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Comparative Study
. 2006 Oct;16(10):1222-30.
doi: 10.1101/gr.5335506. Epub 2006 Sep 5.

Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes

Anne Helmrich  1 , Karen Stout-Weider, Klaus Hermann, Evelin Schrock, Thomas Heiden
Affiliations
Comparative Study

Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes

Anne Helmrich et al. Genome Res. 2006 Oct.

Abstract

Common fragile sites (CFSs) are seen as chromosomal gaps and breaks brought about by inhibition of replication, and it is thought that they cluster with tumor breakpoints. This study presents a comprehensive analysis using conventional and molecular cytogenetic mapping of CFSs and their expression frequencies in two mouse strains, BALB/c and C57BL/6, and in human probands. Here we show that induced mouse CFSs relate to sites of spontaneous gaps and breaks and that CFS expression levels in chromosome bands are conserved between the two mouse strains and between syntenic mouse and human DNA segments. Furthermore, four additional mouse CFSs were found to be homologous to human CFSs on the molecular cytogenetic level (Fra2D-FRA2G, Fra4C2-FRA9E, Fra6A3.1-FRA7G, and Fra6B1-FRA7H), increasing the number of such CFSs already described in the literature to eight. Contrary to previous reports, DNA helix flexibility is not increased in the 15 human and eight mouse CFSs molecularly defined so far, compared to large nonfragile control regions. Our findings suggest that the mechanisms that provoke instability at CFSs are evolutionarily conserved. The role that large transcriptionally active genes may play in CFS expression is discussed.

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Figures

Figure 1.
Figure 1.
Example of mouse CFS mapping. The lesions appearing as chromatid gaps (black arrows), chromosome breaks/deletions (blue arrows), or translocations (red arrows) were mapped to their cytogenetic locations according to the SKY classification (left) and the DAPI banding pattern (right). The figure shows an especially heavily rearranged metaphase with all three kinds of lesions.
Figure 2.
Figure 2.
Frequencies of chromatin gaps (G) and double-strand breaks (DB) at different APC concentrations in (B) BALB/c and (C) C57BL/6 mouse splenocytes. The y-axis shows the mean numbers of G and DB per metaphase; for each strain and APC concentration, means ± standard errors were calculated from counts in 125 metaphases (five mice). Statistically significant differences (Mann- Whitney U-test, P < 0.05) between strains are indicated with asterisks (*). The numbers of induced G and DB are slightly higher in BALB/c compared to C57BL/6 cells.
Figure 3.
Figure 3.
Relation of CFS expression levels (including G and DB at0.4 μM APC, shown as percent of analyzed chromosomes) in 392 cyto- genetic bands of BALB/c and C57BL/6 mice. The line of best fit is shown. R is the Spearman test correlation coefficient. CFS expression on the chromosome band level is conserved in the two mouse strains.
Figure 4.
Figure 4.
Log scale CFS expression levels in 392 mouse chromosome bands. The mouse chromosome ideogram (D. Adler, Department of Pathology at the University of Washington, supplemented according to http://www.ensembl.org/Mus_musculus/index.html) is displayed horizontally. All chromosome bands (A–H), sub-bands (1–6), and sub-sub-bands (1–3) are labeled for chromosome 1; sub-bands of the remaining chromosomes are, for the sake of clarity, not labeled and can be identified according to their position within chromosome bands and in relation to the indicated sub-sub-bands. CFS expression data were obtained in BALB/c and C57BL/6 splenocytes treated with 0.2 μM and 0.4 μM APC and are shown as the percent of analyzed chromosomes. Stable chromosome bands (S, white bars) with low APC sensitivity and bands with medium (gray) and high (black) CFS expression were identified with a nonrandom test (see Methods). Each spontaneous gap (G) and double-strand break (DB) found in untreated control cells are indicated.
Figure 5.
Figure 5.
CFS expression levels in chromosome bands of 17 large (two or more cytogenetic bands) syntenic regions of the human and mouse (BALB/c and C57BL/6) genomes. x-axis: mouse and human chromosome bands; y-axis: frequency of CFS expression in percentages.
Figure 6.
Figure 6.
Expression levels of large human genes (≥650 kb) in CFSs and stable control regions. Shown on the x-axis are the large genes situated in nine of 15 CFSs and in five of 11 control regions. Gray bars indicate the frequency of CFS expression (left y-axis); black bars show the extent of gene expression (right y-axis, based on RNA expression array data from http://symatlas.gnf.org/SymAtlas/).
See this image and copyright information in PMC

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