How long threadlike eukaryotic chromosomes fit tidily in the small volume of the nucleus without significant entanglement is just beginning to be understood, thanks to major advances in experimental techniques. Several polymer models, which reproduce contact maps that measure the probabilities that two loci are in spatial contact, have predicted the three-dimensional structures of interphase chromosomes. Data-driven approaches, using contact maps as input, predict that mitotic helical chromosomes are characterized by switch in handedness, referred to as "perversion". By using experimentally derived effective interactions between chromatin loci in simulations, structures of conventional and inverted nuclei have been accurately predicted. Polymer theory and simulations show that the dynamics of individual loci in chromatin exhibit subdiffusive behavior but the diffusion exponents are broadly distributed, which accords well with experiments. Although coarse-grained models are successful, many challenging problems remain, which require the creation of new experimental and computational tools to understand genome biology.
During eukaryotic cell division, a microtubule-based structure called the spindle exerts forces on chromosomes, thereby organizing and segregating them Extensive work demonstrates that the forces acting parallel to the spindle axis, including those responsible for separating sister chromatids, are generated by microtubule polymerization and depolymerization, and molecular-motors. In contrast, little is known about the forces acting perpendicular to the spindle axis, which determine the configuration of chromosomes at the metaphase plate, and thus impact nuclear localization and rates of segregation errors. Here, we use quantitative live-cell microscopy to show that metaphase chromosomes are spatially anti-correlated in mouse oocyte spindles, indicating the existence of hitherto unknown long-range forces acting perpendicular to the spindle axis. We explain this observation by first demonstrating that the spindle's microtubule network behaves as a nematic liquid crystal, and then arguing that deformation of the nematic field around embedded chromosomes causes long-range repulsion between them. Our work highlights the surprising relevance of materials physics in understanding the stru
Background. The large-scale pattern of distribution of genes on the chromosomes in the known animal genomes is not well characterized. We hypothesized that individual genes will be distributed on chromosomes in a mathematically ordered manner across the animal kingdom. Results. Twenty-one animal genomes reported in the NCBI database were examined. Numerically, there was a trend towards increasing overall gene content with increasing size of the genome as reflected by the chromosomal complement. Gene frequency on individual chromosomes in each animal genome was analyzed and demonstrated uniformity of proportions within each animal with respect to both average gene frequency on individual chromosomes and gene distribution across the unique genomes. Further, average gene distribution across animal species followed a relationship whereby it was, approximately, inversely proportional to the square root of the number of chromosomes in the unique animal genomes, consistent with the notion that there is an ordered increase in gene dispersion as the complexity of the genome increased. To further corroborate these findings a derived measure, termed gene spacing on chromosomes correlated with
The interplay between bacterial chromosome organization and functions such as transcription and replication can be studied in increasing detail using novel experimental techniques. Interpreting the resulting quantitative data, however, can be theoretically challenging. In this minireview, we discuss how connecting experimental observations to biophysical theory and modeling can give rise to new insights on bacterial chromosome organization. We consider three flavors of models of increasing complexity: simple polymer models that explore how physical constraints, such as confinement or plectoneme branching, can affect bacterial chromosome organization; bottom-up mechanistic models that connect these constraints to their underlying causes, for instance chromosome compaction to macromolecular crowding, or supercoiling to transcription; and finally, data-driven methods for inferring interpretable and quantitative models directly from complex experimental data. Using recent examples, we discuss how biophysical models can both deepen our understanding of how bacterial chromosomes are structured, and give rise to novel predictions about bacterial chromosome organization.
A difficult step in the process of karyotyping is segmenting chromosomes that touch or overlap. In an attempt to automate the process, previous studies turned to Deep Learning methods, with some formulating the task as a semantic segmentation problem. These models treat separate chromosome instances as semantic classes, which we show to be problematic, since it is uncertain which chromosome should be classed as #1 and #2. Assigning class labels based on comparison rules, such as the shorter/longer chromosome alleviates, but does not fully resolve the issue. Instead, we separate the chromosome instances in a second stage, predicting the orientation of the chromosomes by the model and use it as one of the key distinguishing factors of the chromosomes. We demonstrate this method to be effective. Furthermore, we introduce a novel Double-Angle representation that a neural network can use to predict the orientation. The representation maps any direction and its reverse to the same point. Lastly, we present a new expanded synthetic dataset, which is based on Pommier's dataset, but addresses its issues with insufficient separation between its training and testing sets.
The probability of two loci, separated by a certain genome length, being in contact can be inferred using the Chromosome Conformation Capture (3C) method and related Hi-C experiments. How to go from the contact map, a matrix listing the mean contact probabilities between a large number of pairs of loci, to an ensemble of three-dimensional structures is an open problem. A solution to this problem, without assuming an assumed energy function, would be the first step in understanding the way nature has solved the packaging of chromosomes in tight cellular spaces. We created a theory, based on polymer physics characteristics of chromosomes and the maximum entropy principles, referred to as HIPPS (Hi-C-Polymer-Physics-Structures) method, that allows us to calculate the 3D structures solely from Hi-C contact maps. We created an ensemble of 3D structures for the 23 chromosomes from lymphoblastoid cells using the measured contact maps as inputs. The HIPPS method shows that conformations of chromosomes are heterogeneous even in a single cell type. The differences in the conformational heterogeneity of the same chromosome in different cell types (normal as well as cancerous cells) can also b
Multiply inverted balancer chromosomes that suppress exchange with their homologs are an essential part of the genetic toolkit in Drosophila melanogaster. Despite their widespread use, the organization of balancer chromosomes has not been characterized at the molecular level, and the degree of sequence variation among copies of any given balancer chromosome is unknown. To map inversion breakpoints and study potential sequence diversity in the descendants of a structurally identical balancer chromosome, we sequenced a panel of laboratory stocks containing the most widely used X-chromosome balancer, First Multiple 7 (FM7). We mapped the locations of FM7 breakpoints to precise euchromatic coordinates and identified the flanking sequence of breakpoints in heterochromatic regions. Analysis of SNP variation revealed megabase-scale blocks of sequence divergence among currently used FM7 stocks. We present evidence that this divergence arose by rare double crossover events that replaced a female-sterile allele of the singed gene (sn[X2]) on FM7c with wild type sequence from balanced chromosomes, and propose that many FM7c chromosomes in the Bloomington Drosophila Stock Center have lost sn[X
In medicine, visualizing chromosomes is important for medical diagnostics, drug development, and biomedical research. Unfortunately, chromosomes often overlap and it is necessary to identify and distinguish between the overlapping chromosomes. A segmentation solution that is fast and automated will enable scaling of cost effective medicine and biomedical research. We apply neural network-based image segmentation to the problem of distinguishing between partially overlapping DNA chromosomes. A convolutional neural network is customized for this problem. The results achieved intersection over union (IOU) scores of 94.7% for the overlapping region and 88-94% on the non-overlapping chromosome regions.
Herein it is shown that in order to study the statistical properties of DNA sequences in bacterial chromosomes it suffices to consider only one half of the chromosome because they are similar to its corresponding complementary sequence in the other half. This is due to the inverse bilateral symmetry of bacterial chromosomes. Contrary to the classical result that DNA coding regions of bacterial genomes are purely uncorrelated random sequences, here it is shown, via a renormalization group approach, that DNA random fluctuations of single bases are modulated by log-periodic variations. Distance series of triplets display long-range correlations in each half of the intact chromosome and in intronless protein-coding sequences, or both long-range correlations and log-periodic modulations along the whole chromosome. Hence scaling analyses of distance series of DNA sequences have to consider the functional units of bacterial chromosomes.
The ever-increasing number of genome sequencing and resequencing projects is a central source of insights into the ecology and evolution of non-model organisms. An important aspect of genomics is the elucidation of sex determination systems and identifying genes on sex chromosomes. This not only helps reveal mechanisms behind sex determination in the species under study, but their characteristics make sex chromosomes a unique tool for studying the mechanisms and effects of recombination and genomic rearrangements and how they affect adaption and selection. Despite this, many sequencing projects omit such investigations. Here, we apply a simple method using sequencing coverage statistics to identify scaffolds belonging to the sex chromosomes of minke whale, and show how the sex chromosome system can be determined using coverage statistics alone. Using publicly available data, we identify the previously unknown sex of an Antarctic minke whale as female. We further investigate public sequence data from the different species and sub-species of minke whale, and classify genomic scaffolds from a published minke whale assembly as X or Y chromosomal sequences. Our findings are consistent w
The unique inheritance pattern of X chromosomes makes them preferential targets of adaptive evolution. We here investigate natural selection on the X chromosome in all species of great apes. We find that diversity is more strongly reduced around genes on the X compared with autosomes, and that a higher proportion of substitutions results from positive selection. Strikingly, the X exhibits several megabase long regions where diversity is reduced more than five fold. These regions overlap significantly among species, and have a higher singleton proportion, population differentiation, and nonsynonymous to synonymous substitution ratio. We rule out background selection and soft selective sweeps as explanations for these observations, and conclude that several strong selective sweeps have occurred independently in similar regions in several species. Since these regions are strongly associated with ampliconic sequences we propose that intra-genomic conflict between the X and the Y chromosomes is a major driver of X chromosome evolution.
We present a framework based on conditional entropy and the Dirichlet distribution for classifying chromosomes based on the degree to which they use synonymous codons uniformly or preferentially, that is, whether or not codons that code for an amino acid appear with the same relative frequency. Applying the approach to a large collection of annotated bacterial chromosomes reveals three distinct groups of bacteria.
We investigated the viscoelastic response of model interphase chromosomes by tracking the three-dimensional motion of hundreds of dispersed Brownian particles of sizes ranging from the thickness of the chromatin fiber up to slightly above the mesh size of the chromatin solution. In agreement with previous computational studies on polymer solutions and melts, we found that the large-time behaviour of diffusion coefficient and the experienced viscosity of moving particles as functions of particle size deviate from the traditional Stokes-Einstein relation, and agree with a recent scaling theory of diffusion of non-sticky particles in polymer solutions. Interestingly, we found that at short times large particles are temporary "caged" by chromatin spatial constraints, which thus form effective domains whose size match remarkably well recent experimental results for micro-tracers inside interphase nuclei. Finally, by employing a known mathematical relation between the time mean-square displacement of tracked particles and the complex shear modulus of the surrounding solution, we calculated the elastic and viscous moduli of interphase chromosomes.
Several orders of magnitude typically separate the contour length of eukaryotic chromosomes and the size of the nucleus where they are confined. The ensuing topological constraints can slow down the relaxation dynamics of genomic filaments to the point that mammalian chromosomes are never in equilibrium over a cell's lifetime. In this opinion article, we revisit these out-of-equilibrium effects and discuss how their inclusion in physical models can enhance the spatial reconstructions of interphase eukaryotic genomes from phenomenological constraints collected during interphase.
Genome-wide analysis of distributions of densities of long-range interactions of human chromosomes with each other, nucleoli, nuclear lamina, and binding sites of chromatin state regulatory proteins, CTCF and STAT1, identifies non-random highly correlated patterns of density distributions along the chromosome length for all these features. Marked co-enrichments and clustering of all these interactions are detected at discrete genomic regions on selected chromosomes, which are located within pericentromeric heterochromatin and designated Centromeric Regions of Interphase Chromatin Homing (CENTRICH). CENTRICH manifest 199-716-fold higher density of inter-chromosomal binding sites compared to genome-wide or chromosomal averages (p = 2.10E-101-1.08E-292). Sequence alignment analysis shows that CENTRICH represent unique DNA sequences of 3.9 to 22.4 Kb in size which are: 1) associated with nucleolus; 2) exhibit highly diverse set of DNA-bound chromatin state regulators, including marked enrichment of CTCF and STAT1 binding sites; 3) bind multiple intergenic disease-associated genomic loci (IDAGL) with documented long-range enhancer activities and established links to increased risk of de
The 3D organisation of the genome in interphase cells is not a randomly folded polymer. Rather, experiments show that chromosomes arrange into a network of 3D compartments that correlate with biological processes, such as transcription, chromatin modifications, and protein binding. However, these compartments do not exist during cell division when the DNA is condensed, and it is unclear how and when they emerge. In this paper, we focus on the early stages after cell-division as the chromosomes start to decondense. We use a simple polymer model to understand the types of 3D structures that emerge from local unfolding of a compact initial state. From simulations, we recover 3D compartments, such as TADs and A/B compartments, that are consistently detected in Chromosome Capture Experiments across cell types and organisms. This suggests that the large-scale 3D organisation is a result of an inflation process.
During mitosis, near-spherical chromosomes reconfigure into rod-like structures to ensure their accurate segregation to daughter cells. We explore here, the interplay between the nonequilibrium activity of molecular motors in determining the chromosomal organization in mitosis and its characteristic symmetry-breaking events. We present a hybrid motorized chromosome model that highlights the distinct roles of condensin I and II in shaping mitotic chromosomes. Guided by experimental observations, the simulations suggest that condensin II facilitates large-scale scaffold formation, while condensin I is paramount in local helical loop arrangement. Together, these two distinct grappling motors establish the hierarchical helical structure characteristic of mitotic chromosomes, which exhibit striking local and, sometimes global, chirality and contribute to the robust mechanical properties of mitotic chromosomes. Accompanying the emergence of rigidity, the model provides mechanisms of forming defects, including perversions and entanglements, and shows how these may be partially resolved through condensin activity and topoisomerase action. This framework bridges coarse-grained energy landsc
Pathogenic chromosome abnormalities are very common among the general population. While numerical chromosome abnormalities can be quickly and precisely detected, structural chromosome abnormalities are far more complex and typically require considerable efforts by human experts for identification. This paper focuses on investigating the modeling of chromosome features and the identification of chromosomes with structural abnormalities. Most existing data-driven methods concentrate on a single chromosome and consider each chromosome independently, overlooking the crucial aspect of homologous chromosomes. In normal cases, homologous chromosomes share identical structures, with the exception that one of them is abnormal. Therefore, we propose an adaptive method to align homologous chromosomes and diagnose structural abnormalities through homologous similarity. Inspired by the process of human expert diagnosis, we incorporate information from multiple pairs of homologous chromosomes simultaneously, aiming to reduce noise disturbance and improve prediction performance. Extensive experiments on real-world datasets validate the effectiveness of our model compared to baselines.
Sex chromosomes have independently evolved in species with separate sexes in most lineages across the tree of life. However, the well-accepted canonical model of sex chromosome evolution is not universally supported. There is no single trajectory for sex chromosome formation and evolution across the tree of life, suggesting the underlying mechanisms and evolutionary forces are diverse and lineage specific. We review the diversity of sex chromosome systems, describe the canonical model of sex chromosome evolution, and summarize studies challenging various aspects of this model. They include evidence that many lineages experience frequent sex chromosome turnovers or maintain homomorphic sex chromosomes over long periods of time, suggesting sex chromosome degeneration is not inevitable. Sometimes the sex-limited Y/W chromosomes expand before they contract in size. Both transposable elements and gene gains could contribute to this size expansion, which further challenges gene loss being the hallmark of sex chromosome degeneration. Finally, empirical support for the role of sexually antagonistic selection as a driver of recombination suppression on sex chromosomes remains elusive. We su
Chromosomal crossovers play a crucial role in meiotic cell division, as they ensure proper chromosome segregation and increase genetic variability. Experiments have consistently revealed two key observations across species: (i) the number of crossovers per chromosome is typically small, but at least one, and (ii) crossovers on the same chromosome are subject to interference, i.e., they are more separated than expected by chance. These observations can be explained by a recently proposed coarsening model, where the dynamics of droplets associated with chromosomes designate crossovers. We provide a comprehensive analysis of the coarsening model, which we also extend by including material exchanges between droplets, the synaptonemal complex, and the nucleoplasm. We derive scaling laws for the crossover count, which allows us to analyze data across species. Moreover, our model provides a coherent explanation of experimental data across mutants, including the wild-type and zyp1-mutant of A. thaliana. Consequently, the extended coarsening model provides a solid framework for investigating the underlying mechanisms of crossover placement.