Spontaneous symmetry breaking in genome evolution

The quest for evolutionary mechanisms providing separation between the coding (exons) and noncoding (introns) parts of genomic DNA remains an important focus of genetics. This work combines an analysis of the most recent achievements of genomics and fundamental concepts of random processes to provide a novel point of view on genome evolution. Exon sizes in sequenced genomes show a lognormal distribution typical of a random Kolmogoroff fractioning process. This implies that the process of intron incretion may be independent of exon size, and therefore could be dependent on intron-exon boundaries. All genomes examined have two distinctive classes of exons, each with different evolutionary histories. In the framework proposed in this article, these two classes of exons can be derived from a hypothetical ancestral genome by (spontaneous) symmetry breaking. We note that one of these exon classes comprises mostly alternatively spliced exons.     

Addressing the intrinsic disorder bottleneck in structural proteomics

The Center for Eukaryotic Structural Genomics (CESG), as part of the Protein Structure Initiative (PSI), has established a high-throughput structure determination pipeline focused on eukaryotic proteins. NMR spectroscopy is an integral part of this pipeline, both as a method for structure determinations and as a means for screening proteins for stable structure. Because computational approaches have estimated that many eukaryotic proteins are highly disordered, about 1 year into the project, CESG began to use an algorithm (the Predictor of Naturally Disordered Regions, PONDR to avoid proteins that were likely to be disordered. We report a retrospective analysis of the effect of this filtering on the yield of viable structure determination candidates. In addition, we have used our current database of results on 70 protein targets from Arabidopsis thaliana and 1 from Caenorhabditis elegans, which were labeled uniformly with nitrogen-15 and screened for disorder by NMR spectroscopy, to compare the original algorithm with 13 other approaches for predicting disorder from sequence. Our study indicates that the efficiency of structural proteomics of eukaryotes can be improved significantly by removing targets predicted to be disordered by an algorithm chosen to provide optimal performance.     

Pseudocyclical similarities and structural evolution of modular organisms

It was found that pseudocyclical similarities are common in modular organisms due to the peculiarities of their morphogenesis and ontogenesis and the system specifics of the modular organization. An analysis of the structural evolution in the different groups of modular living beings according to the concept of pseudocycles is topical, as it will contribute to the further development of evolutionary morphology and theoretical biology.     

Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization

The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling.     

A structural perspective on genome evolution

Protein translations of over 100 complete genomes are now available. About half of these sequences can be provided with structural annotation, thereby enabling some profound insights into protein and pathway evolution. Whereas the major domain structure families are common to all kingdoms of life, these are combined in different ways in multidomain proteins to give various domain architectures that are specific to kingdoms or individual genomes, and contribute to the diverse phenotypes observed. These data argue for more targets in structural genomics initiatives and particularly for the selection of different domain architectures to gain better insights into protein functions.     

Sequence-based structural signatures of genome evolution

Among the multitude of methods available for the study of origin and evolution of various life forms on Earth, the phylogenetic approach, i.e. the delineation of natural genetic relatedness amongst different groups of organisms, has been of particular interest to evolutionary biologists. An approach towards analysing phylogeny is the comparison of genome sequences of extant organisms by a variety of computational techniques. These studies rely mostly on the similarity or dissimilarity in global character of the genome in terms of sequence, without any consideration to its structure. In this work, we report a potentially new methodology towards elucidation of molecular phylogeny. The approach considers a structural parameter of the genome, namely its flexibility, and uses it to compare the small subunit ribosomal ribonucleic acid (SSU rRNA) gene from a cross-section of species. We find that the flexibility pattern of the genome is strikingly similar in organisms that are closer in evolutionary distance than the ones that are separated. This method of comparison thus might be utilised in constructing phylogenetic trees from flexibility patterns derived from nucleotide sequence.     

Utilization of protein intrinsic disorder knowledge in structural proteomics

Intrinsically disordered proteins (IDPs) and proteins with long disordered regions are highly abundant in various proteomes. Despite their lack of well-defined ordered structure, these proteins and regions are frequently involved in crucial biological processes. Although in recent years these proteins have attracted the attention of many researchers, IDPs represent a significant challenge for structural characterization since these proteins can impact many of the processes in the structure determination pipeline. Here we investigate the effects of IDPs on the structure determination process and the utility of disorder prediction in selecting and improving proteins for structural characterization. Examination of the extent of intrinsic disorder in existing crystal structures found that relatively few protein crystal structures contain extensive regions of intrinsic disorder. Although intrinsic disorder is not the only cause of crystallization failures and many structured proteins cannot be crystallized, filtering out highly disordered proteins from structure-determination target lists is still likely to be cost effective. Therefore it is desirable to avoid highly disordered proteins from structure-determination target lists and we show that disorder prediction can be applied effectively to enrich structure determination pipelines with proteins more likely to yield crystal structures. For structural investigation of specific proteins, disorder prediction can be used to improve targets for structure determination. Finally, a framework for considering intrinsic disorder in the structure determination pipeline is proposed.     

Chromatin structure and evolution in the human genome

Background  

Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time.     

Brain evolution and uniqueness in the human genome

Despite an ever-expanding database of sequenced mammalian genomes to be mined for clues, the emergence of the unique human brain remains an evolutionary enigma. In their new study, trawl the human genome and those of other mammals in search of short conserved DNA elements that show extremely rapid evolution only in humans. As they report in a recent issue of Nature, their scan yielded a gene for a novel noncoding RNA that adopts a human-specific structure and may regulate neurodevelopment.     

Retroposons in modern human genome evolution

The ascertainment of the rates and driving forces of human genome evolution along with the genetic diversity of populations or separate population groups remains a topical problem of fundamental and applied genomics. According to the results of comparative analysis, the most numerous human genome structure peculiarities are connected with the distribution of mobile genetic retroelements—LTR, LINE1, SVA, and Alu repeats. Due to the wide distribution in different genome loci, conversed retropositional activity, and the retroelements’ regulatory potential, let us regard them as one of the significant evolutionary driving forces and the source of human genome variability. In the current review, we summarize published data and recent results of our research aimed at the analysis of the evolutionary impact of the young retroelements group on the function and variability of the human genome. We examine modern approaches of the polygenomic identification of polymorphic retroelements inserts. Using an original Internet resource, we analyze special features of the genomic polymorphic inserts of AluY repeats. We thoroughly characterize the strategy of large-scale functional analysis of polymorphic retroelement inserts. The presented results confirm the hypothesis of the roles of retroelements as active cis regulatory elements that are able to modulate surrounding genes.     

Localizing recent adaptive evolution in the human genome

Identifying genomic locations that have experienced selective sweeps is an important first step toward understanding the molecular basis of adaptive evolution. Using statistical methods that account for the confounding effects of population demography, recombination rate variation, and single-nucleotide polymorphism ascertainment, while also providing fine-scale estimates of the position of the selected site, we analyzed a genomic dataset of 1.2 million human single-nucleotide polymorphisms genotyped in African-American, European-American, and Chinese samples. We identify 101 regions of the human genome with very strong evidence (p < 10⁻⁵) of a recent selective sweep and where our estimate of the position of the selective sweep falls within 100 kb of a known gene. Within these regions, genes of biological interest include genes in pigmentation pathways, components of the dystrophin protein complex, clusters of olfactory receptors, genes involved in nervous system development and function, immune system genes, and heat shock genes. We also observe consistent evidence of selective sweeps in centromeric regions. In general, we find that recent adaptation is strikingly pervasive in the human genome, with as much as 10% of the genome affected by linkage to a selective sweep.     

The role of constrained self-organization in genome structural evolution

A hypothesis of genome structural evolution is explored. Rapid and cohesive alterations in genome organization are viewed as resulting from the dynamic and constrained interactions of chromosomal subsystem components. A combination of macromolecular boundary conditions and DNA element involvement in far-from-equilibrium reactions is proposed to increase the complexity of genomic subsystems via the channelling of genome turnover; interactions between subsystems create higher-order subsystems expanding the phase space for further genetic evolution. The operation of generic constraints on structuration in genome evolution is suggested by i) universal, homoplasic features of chromosome organization and ii) the metastable nature of genome structures where lower-level flux is constrained by higher-order structures. Phenomena such as genomic shock, bursts of transposable element activity, concerted evolution, etc., are hypothesized to result from constrained systemic responses to endogenous/exogenous, micro/macro perturbations. The constraints operating on genome turnover are expected to increase with chromosomal structural complexity, the number of interacting subsystems, and the degree to which interactions between genomic components are tightly ordered.     

Progress in the detection of human genome structural variations

The emerging of high-throughput and high-resolution genomic technologies led to the detection of submicroscopic variants ranging from 1 kb to 3 Mb in the human genome. These variants include copy number variations (CNVs), inversions, insertions, deletions and other complex rearrangements of DNA sequences. This paper briefly reviews the commonly used technologies to discover both genomic structural variants and their potential influences. Particularly, we highlight the array-based, PCR-based and sequencing-based assays, including array-based comparative genomic hybridization (aCGH), representational oligonucleotide microarray analysis (ROMA), multiplex amplifiable probe hybridization (MAPH), multiplex ligation-dependent probe amplification (MLPA), paired-end mapping (PEM), and next-generation DNA sequencing technologies. Furthermore, we discuss the limitations and challenges of current assays and give advices on how to make the database of genomic variations more reliable. Supported by the National High Technology Research and Development Program of China (Grant No. 2006AA020704).     

Recombination drives the evolution of GC-content in the human genome

Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major issue in the identification of functional sequence features. Mammalian genomes show large-scale regional variations of GC-content (the isochores), but the substitution processes at the origin of this structure are poorly understood. We have analyzed the pattern of neutral substitutions in 14.3 Mb of primate noncoding regions. We show that the GC-content toward which sequences are evolving is strongly correlated (r(2) = 0.61, P 相似文献   

Modeling the evolution of the human mitochondrial genome.

Mitochondrial DNA data have been used extensively to study evolution and early human origins. These applications require estimates of the rate at which nucleotide substitutions occur in the DNA sequence. We consider the problem of estimating substitution rates in the presence of site-to-site rate variation. A coalescent model is presented that allows for different substitution rates for purines and pyrimidines, as well as more detailed models that allow fast and slow rates within each of the purine and pyrimidine classes. A method for estimating such rates is presented. Even for these simple models of site heterogeneity, there are, typically, insufficient data to obtain reliable estimates of site-specific substitution rates. However, estimates of the average rate across all sites appear to be relatively stable even in the presence of site heterogeneity. Simulations of models with site-to-site variation in mutation rate show that hypervariable sites can produce peaks in the pairwise difference curves that have previously been attributed to population dynamics.     

Origin and evolution of a placental-specific microRNA family in the human genome

Background  

MicroRNAs (miRNAs) are a class of short regulatory RNAs encoded in the genome of DNA viruses, some single cell organisms, plants and animals. With the rapid development of technology, more and more miRNAs are being discovered. However, the origin and evolution of most miRNAs remain obscure. Here we report the origin and evolution dynamics of a human miRNA family.     

Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome

The hotspots of structural polymorphisms and structural mutability in the human genome remain to be explained mechanistically. We examine associations of structural mutability with germline DNA methylation and with non-allelic homologous recombination (NAHR) mediated by low-copy repeats (LCRs). Combined evidence from four human sperm methylome maps, human genome evolution, structural polymorphisms in the human population, and previous genomic and disease studies consistently points to a strong association of germline hypomethylation and genomic instability. Specifically, methylation deserts, the ~1% fraction of the human genome with the lowest methylation in the germline, show a tenfold enrichment for structural rearrangements that occurred in the human genome since the branching of chimpanzee and are highly enriched for fast-evolving loci that regulate tissue-specific gene expression. Analysis of copy number variants (CNVs) from 400 human samples identified using a custom-designed array comparative genomic hybridization (aCGH) chip, combined with publicly available structural variation data, indicates that association of structural mutability with germline hypomethylation is comparable in magnitude to the association of structural mutability with LCR-mediated NAHR. Moreover, rare CNVs occurring in the genomes of individuals diagnosed with schizophrenia, bipolar disorder, and developmental delay and de novo CNVs occurring in those diagnosed with autism are significantly more concentrated within hypomethylated regions. These findings suggest a new connection between the epigenome, selective mutability, evolution, and human disease.