA, Vinton RM, Bessling SL, McCallion AS. 2006. Conservation of RET regulatory function from human to zebrafish without sequence similarity. Science 312:276-279.). To investigate this phenomenon at the genomic scale, we studied homologous introns in a quartet of insect species, and in a quartet of vertebrate species. Each quartet consisted of two pairs of moderately distant genomes, with a much larger evolutionary distance between the pairs. In both quartets, we found that introns that carry a regulatory segment or a conserved segment in the first pair tend to carry a conserved segment in the second pair, even though no similarity of these segments could be detected between the two pairs. Furthermore, introns from one pair that are preserved in the other pair tend to carry a conserved segment within the first pair, and be longer in the first pair, compared with the introns that were lost between pairs, even though no similarity between pairs could be detected in such preserved introns. These results indicate that selective constraint, presumably caused by conservation of the ancestral function, often persists even after the homologous DNA segments become unalignable.
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