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PubMed1999

Universal DNA microarray method for multiplex detection of low abundance point mutations.

Cancers arise from the accumulation of multiple mutations in genes regulating cellular growth and differentiation. Identification of such mutations in numerous genes represents a significant challenge in genetic analysis, particularly when the majority of DNA in a tumor sample is from wild-type stroma. To overcome these difficulties, we have developed a new type of DNA microchip that combines polymerase chain reaction/ligase detection reaction (PCR/LDR) with "zip-code" hybridization. Suitably designed allele-specific LDR primers become covalently ligated to adjacent fluorescently labeled primers if and only if a mutation is present. The allele-specific LDR primers contain on their 5'-ends "zip-code complements" that are used to direct LDR products to specific zip-code addresses attached covalently to a three-dimensional gel-matrix array. Since zip-codes have no homology to either the target sequence or to other sequences in the genome, false signals due to mismatch hybridizations are not detected. The zip-code sequences remain constant and their complements can be appended to any set of LDR primers, making our zip-code arrays universal. Using the K- ras gene as a model system, multiplex PCR/LDR followed by hybridization to prototype 3x3 zip-code arrays correctly identified all mutations in tumor and cell line DNA. Mutations present at less than one per cent of the wild-type DNA level could be distinguished. Universal arrays may be used to rapidly detect low abundance mutations in any gene of interest.

Alleles↗
PubMed1992

APC mutations occur early during colorectal tumorigenesis.

Human tumorigenesis is associated with the accumulation of mutations both in oncogenes and in tumour suppressor genes. But in no common adult cancer have the mutations that are critical in the early stages of the tumorigenic process been defined. We have attempted to determine if mutations of the APC gene play such a role in human colorectal tumours, which evolve from small benign tumours (adenomas) to larger malignant tumours (carcinomas) over the course of several decades. Here we report that sequence analysis of 41 colorectal tumours revealed that the majority of colorectal carcinomas (60%) and adenomas (63%) contained a mutated APC gene. Furthermore, the APC gene met two criteria of importance for tumour initiation. First, mutations of this gene were found in the earliest tumours that could be analysed, including adenomas as small as 0.5 cm in diameter. Second, the frequency of such mutations remained constant as tumours progressed from benign to malignant stages. These data provide strong evidence that mutations of the APC gene play a major role in the early development of colorectal neoplasms.

Adenoma↗
PubMed2002

The p23 protein of citrus tristeza virus controls asymmetrical RNA accumulation.

Citrus tristeza virus (CTV), a member of the Closteroviridae, has a 19.3-kb positive-stranded RNA genome that is organized into 12 open reading frames (ORFs) with the 10 3' genes expressed via a nested set of nine or ten 3'-coterminal subgenomic mRNAs (sgRNAs). Relatively large amounts of negative-stranded RNAs complementary to both genomic and sgRNAs accumulate in infected cells. As is characteristic of RNA viruses, wild-type CTV produced more positive than negative strands, with the plus-to-minus ratios of genomic and sgRNAs estimated at 10 to 20:1 and 40 to 50:1, respectively. However, a mutant with all of the 3' genes deleted replicated efficiently, but produced plus to minus strands at a markedly decreased ratio of 1 to 2:1. Deletion analysis of 3'-end genes revealed that the p23 ORF was involved in asymmetric RNA accumulation. A mutation which caused a frameshift after the fifth codon resulted in nearly symmetrical RNA accumulation, suggesting that the p23 protein, not a cis-acting element within the p23 ORF, controls asymmetric accumulation of CTV RNAs. Further in-frame deletion mutations in the p23 ORF suggested that amino acid residues 46 to 180, which contained RNA-binding and zinc finger domains, were indispensable for asymmetrical RNA accumulation, while the N-terminal 5 to 45 and C-terminal 181 to 209 amino acid residues were not absolutely required. Mutation of conserved cysteine residues to alanines in the zinc finger domain resulted in loss of activity of the p23 protein, suggesting involvement of the zinc finger in asymmetric RNA accumulation. The absence of p23 gene function was manifested by substantial increases in accumulation of negative-stranded RNAs and only modest decreases in positive-stranded RNAs. Moreover, the substantial decrease in the accumulation of negative-stranded coat protein (CP) sgRNA in the presence of the functional p23 gene resulted in a 12- to 15-fold increase in the expression of the CP gene. Apparently the excess negative-stranded sgRNA reduces the availability of the corresponding positive-stranded sgRNA as a messenger. Thus, the p23 protein controls asymmetric accumulation of CTV RNAs by downregulating negative-stranded RNA accumulation and indirectly increases expression of 3' genes.

Amino Acid Sequence↗
PubMed2001

Correlation between p53 gene mutations and circulating antibodies in betel- and tobacco-consuming North Indian population.

Alterations in p53 tumour suppressor gene and its expression may be implicated in the pathogenesis of betel- and tobacco-related oral cancer. There is wide regional variation in betel- and tobacco-consuming habits in different parts of the Indian subcontinent. The purpose of this study was to determine the correlations between p53 gene mutations, protein accumulation and serum antibodies in oral precancer and cancer. We analysed 30 potentially malignant oral lesions (leukoplakia) and 30 oral squamous cell carcinomas (SCCs) from northern India because the betel quid-consuming habits are different from those prevalent in other regions of India. p53 mutations were analysed by polymerase chain reaction amplification of genomic DNA and direct sequencing, p53 protein accumulation by immunohistochemical analysis and circulating p53 antibodies by ELISA. p53 gene mutations, analysed within exons 5-9, were observed in five out of 30 (17%) potentially malignant oral lesions and seven out of 30 (23%) oral SCCs. All the mutations were base substitution mutations. Three missense and two nonsense mutations were observed in potentially malignant oral lesions, while six missense and one nonsense mutations were identified in oral SCCs. The probable hot spots for the mutations were identified at codons 126, 136 and 174, which have not been observed thus far. A good correlation was observed between p53 missense mutation, p53 antibodies and p53 protein accumulation in matched potentially malignant and malignant oral lesions. All the potentially malignant and cancerous lesions harbouring missense mutations showed accumulation of p53 protein and the majority of these patients showed circulating p53 antibodies suggesting that serological detection of p53 antibodies may serve as a surrogate marker for p53 alterations in oral lesions.

Adolescent↗
PubMed1998

Polygenic mutation in Drosophila melanogaster: genotype x environment interaction for spontaneous mutations affecting bristle number.

A highly inbred line of Drosophila melanogaster was subdivided into replicate sublines that were subsequently maintained independently with 10 pairs of parents per generation. The parents were randomly sampled for 19 'unselected' sublines and artificially selected for high or low abdominal or sternopleural bristle number for 12 'selected' sublines (with 3 replicate selection lines/trait/direction of selection). Divergence in mean bristle number among the unselected sublines, and response of the selected sublines to selection, are attributable to the accumulation of new mutations affecting bristle number. The input of mutational variance per generation, VM, can be estimated from the magnitude of response or divergence, assuming neutrality of mutations affecting the bristle traits. We reared unselected lines at generations 222 and 224, and selected lines at generations 182-184 of mutation accumulation at each of three temperatures (18 degrees C, 25 degrees C, 28 degrees C), and estimated the mutational variance common to all environments and the mutational variance from genotype x environment interaction. For sternopleural bristle number, the mutational interaction variance was 26% of the mutational variance common to all temperatures, and the interaction variance was due to temperature x line interaction. For abdominal bristle number, the mutational interaction variance was 142% of the mutational variance common to all temperatures, and the interaction variance was due to interactions of temperature x line, sex x line, and temperature x sex x line. It is possible that segregating variation for bristle number is maintained partly by genotype x environment interaction, but information on the fitness profiles of mutations affecting bristle number in each environment will be necessary to evaluate this hypothesis quantitatively.

Abdomen↗
PubMed1995

Microevolution of type 3 Sabin strain of poliovirus in cell cultures and its implications for oral poliovirus vaccine quality control.

Screening for sequence heterogeneities in Sabin Type 3 strains of attenuated poliovirus demonstrated mutations that consistently accumulate to significant levels following 10 passages in cultures of primary African green monkey kidney (AGMK) cells or continuous cultures of Vero cells. Fourteen newly identified mutations were quantified by mutant analysis by PCR and restriction enzyme cleavage in passages and in batches of commercial vaccines made in AGMK and Vero cells from the Sabin original (SO) seed virus and from a seed virus rederived by RNA plaque purification (RSO or "Pfizer" seed). Nine of the 14 mutations were reproducibly observed in more than one series of passages. Although 5 other mutations were observed in only one set of passages each, their content gradually increased to a high percentage, suggesting that all the mutations that we found accumulated consistently. SO-derived samples accumulated more mutations than did RSO-derived ones, and the number of mutations and the rates of their accumulation were higher in Vero than in AGMK cells. While the rates of accumulation of most mutations were higher when passaging was performed at 37 degrees, a U-->C transition at nucleotide 5832 occurred faster at 34 degrees, the temperature used for vaccine production. Analysis of Type 3 oral poliovirus vaccine (OPV) monopools made by six manufacturers found only 5 of these newly identified mutations in vaccine batches (nucleotides 3956, 4935, 5357, 5788, and 5832). Some of the mutations were found in trace amounts (less than 0.1%) while others were present at up to 1.8% levels. The pattern of these mutations was characteristic for the type of seed virus and the cell substrate but demonstrated no correlation with results of the monkey neurovirulence test. Therefore the only mutation occurring in Type 3 OPV which contributed to neurovirulence in monkeys was the previously described reversion at nucleotide 472. Quantitation of reversion at nucleotide 472 can be utilized for assessment of acceptability of vaccine lots, while other mutations can be used for monitoring the consistency of vaccine production.

Animals↗
PubMed2003

Radiation-induced DNA damage and delayed induced genomic instability.

Ionizing radiation induces genomic instability, which is transmitted over many generations after irradiation through the progeny of surviving cells. Induced genomic instability is manifested as the expression of the following delayed effects: delayed reproductive death or lethal mutation, chromosomal instability, and mutagenesis. Since induced genomic instability accumulates gene mutations (actually genomic instability is the process whereby gene mutation increases subtle difference) and gross chromosomal rearrangements, it has been thought to play a role in radiation-induced carcinogenesis. Radiation-induced genomic instability exerts its effects for prolonged periods of time, suggesting the presence of a mechanism by which the initial DNA damage in the surviving cells is memorized. Recent studies have shown that such memory transmission causes delayed DNA breakage, which in turn plays a role in the induction of delayed phenotypes. Although radiation-induced genomic instability has been studied for years, many questions remain to be answered. This review summarizes the current data on radiation-induced genomic instability. In particular, the mechanism(s) involved in the initiation and perpetuation of radiation-induced genomic instability, and a role of delayed activation of p53 protein are discussed.

Animals↗
PubMed2004

Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir.

Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC(50)) change in susceptibility to nelfinavir only. Other mutations increased IC(50) correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% +/- 22% to 22% +/- 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.

Cohort Studies↗
PubMed2002

[Advances in research for relationship between mitochondrial DNA and solid tumor].

Mitochondrial DNA (mtDNA) encodes the polypeptides required for oxidative phosphorylation and genesis of ATP. It has been though to be involved in carcinogenesis because of its high mutation rate and lacking effective repair mechanism in contrast to nuclear DNA. Since mtDNA lacks introns, it has been suggested that most mutations will occur in this coding sequence and subsequent accumulation of mutation may lead to tumor formation. Alteration in expression of mitochondrial DNA may be a general characteristic of cancer cells. The research on mtDNA such as the mitochondrial genome instability (mtGI) and the integration between the mtDNA and nuclear genome have, mainly in solid tumor, been reported recently, meanwhile it will be a critical topic in solid tumors. In this paper, we reviewed the advances in research for relationship among mitochondrial DNA mutation, abnormal expression, integration, and mtGI in solid tumors lately.

Adenosine Triphosphate↗
PubMed1996

Tolerance of single, but not multiple, amino acid replacements in antibody VH CDR 2: a means of minimizing B cell wastage from somatic hypermutation?

Mutations in the heavy chain complementarity determining region 2 (CDR2) of the phosphocholine-specific T15 Ab can have a dramatic effect on the ability of the Ab to bind Ag. A panel of multisite mutants that had lost detectable binding to phosphocholine-containing Ags was previously created by saturation mutagenesis of the CDR2 region of T15. Based on the predicted importance of amino acid changes represented in the multisite mutants, we have created single-site mutations, yielding a panel of Abs with which to test 17 of the 19 CDR2 residues. Of the 17 positions examined, only one, Arg52, is intolerant to change, yielding a nonbinder phenotype even with conservative amino acid replacement. Mutation at two other sites, Ala50 and Tyr55, can yield a nonbinder phenotype depending on the amino acid replacement. Single-site mutations of the remaining 14 positions allowed retention of binding ability. Thus, except for positions 50, 52, and 55, multiple mutations must be introduced into the CDR2 region to create a nonbinder phenotype. We provide a newly refined model of T15, illustrating the structure and the interactions of the CDR2 region. Our results imply that introduction of point mutations would not normally delete Ag-binding ability until two or more mutations had accumulated. This would minimize potentially harmful effects of somatic mutation on Ig V region genes and improve the chance of survival for an Ab such as T15, which in its unmutated form is already well suited to bind Ag.

Amino Acid Sequence↗
PubMed2004

Distinct mechanisms lead to HPRT gene mutations in leukemic cells.

Leukemias are considered malignant clonal disorders arising from the accumulation of mutations in hematopoietic cells; the majority of these mutations are thought to be acquired somatically. Measurement of mutation frequency (Mf) at the hypoxanthine phosphoribosyltransferase (HPRT) locus has been developed as a method for estimating genomic instability. We investigated the Mf in 16 leukemic cell lines to determine whether these cell lines showed evidence of genomic instability. Although some leukemic cell lines had markedly elevated Mfs, the Mfs at the HPRT locus in leukemic cell lines were not always higher than those of B-lymphoblastoid cell lines and T lymphocytes from normal individuals. We were able to identify the HPRT mutation for 159 of 160 individual HPRT mutants. The HPRT mutations were characterized at a molecular level and classified as either gross chromosomal rearrangements (GCRs) or point mutations, such as single-nucleotide substitutions, insertions, or deletions. With rare exceptions, individual leukemic cell lines showed either point mutations or GCR, but not both. Of note, all the cell lines that primarily showed point mutations are known to be defective in mismatch repair machinery.

Adolescent↗
PubMed2002

Mutations of the BRAF gene in human cancer.

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

3T3 Cells↗
PubMed2002

P53 mutation as a source of aberrant beta-catenin accumulation in cancer cells.

beta-catenin is involved in both cell-cell interactions and wnt pathway-dependent cell fate determination through its interactions with E-cadherin and TCF/LEF transcription factors, respectively. Cytoplasmic/nuclear levels of beta-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of beta-catenin through Axin1- and APC-dependent phosphorylation by CKI and GSK-3beta. Deregulation of beta-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of beta-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (beta-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display beta-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant beta-catenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type beta-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and beta-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of beta-catenin in cancer cells.

Cytoskeletal Proteins↗
PubMed1986

[The need for protein synthesis in UV-irradiated Escherichia coli cells for fixation of induced Str mutations].

The kinetics of accumulation of fixed Str mutations was determined during incubation in nutritional medium of Escherichia coli WP2 irradiated with 6.8 J/m2 either at log growth phase or after completion of DNA replication. Those Str mutations which lost ability for photoreactivation (fixation I) or susceptibility to antimutagenic activity of mfd-type (fixation II) were considered as fixed mutations. It was shown that both fixations occurred synchronously, starting in about 10 min after irradiation and being over in 40-50 min. In cells irradiated after completion of replication, fixation depended on protein synthesis de novo: chloramphenicol added to irradiated culture blocked fixation. An attempt to study the effect of chloramphenicol on fixation in a culture irradiated at the log phase failed, because of high lethal action of the antibiotic on such cells. Fixation could proceed in the presence of acriflavine. Possible mechanisms for fixation of Str mutations are discussed in connection with the fact of its dependence on protein synthesis.

Bacterial Proteins↗
PubMed1984

Vesicular stomatitis virus mutants resistant to defective-interfering particles accumulate stable 5'-terminal and fewer 3'-terminal mutations in a stepwise manner.

We have studied the evolution of sequences which include the RNA polymerase binding sites at the 5' and 3' termini of vesicular stomatitis virus mutants (Sdi-) resistant to defective-interfering particles. We observed a striking stepwise accumulation of stable base substitutions within the area of replication initiation at the 5'-terminal 54 nucleotides of Sdi- mutants isolated at intervals from persistent infections and undiluted lytic passage series. Fewer mutations accumulated in the region of transcription initiation at the 3' end and in those portions of the N and L protein coding cistrons examined. The termini changes are not strictly required to obtain the Sdi- phenotype. However, it is possible that they represent stepwise compensatory changes to accommodate Sdi- mutations affecting viral replication or encapsidation gene products or both. These results have important implications for RNA virus genome evolution.

Base Sequence↗
PubMed1996

Curable and non-curable malignancies: lessons from paediatric cancer.

The tremendous progress achieved in understanding the molecular basis of cancer, was unfortunately not followed by a mutual improvement in the morbidity and mortality of adult cancer. In contrast, the success rate achieved in paediatric oncology has increased significantly during the past 30 years, and more than two-thirds of the children with cancer can now be cured. p53 has been shown to have a central role on apoptosis in various cells. As apoptosis is a final common pathway for much of our anti cancer therapy, resistance to apoptosis due to a normal activity of p53 is an important mechanism of tumor resistance and treatment failure. Contrary to the findings in most adult tumors, where about 50% of the tumors lack p53 activity, the rate of p53 mutations in childhood cancer is surprisingly low. This may be the key to the much better prognosis of children with cancer. In most adult tumors, multiple genetic events, between five and seven, are usually involved. The oncogenes involved in such tumors usually represent those located upstream of the nuclear transcription factors. In most paediatric tumors, in contrast, the initiating event is the activation of nuclear transcription factors secondary to chromosomal translocations. It can be speculated that multiple events activating various components of the signal transduction machinery are needed for tumorigenesis, and hence the evolution and progression of such tumors is slow. Moreover, if the malignant cell has to accumulate multiple mutations, the chances of crippling the apoptotic mechanism are higher. Genomic instability evidenced by microsatellite variation has been found in colon, pancreas, breast, liver and ovarian adult tumors, and not in paediatric tumors. As multiple somatic mutations are needed for the initiation and progression of the common adult malignancies, inherent genomic instability can dispose to accumulation of multiple mutations. All these molecular interactions are discussed with relevance to the difference between non-curable, mostly adult tumors, and curable, mostly paediatric tumors.

Antineoplastic Agents↗
PubMed1975

Strain of Escherichia coli with a temperature-sensitive mutation affecting ribosomal ribonucleic acid accumulation.

A mutant of Escherichia coli has been isolated that has a temperature-sensitive mutation that results in specific loss of ribosomal ribonucleic acid (RNA) synthesis and some reduction in messenger RNA synthesis. When the strain was grown in glucose medium at a restrictive temperature, RNA accumulation ceased, but both messenger RNA and protein synthesis continued for an extended time. Because carbon metabolism was slowed drastically when strain AA-157 was placed at the restrictive temperature, this phenotype can be compared with carbon depletion conditions present during diauxic lag. However, the phenotype of mutant AA-157 differs from shift-down conditions in that guanosine-3',5'-tetraphosphate levels are unaffected; therefore, a different site is affected. This mutant strain (AA-157) thus shows many characteristics similar to an aldolase mutant previously reported (Böck and Neidhardt, 1966). However, the mutation occurred in a different position on the E. coli genetic map, and furthermore, aldolase was not temperature sensitive in strain AA-157. In this paper we present a study of macromolecular biosynthesis in this mutant.

Amino Acids↗
PubMed1977

Spontaneous and ethyl methanesulfonate-induced mutations controlling viability in Drosophila melanogaster. II. Homozygous effect of polygenic mutations.

Polygenic mutations affecting viability were accumulated on the second chromosome of Drosophila melanogaster by treating flies with EMS in successive generations. The treated chromosomes were later made homozygous and tested for their effects on viability by comparison of the frequency of such homozygotes with that of other genotypes in the same culture. The treated wild-type chromosomes were kept heterozygous in Pm/+ males by mating individual males in successive generations to Cy/Pm females. The number of generations of accumulation was 1 to 30 generations, depending on the concentration of EMS. A similar experiment for spontaneous polygenic mutations was also conducted by accumulating mutations for 40 generations. The lower limit of the spontaneous mutation rate of viability polygenes is estimated to be 0.06 per second chromosome per generation, which is about 12 times as high as the spontaneous recessive lethal mutation rate, 0.005. EMS-induced polygenic mutations increase linearly with the number of treated generations and with the concentration of EMS. The minimum mutation rate of viability polygenes is about 0.017 per 10(-4)m, which is only slightly larger than the lethal rate of 0.013 per 10(-4) m. The maximum estimate of the viability reduction of a single mutant is about 6 to 10 percent of the normal viability. The data are consistent with a constant average effect per mutant at all concentrations, but this is about three times as high as that for spontaneous mutants. It is obvious that one can obtain only a lower limit for the mutation rate, since some mutants may have effects so near to zero that they cannot be detected. The possibility of measuring something other than the lower limit is discussed. The ratio of the load due to detrimental mutants to that caused by lethals, the D/L ratio, is about 0.2 to 0.3 for EMS-induced mutants, as compared to about 0.5 for spontaneous mutants. This is to be expected if EMS treatment produces a large fraction of small deletions and other chromosome rearrangements which are more likely to be lethal.

Animals↗