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Common Fragile Sites Are Conserved Features of Human and Mouse Chromosomes and Relate to Large Active Genes

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Common Fragile Sites Are Conserved Features of Human and Mouse Chromosomes and Relate to Large Active Genes Downloaded from genome.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes Anne Helmrich,1,2,4,5 Karen Stout-Weider,1,2 Klaus Hermann,3 Evelin Schrock,1,2 and Thomas Heiden1,2 1Institute of Clinical Genetics, Medical Faculty “Carl Gustav Carus,” University of Technology, 01307 Dresden, Germany; 2Institute of Medical Genetics, Charité, Humboldt University, 13353 Berlin, Germany; 3Signature-Diagnostics, 14469 Potsdam, Germany 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. [Supplemental material is available online at www.genome.org.] Common fragile sites (CFSs) are chromosomal loci that become been molecularly defined. These are Fra6C1, which corresponds visible (expressed) as chromatid gaps or chromosome breaks in a to the human CFS FRA4F (Rozier et al. 2004); Fra8E1, the homo- cell-type-dependent manner (Elder and Robinson 1989; Murano log of human FRA16D (Krummel et al. 2002); Fra12C1 in the et al. 1989a) after culturing cells under replicative stress. CFS ex- homologous region of FRA7K (Helmrich et al. 2006); and pression has been observed in various mammalian species (Arlt Fra14A2 in the FRA3B corresponding region (Glover et al. 1998). et al. 2003). Cytogenetic CFS mapping studies on murine lym- DNA sequence comparison detected highly conserved regions phocytes revealed 19 CFSs defined as chromosome bands with between mouse and human homologous CFSs (Shiraishi et al. significantly elevated gap/break frequencies that expressed the 2001; Krummel et al. 2002). It is therefore possible that despite lesion homozygously as well (Elder and Robinson 1989). Com- their instability, CFSs represent (at least over some time) evolu- parative analysis in lymphocyte chromosomes of human, three tionarily stable regions. great apes (chimpanzee, gorilla, orangutan), and a simian mon- But what is the molecular mechanism that forces breakage key species (Macaca fascicularis) has demonstrated that a high at specific sites? The amount and composition of repetitive ele- percentage of human CFSs were found in the equivalent location ments within molecularly mapped CFSs were shown to be similar on chromosomes of apes/monkeys, although with sometimes to overall distributions found in mouse and human genomes significantly different expression frequencies (Yunis and Soreng (Mishmar et al. 1998; Ried et al. 2000; Shiraishi et al. 2001; Krum- 1984; Smeets and van de Klundert 1990; Ruiz-Herrera et al. 2002). mel et al. 2002; Morelli et al. 2002; Limongi et al. 2003; Mat- A possible coincidence of CFSs with evolutionarily rearranged suyama et al. 2003). Several publications present evidence for the sites was also described (Smeets and van de Klundert 1990; Ruiz- existence of areas with elevated DNA helix flexibility (potential Herrera et al. 2002). However, considering only the most break- local conformational variations in the molecule) within the CFS age-prone sites of each primate, very few appeared to correspond regions. Islands with high flexibility were found in all of the to a synteny break (SB). To summarize, cytogenetic studies gave currently analyzed nine human and three mouse CFS sequences varying results and could not clarify to what degree CFSs were (Mishmar et al. 1998; Ried et al. 2000; Krummel et al. 2002; conserved over species frontiers or if they colocalize with evolu- Morelli et al. 2002; Limongi et al. 2003; Matsuyama et al. 2003; tionary rearrangements. Until now only four mouse CFSs have Zlotorynski et al. 2003; Rozier et al. 2004). Unfortunately, an appropriate number of analyzed stringently selected control re- gions was always missing. The initial study summed up the re- 4Present address: Institut de Génétique et de Biologie Moléculaire et sults for 14 very small regions consisting of 1.1 Mb total length Cellulaire, CU de Strasbourg, 67404 Illkirch, France. (Mishmar et al. 1998). In a recent paper, 17.2 Mb of control 5 Corresponding author. sequences were analyzed; however, these sequences were also E-mail [email protected]; fax 33-3-88-65-32-01. Article published online before print. Article and publication date are at http:// combined from smaller regions, and therefore their individual www.genome.org/cgi/doi/10.1101/gr.5335506. helix flexibility values were not shown (Zlotorynski et al. 2003). 1222 Genome Research 16:1222–1230 ©2006 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/06; www.genome.org www.genome.org Downloaded from genome.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Conservation of CFSs phocytes. In almost all of the mouse and human (K. Stout-Weider, unpubl.) chro- mosome bands observed at the 350–400 band level, we detected aphidicolin (APC)-induced lesions with different fre- quencies. CFS expression levels are conserved in mouse strains BALB/c and C57BL/6 Spectral karyotyping (SKY) was applied in order to accomplish a reliable classifi- cation of the mouse chromosomes; chromosomal bands were identified with DAPI banding. All spontaneously occurring or APC-induced chromatid gaps, deletions, and translocations were mapped along Figure 1. Example of mouse CFS mapping. The lesions appearing as chromatid gaps (black arrows), with their frequencies to their respective chromosome breaks/deletions (blue arrows), or translocations (red arrows) were mapped to their chromosomal band location (Fig. 1). cytogenetic locations according to the SKY classification (left) and the DAPI banding pattern (right). Chromatid gaps (G) and double- The figure shows an especially heavily rearranged metaphase with all three kinds of lesions. strand breaks (DB) including deletion breakpoints and exchange figures oc- 0.2 ע BALB/c) and 0.3) 0.1 ע All four molecularly defined mouse CFSs and their corre- curred at low frequencies of 0.2 -SE) in con 1.96ע sponding human CFSs localize to genes that span >750 kb of (C57BL/6) (events per metaphase, mean values genomic sequence: Grid2/GRID2 (Fra6C1/FRA4F), Wwox/WWOX trol cells not exposed to APC. CFS expression showed a clear (Fra8E1/FRA16D), Immp2l/IMMP2L (Fra12C1/FRA7K), and Fhit/ tendency to increase, with ascending APC concentrations, to FHIT (Fra14A2/FRA3B). Moreover, three human CFSs span the higher levels in BALB/c as compared to C57BL/6 mice (BALB/c, ;at 0.4 µM APC 0.6 ע at 0.2 µM APC, DB: 2.6 1.7 ע sequences of large genes: FRA6E (PARK2) (Denison et al. 2003), G: 3.8 at 0.4 µM 0.5 ע at 0.2 µM APC, DB: 1.6 1.3 ע FRA7H (EXOC4, formerly known as SEC8) (Mishmar et al. 1998), C57BL/6, G: 1.5 and FRA7I (CNTNAP2) (Ciullo et al. 2002). Therefore, features APC; P < 0.05) (Fig. 2). present in large genes were suggested to be causally related to CFS Correlation analysis of CFS frequencies of BALB/c and formation (Rozier et al. 2004). C57BL/6 mice at 0.4 µM APC showed a significant relation of In this study, we scored mouse CFSs, defined as chromo- medium strength (R = 0.67, P < 0.0001) (Fig. 3), that is, a conser- somal regions that express gaps, double-strand breaks, or ex- vation of the band-specific CFS expression levels in the two change figures under induced replicative stress, and then used strains. statistics to classify the different chro- mosomal bands as having low, middle, or high CFS expression. We mapped spontaneous gaps/breaks as well as in- duced CFSs in the genomes of two mouse strains (BALB/c and C57BL/6) and then compared the expression of CFSs between the mouse and the human genomes. Furthermore, we characterized at the molecular level several mouse CFSs that showed synteny to human CFSs. We also examined the DNA helix flexibility for 23 mapped human and mouse CFSs and large control regions, and searched for tissue-specific gene ex- pression of large genes that reside within CFSs and control regions. Results Cytogenetic mapping of mouse and human CFSs Figure 2. Frequencies of chromatin gaps (G) and double-strand breaks (DB) at different APC con- We performed a comprehensive cytoge- centrations in (B) BALB/c and (C) C57BL/6 mouse splenocytes. The y-axis shows the mean numbers of standard errors were ע G and DB per metaphase; for each strain and APC concentration, means netic analysis of CFSs in lymphocytes of calculated from counts in 125 metaphases (five mice). Statistically significant differences (Mann- the two mouse strains BALB/c and Whitney U-test, P < 0.05) between strains are indicated with asterisks (*). The numbers of induced G C57BL/6 in comparison to human lym- and DB are slightly higher in BALB/c compared to C57BL/6 cells. Genome Research 1223 www.genome.org Downloaded from genome.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Helmrich et al.
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