Kado, T. Yoshimaru, Y. Tsumura, and H. DNA variation in a conifer, Cryptomeria japonica Cupressaceae sensu lato. Katju, V. The structure and early evolution of recently arisen gene duplicates in the Caenorhabditis elegans genome. Keightley, P. Deleterious mutations and the evolution of sex. Kimura, M. On the probability of fixation of mutant genes in populations. Genetics 47 : — The neutral theory of molecular evolution.
Knoll, A. The early evolution of eukaryotes: a geological perspective. Kondrashov, A. Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases.
Kozak, M. Determinants of translational fidelity and efficiency in vertebrate mRNAs. Biochimie 76 : — Pushing the limits of the scanning mechanism for initiation of translation. Gene : 1 — Kumar, S. Mutation rates in mammalian genomes. USA 99 : — Lagercrantz, U. Kruskopf Osterberg, and M. Sequence variation and haplotype structure at the putative flowering-time locus COL1 of Brassica nigra. Lambowitz, A. Mobile group II introns. Laporte, V. Effective population size and population subdivision in demographically structured populations.
Leeds, P. Wood, B. Lee, and M. Gene products that promote mRNA turnover in Saccharomyces cerevisiae. Liston, D. Analysis of a ubiquitous promoter element in a primitive eukaryote: early evolution of the initiator element.
Liu, H. Zhang, and A. Identification of functional exonic splicing enhancer motifs recognized by individual SR proteins. Genes Dev. Long, M. Association of intron phases with conservation at splice site sequences and evolution of spliceosomal introns. Wieczorek Kirk, M. Lambermon, and W. Pre-mRNA splicing in higher plants. Trends Plant Sci. Ludwig, M. Bergman, N. Patel, and M. Evidence for stabilizing selection in a eukaryotic enhancer element. Lynch, M. Mutation accumulation in nuclear, organelle, and prokaryotic genomes: transfer RNA genes.
Intron evolution as a population-genetic process. The evolutionary fate and consequences of duplicate genes. The origins of genome complexity. The probability of duplicate gene preservation by subfunctionalization. Hong, and D. Nonsense-mediated decay and the evolution of eukaryotic gene structure.
Maquat, ed. Nonsense-mediated decay. Landes Bioscience, Georgetown, Tex in press. Messenger RNA surveillance and the evolutionary proliferation of introns. The evolution of spliceosomal introns. Scofield, and X. The evolution of transcription-initiation sites.
O'Hely, B. Walsh, and A. The probability of fixation of a newly arisen gene duplicate. MacArthur, S. Expected rates and modes of evolution of enhancer sequences. Machado, C. Kliman, J. Markert, and J. Inferring the history of speciation from multilocus DNA sequence data: the case of Drosophila pseudoobscura and close relatives.
Maicas, E. Shago, and J. Maquat, L. Nonsense-mediated mRNA decay: a comparative analysis of different species. Genomics 5 : — Maruyama, T. Birky Jr. Effects of periodic selection on gene diversity in organelle genomes and other systems without recombination. McVean, G. Myers, S. Hunt, P. Deloukas, D. Bentley, and P. The fine-scale structure of recombination rate variation in the human genome. Medghalchi, S. Frischmeyer, J. Mendell, A.
Kelly, A. Lawler, and H. Rent1 , a trans-effector of nonsense-mediated mRNA decay, is essential for mammalian embryonic viability.
Meijer, H. Biochem J. Mendell, J. Medghalchi, R. Lake, E. Noensie, and H. Novel Upf2p orthologues suggest a functional link between translation initiation and nonsense surveillance complexes. Michel, F. Structure and activities of group II introns. Mira, A. Ochman, and N. Deletional bias and the evolution of bacterial genomes. Moll, I. Grill, C. Gualerzi, and U. Leaderless mRNAs in bacteria: surprises in ribosomal recruitment and translational control.
Morris, D. Upstream open reading frames as regulators of mRNA translation. Mount, S. Burks, G. Hertz, G. Stormo, O. White, and C. Splicing signals in Drosophila : intron size, information content, and consensus sequences. Nachman, M. Estimate of the mutation rate per nucleotide in humans.
Niehrs, C. Synexpression groups in eukaryotes. Nissim-Rafinia, M. Splicing regulation as a potential genetic modifier. Ochman, H. Neutral mutations and neutral substitutions in bacterial genomes. Lawrence, and E.
Lateral gene transfer and the nature of bacterial innovation. Ohta, T. Slightly deleterious mutant substitutions in evolution. Nature : 96 — Mutational pressure as the main cause of molecular evolution and polymorphism. Selected papers on theoretical population genetics and molecular evolution.
Linkage disequilibrium between two segregating nucleotide sites under the steady flux of mutations in a finite population. Genetics 68 : — Otto, S. The probability of fixation in populations of changing size. Philips, A. RNA processing and human disease. Life Sci. Pickering, B. Cell Dev. Posada, D. Crandall, M. Nguyen, J. Demma, and R. Population genetics of the porB gene of Neisseria gonorrhoeae : different dynamics in different homology groups.
Prince, V. Splitting pairs: the diverging fates of duplicated genes. Voelpel, and M. Insights into recombination from patterns of linkage disequilibrium in humans. Qiu, W. Schisler, and A. The evolutionary gain of spliceosomal introns: sequence and phase preferences. Raff, R. The shape of life. University Chicago Press, Chicago, Ill. Reich, D. Linkage disequilibrium in the human genome. Rest, J. Retroids in Archaea: phylogeny and lateral origins.
Rockman, M. Abundant raw material for cis -regulatory evolution in humans. Rogozin, I. Kochetov, F. Kondrashov, E. Koonin, and L. Bioinformatics 17 : — Wolf, A. Sorokin, B. Mirkin, and E. Remarkable interkingdom conservation of intron positions and massive, lineage-specific intron loss and gain in eukaryotic evolution.
Rousset, F. Effective size in simple metapopulation models. Heredity 91 : — Roy, S. Complex early genes. Rates of intron loss and gain: implications for early eukaryotic evolution. Ruiz-Echevarria, M. Identifying the right stop: determining how the surveillance complex recognizes and degrades an aberrant mRNA. Sarkar, S. Evolution of the core genome of Pseudomonas syringae , a highly clonal, endemic plant pathogen.
Schaal, T. Selection and characterization of pre-mRNA splicing enhancers: identification of novel SR protein-specific enhancer sequences. Schmid, P. Tokeshi, and J. Relation between population density and body size in stream communities. Sharp, P. On the origin of RNA splicing and introns. Cell 42 : — Bailes, R.
Grocock, J. Peden, and R. Variation in the strength of selected codon usage bias among bacteria. Shaw, P. Wratten, A. McGregor, and G. Coevolution in bicoid-dependent promoters and the inception of regulatory incompatibilities among species of higher Diptera. Shukla, G. A catalytically active group II intron domain 5 can function in the Udependent spliceosome. Cell 9 : — Singh, U. Rogers, B. Mann, and W. Petri Jr.
Transcription initiation is controlled by three core promoter elements in the hgl5 gene of the protozoan parasite Entamoeba histolytica. USA 94 : — Slupska, M. King, S. Fitz-Gibbon, J. Besemer, M. Borodovsky, and J. Leaderless transcripts of the crenarchaeal hyperthermophile Pyrobaculum aerophilum. Sontheimer, E. Gordon, and J. Metal ion catalysis during group II intron self-splicing: parallels with the spliceosome.
Stoltzfus, A. On the possibility of constructive neutral evolution. Some effort has also been devoted to elucidating the energy barriers and the kinetic rate constants associated with the accessibility of DNA in the nucleosome [ 12 ] and explaining specific features of force-induced nucleosome unraveling observed in single-molecule experiments [ 12 — 14 ].
Beyond the single nucleosome level, contiguous nucleosomes separated by short sections of naked DNA called linker DNAs yield the classic beads-on-a-string structure depicted in Figure 2. While, in vivo imaging of cell nuclei has yielded little information on the secondary structure of chromatin, and has even brought into question the very existence of a nm fiber [ 15 , 16 ], electron microscopy of isolated nucleosomal arrays have been successful in imaging the transition from nm beads-on-a-string structures to nm condensed structures with increasing salt concentrations [ 15 , 17 ].
Regardless of the gaps in our knowledge of the secondary structure of chromatin in vivo , this structure is expected to dictate the accessibility of DNA sequences for interactions with nuclear machinery and is also likely to play a role in the recruitment of histone modifying and remodeling factors to specific regions of the genome. Local packing of nucleosomes within the chromatin fiber could also potentially affect its interactions with distant portions of the fiber or other chromatin fibers through processes like interdigitation [ 18 ].
Despite decades of research, the internal structure of the nm chromatin fiber remains controversial. This controversy arises because of two main reasons: 1 in vivo chromatin is too "messy" to be visualized with even the most advanced microscopy techniques [ 15 ] and 2 in vitro reconstituted nucleosome arrays are too large and flexible to be crystallized, and too compact at physiological conditions for their linkers to be fully resolved through microscopy.
These limitations have led researchers to adopt indirect ways of deducing the internal structure of chromatin, using chemical cross-linking and single-molecule pulling techniques, with varying degrees of success.
Based on the data, two types of models for the chromatin structure have been proposed that differ mainly in the location and configuration of the linkers.
In the one-start solenoid model, linkers exhibit a strongly bent configuration and reside at the fiber interior [ 17 , 19 , 20 ]. In the two-start helix, linkers exhibit a straight or gently bent configuration, and they could reside at the periphery of the fiber in one version of the model [ 21 ] or inside the fiber close to its axis in a zigzag manner in another version [ 22 — 24 ]. Computational modeling has played an integral role in providing new insights into chromatin architecture.
The main challenge in modeling chromatin is the vast degrees of freedom possessed by even small segments of the fiber e. Hence, all-atom approaches demand prohibitive amounts of computational resources to converge to equilibrium structures. Further, the larger and the more flexible the system, the less adequate a description by one single equilibrium conformation because of the large variation in possible structures around thermal equilibrium.
In other words, the systems become "fuzzy" and can only be described in terms of statistical averages. The advantage of this situation is that atomic-detail resolution may easily be abandoned for vast gains in computational speed in a coarse-grained model. To this end, a major focus of computational modeling has been on developing lower-resolution models or "force fields" of nucleosome arrays that still account for the energetic interactions and constraints between the different components of the arrays.
A large effort in computational modeling also lies in developing efficient procedures for "sampling" low-energy conformations of the nucleosome array subject to appropriate force fields. A range of computational models that include widely differing amounts of detail have been developed. Woodcock et al. Two-angle models with consideration for the excluded volume of nucleosomes have been extremely useful in providing sterically permissible conformations of nucleosomal arrays for specified constraints on nucleosome packing ratio, fiber diameter and linker length [ 27 — 31 ].
Chromatin Modeling. Coarse grained models of 10 nm chromatin fiber with different level of details. The E2A model is an extension of the two angle model [ 25 ] that also accounts for the cylindrical shape of the nucleosomes [ 32 ].
Simulations based on the E2A model are ideally suited for studying long nucleosomal arrays as they overcome the difficulty of lack of knowledge of actual interaction potentials between nucleosomes by using model parameters obtained from experimental data.
In particular, the E2A model has been used for studying the effects of variability in linker lengths and variability in linker histone occupancy [ 32 ]. In combination with high-resolution light microscopy experiments these simulations promise a way to capture local chromatin structure in the range of 10 - 40 nm resolution [ 33 ].
The next class of models, in addition to including the features of the two-angle model, include the mechanics and electrostatics of the linker DNAs along with a simple treatment of inter-nucleosome interactions [ 34 — 36 ].
The linker DNA is treated as a discretized wormlike chain, possessing energy terms for stretching and bending of the bead-chain with an additional energy term for the relative twist angle between adjacent beads to account for the twisting rigidity of DNA [ 37 ] Figure 3b.
The inter-nucleosome interactions have thus far been treated as hard spheres, interacting with a hard-core attraction [ 34 ] or as cylinders interacting with Gay-Berne [ 35 , 36 ] and Zewdie potentials [ 36 ]. The nucleosome array conformations and packing ratios obtained using Monte Carlo simulations [ 35 , 36 ] based on these models generally resemble those obtained by electron microscopy for moderately folded chromatin.
These models [ 34 ] have also provided valuable insights into the stretching behavior of chromatin and yielded first estimates of the strength of internucleosome interactions by matching simulated force-extension curves to those obtained experimentally [ 39 ].
Importantly, the models have revealed the sensitivity of the chromatin structure to the internucleosome interaction strength and linker lengths [ 36 ].
Furthermore, it was observed that nucleosome arrays exhibit a zigzag structure without the linker histone and a more solenoidal structure for linker histone-bound arrays [ 40 ]. Very detailed models of local interactions within oligonucleosomes have been developed by Schlick and coworkers [ 3.
The earliest model [ 3. The magnitude of the charges were optimized to reproduce as closely as possible the electric field in the vicinity of the nucleosome. This approach allowed one to account for the salt-dependence in the inter-nucleosome interactions.
The model was later refined by employing an irregular-shaped representation of the nucleosome [ 43 ] that was based on a more recent nucleosome crystal structure with all histone tails fully resolved [ 50 ]. The model reproduced the experimentally observed [ 15 , 17 ] compaction of the arrays with increasing salt concentration and indicated that the arrays maintain a zigzag morphology under monovalent salt conditions.
Further, the simulations demonstrated that reduced electrostatic repulsion between the linkers is the main mechanism responsible for the folding of arrays at high salt. These models are also being used to study the dynamics of chromatin arrays, especially under different kinds of forces including torsional stresses [ 51 ]. Recently, this model was further improved by accounting for histone tail flexibility [ 44 ], linker histone binding [ 47 ], and effects of divalent ions [ 47 ].
The tails were treated as coarse-grained bead-chains, where each bead represented five amino acid residues. The stretching, bending, and the electrostatic terms in the bead-chain were parametrized using an iterative procedure.
The linker histone was coarse-grained as three charged beads rigidly bound at the nucleosome dyad with the magnitude of the charges optimized to reproduce the electric field of the atomic linker histone. Divalent ions were treated phenomenologically in terms of their effect on flexibility and electrostatic screening of the linker DNAs. A configurational-bias Monte Carlo approach was used to sample the tail configurations and translation, rotation and pivot moves were used to sample the global array configurations [ 46 ].
This model helped elucidate the role of each histone tail, the linker histone and physiological salt condition in chromatin folding [ 45 , 49 ]. Divalent ions were also found to facilitate tight packing of nucleosomes by allowing a fraction of the linkers to bend and by strongly screening the linker repulsion at the fiber axis.
Moreover, the model, in conjunction with sophisticated cross-linking experiments, confirmed the existence of a heteromorphic fiber containing both zigzag and solenoid conformations in the presence of additional divalent cations and linker histones [ 49 ]. This model has also recently been used to reproduce the linker length dependence in the observed chromatin structures [ 48 ]. In summary, mesoscale models at varying levels of sophistication such as those discussed above are proving to be valuable tools for examining chromatin structure.
The choice of which model to use is dictated by the amount of detail required and the amount of computational resources available. For instance, the detailed models accounting for histone tail flexibility and nucleosome geometry may provide the most accurate representation of short nucleosome arrays. For long arrays containing hundreds of nucleosomes, these models rapidly become computationally intractable and the intermediate-resolution models like the E2A model [ 32 ] become more suitable.
In the previous section, we discussed the secondary structure of chromatin from a static perspective. In reality, the chromatin fiber within the cell nucleus is present in a dynamic state [ 52 ]-it is flexible over lengths much larger than the fiber diameter [ 53 ] and it is constantly being subjected to various kinds of remodeling activities, including histone modifications [ 54 — 56 ], sliding and depletion of nucleosomes [ 57 — 64 ], and incorporation of histone variants [ 65 ].
There is strong evidence from light microscopy studies indicating that at the gene locus level the chromatin fiber is organized into loops [ 66 ]. Studies on several multigene clusters conceive such loops as instrumental in bringing together distant enhancer and promoter regions crucial for gene activation, regulation and recombination [ 67 — 69 ].
Although the detailed mechanism of looping is not fully understood, there is no question that the "intrinsic" bending rigidity of the chromatin fiber dictates to a considerable degree the loop size-dependent statistical probability of two distant regions of the fiber coming into close proximity to form a loop. Emerging evidence suggests that the relationship between flexibility and looping probability may be utilized by cells for gene regulation.
Strong support for this idea also comes from recent experiments in the Murre lab that show large-scale conformational changes in the IgH -locus during B-Cell development accompanying genome-wide and locus-specific histone modifications and nucleosome depletion events [ 66 , 71 , 72 ]. Thus, it seems that chromatin remodeling events, apart from modulating the local structure of chromatin and DNA accessibility, could lead to changes in the higher-order folding of chromatin through its effects on macroscopic properties of the fiber such as its flexibility.
Chromatin flexibility as characterized by its persistence length, L p , seems to exhibit large variations, depending on the experimental method used for its determination and the conditions and type of chromatin investigated.
However, it is important to review these results in light of a recent fundamental study [ 76 ] indicating that standard definitions of persistence length as used in these studies may not describe the local intrinsic flexibility of chromatin. Aumann et al. The persistence length was obtained from the decay in the correlation of the tangent vector representing the local fiber axis. A comparison between the magnitude of the bending and elastic rigidity suggested that chromatin is much easier to bend than stretch, leading to the interesting hypothesis that it may be easier for the cells to pack chromatin via tight loops rather than by linear compression of the fiber.
As discussed earlier, chromatin exists in a highly dynamic state within the cell nucleus. Heermann and coworkers [ 78 , 79 ] have recently examined the effects of such depletion events on the persistence length and conformation of nucleosome arrays Figure 4. An adaptation of the E2A model with experimental distribution of nucleosome repeat lengths yields a quantitative estimate for persistence length modification.
This leads to sharp bends in the fiber allowing for formation of loops in the kilo base pair range [ 79 ], an important feature of genome organization visualized in experiments [ 69 ]. Nucleosome Depletion. Schematic of nucleosomal depletion associated persistence length modification and consequent local conformation change in the cell nucleus.
We have recently begun to examine the mechanisms behind the conformational collapse in the IgH - locus observed by Murre and coworkers during B-cell development [ 66 ]. We hypothesize that chromatin remodeling events nucleosome depletion and histone modifications [ 71 , 72 ] introduce flexible "hinges" within the chromatin fiber causing it to collapse Figure 4.
By treating the chromatin fiber as a worm-like chain WLC with fixed contour length L c and variable persistence length L p , we showed that the compaction, as characterized by the ratio of the final to initial mean square end-to-end distances, is given by the ratio of the final to initial persistence length in the ideal chain limit see Appendix for complete derivation.
This happened regardless of whether the maternal population was from the north or from the south. See illustration on page Mitochondria are ancient endosymbionts that over time lost many of their genes—some of which migrated to the nuclear genome—and increasingly came to rely on the nuclear genes to supply the basic raw materials necessary for mitochondrial function.
When it came to genome analyses seeking to identify the genetic basis of adaptive change, mitochondrial genes were often ignored. For 1. Mitochondrial gene products interact with those encoded in nuclear genes, and sometimes with the nuclear genome itself. Because the mitochondrial genome mutates faster than the nuclear genome, it takes the lead in the mitonuclear evolutionary dance, while the nuclear genome follows, evolving compensatory mutations to maintain coadapted gene complexes.
Researchers are now coming to appreciate that this has consequences for physiology and even macroevolution. Researchers have long known that many proteins are made of several components, some of which are coded for in the mitochondrial genome, and others being coded for in the nuclear genome.
Cytochrome oxidase, the last enzyme in the respiratory electron transport chain, is one example. Mitochondria require nuclear gene products to continually produce energy for the cell. For example, mitochondrial protein translation requires aminoacyl tRNA synthetases aaRS encoded by the nuclear genome to attach amino acids to the corresponding tRNAs encoded by the mitochondrial genome.
Mitochondrial gene products can influence the expression of nuclear genes, though the mechanisms are as yet unclear. Over the past 20 years, however, researchers have begun to document the effects of variation in the mitochondrial genome on physiological functions such as growth rate and reproductive success in flies, copepods, and various fish species. Crosstalk between the two genomes is probably an important part of a lot of physiology.
The evolution of the mitochondrial genome might also matter, the field has come to realize, for adaptation and speciation. Mitochondria replicate their genomes more than once per cell cycle, and they do so in an environment full of DNA-damaging free radicals produced as a byproduct of the metabolic process that generates ATP within the organelles.
Synergy between sequence and size in large-scale genomics. Nature Reviews Genetics 6 , — doi Parra, G. Tandem chimerism as a means to increase protein complexity in the human genome.
Genome Research 16 , 37—44 Reenan, R. Molecular determinants and guided evolution of species-specific RNA editing. Van Straalen, N. Venter, J. The sequence of the human genome. Yandell, M. A computational and experimental approach to validating annotations and gene predictions in the Drosophila melanogaster genome. Proceedings of the National Academy of Sciences , — Restriction Enzymes. Genetic Mutation. Functions and Utility of Alu Jumping Genes.
Transposons: The Jumping Genes. DNA Transcription. What is a Gene? Colinearity and Transcription Units. Copy Number Variation. Copy Number Variation and Genetic Disease. Copy Number Variation and Human Disease. Tandem Repeats and Morphological Variation.
Chemical Structure of RNA. Eukaryotic Genome Complexity. RNA Functions. Pray, Ph. Citation: Pray, L. Nature Education 1 1 How many genes are there? This question is surprisingly not very important, and has nothing to do with the organism's complexity. There is more to genomes than protein-coding genes alone. Aa Aa Aa. Figure 1: Chromatin has highly complex structure with several levels of organization. Genetics: A Conceptual Approach , 2nd ed. All rights reserved.
Does Size Matter? Figure 2. References and Recommended Reading Anderson, S. Genome Research 16 , 37—44 Reenan, R. Article History Close.
0コメント