Abstract
The three-dimensional organization of tightly condensed chromatin within metaphase chromosomes has been one of the most challenging problems in structural biology since the discovery of the nucleosome. This study shows that chromosome images obtained from typical banded karyotypes and from different multicolour cytogenetic analyses can be used to gain information about the internal structure of chromosomes. Chromatin bands and the connection surfaces in sister chromatid exchanges and in cancer translocations are planar and orthogonal to the chromosome axis. Chromosome stretching produces band splitting and even the thinnest bands are orthogonal and well defined, indicating that short stretches of DNA can occupy completely the chromosome cross-section. These observations impose strong physical constraints on models that attempt to explain chromatin folding in chromosomes. The thin-plate model, which consists of many stacked layers of planar chromatin perpendicular to the chromosome axis, is compatible with the observed orientation of bands, with the existence of thin bands, and with band splitting; it is also compatible with the orthogonal orientation and planar geometry of the connection surfaces in chromosome rearrangements. The results obtained provide a consistent interpretation of the chromosome structural properties that are used in clinical cytogenetics for the diagnosis of hereditary diseases and cancers.
Highlights
Stages[13], suggested a model based on hierarchical folding of fibres of increasing diameter; in this model the chromatids are segmented longitudinally into layers (~250 nm thickness) formed by the thicker fibre
Further studies using polarizing microscopy, electron tomography, AFM imaging in aqueous media, and AFM-based nanotribology and force spectroscopy[18,19,20] showed that in each layer the chromatin filament forms a flexible two-dimensional network in which nucleosomes are irregularly oriented, allowing the compaction of the structure by interdigitation of adjacent layers
Cytogenetics is mainly concerned with the study of chromosome structure for clinical diagnostics[28], there is a wealth of cytogenetic data that may give insights about fundamental aspects of chromosome structure
Summary
Chromosome bands are perpendicular to the chromosome axis. In the G-banded chromosomes shown in the example presented in Fig. 1a (reproduced from ref. 39), it seems that bands have a transverse orientation. These results correspond to G-banding patterns at ~700-band level. The mean of these measurements is about 90° (Table 1), indicating that splitting does not change the orthogonal orientation of bands with respect to the chromosome axis In three dimensions such a transformation leading to defined sub-bands can only be explained considering that chromatin structure within bands is formed by planar elements that can be relatively pulled apart by stretching forces. It will be discussed below that many structural models of metaphase chromosomes are not compatible with these observations
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