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PubMed2005

Recql5 and Blm RecQ DNA helicases have nonredundant roles in suppressing crossovers.

In eukaryotes, crossovers in mitotic cells can have deleterious consequences and therefore must be suppressed. Mutations in BLM give rise to Bloom syndrome, a disease that is characterized by an elevated rate of crossovers and increased cancer susceptibility. However, simple eukaryotes such as Saccharomyces cerevisiae have multiple pathways for suppressing crossovers, suggesting that mammals also have multiple pathways for controlling crossovers in their mitotic cells. We show here that in mouse embryonic stem (ES) cells, mutations in either the Bloom syndrome homologue (Blm) or the Recql5 genes result in a significant increase in the frequency of sister chromatid exchange (SCE), whereas deleting both Blm and Recql5 lead to an even higher frequency of SCE. These data indicate that Blm and Recql5 have nonredundant roles in suppressing crossovers in mouse ES cells. Furthermore, we show that mouse embryonic fibroblasts derived from Recql5 knockout mice also exhibit a significantly increased frequency of SCE compared with the corresponding wild-type control. Thus, this study identifies a previously unknown Recql5-dependent, Blm-independent pathway for suppressing crossovers during mitosis in mice.

Adenosine Triphosphatases↗

PubMed1990

Underestimation of treatment effect in crossover trials.

In crossover trials each subject serves as his own control. For the study of cardiovascular diseases such as hypertension and angina pectoria, properly designed crossover studies are preferred to parallel studies. There is a considerable between-subject variability of symptoms in some of these conditions. Bias due to this is eliminated by the use of a crossover design. However, a problem is the so-called treatment-by-period interaction. The present study analyzes the potential influences of this on the outcome of the trial. Physical carryover effect, defined as a physical effect of the first treatment period carrying on into the second, tends to minimize differences between two consecutive treatment periods. So does the frustrating experience of an inactive agent in the first treatment period. Outside influences such as the change of the seasons may affect lengthy crossover trials in a similar way. The author concludes that the treatment effect in a crossover trial tends to be underestimated. The current concept that reports of clinical trials are generally biased toward an exaggeration of treatment effects does not seem to apply to crossover trials.

Bias↗

PubMed2004

Sensitivity analysis of causal inference in a clinical trial subject to crossover.

In many clinical trials it is possible for some subjects to cross over between treatment arms. One can evaluate the effect of crossover by modeling it as a missing-data problem, where for subjects who cross over, one treats the unobserved value of the outcome in the original randomization arm as the missing data. The as-treated analysis is invalid if the crossover is nonignorable, in the sense that the crossovers represent a nonrandom sample of the randomized subjects. A recent area of general interest is the development of methods for measuring the sensitivity of inferences to nonignorability in the missing-data mechanism; one such approach is that of Troxel et al. In this paper we apply their method to the problem of measuring sensitivity to nonignorable crossover in randomized trials, extending it to the case where the crossover mechanism may differ between arms. Our method allows us to identify circumstances under which the as-treated analysis may be more or less sensitive to nonignorable crossover. We illustrate it with the example of a randomized clinical trial (RCT) in multiple sclerosis and a study of the effect of military service on income.

Causality↗

PubMed2004

Does crossover interference count in Saccharomyces cerevisiae?

We previously proposed a "counting model" for meiotic crossover interference, in which double-strand breaks occur independently and a fixed number of noncrossovers occur between neighboring crossovers. Whereas in some organisms (group I) this simple model alone describes the crossover distribution, in other organisms (group II) an additional assumption--that some crossovers lack interference--improves the fit. Other differences exist between the groups: Group II needs double-strand breaks and some repair functions to achieve synapsis, while repair in group I generally occurs after synapsis is achieved; group II, but not group I, has recombination proteins Dmc1, Mnd1, and Hop2. Here we report experiments in msh4 mutants that are designed to test predictions of the revised model in a group II organism. Further, we interpret these experiments, the above-mentioned differences between group I and II meiosis, and other data to yield the following proposal: Group II organisms use the repair of leptotene breaks to promote synapsis by generating double-Holliday-junction intermediates that lock homologs together (pairing pathway). The possible crossover or noncrossover resolution products of these structures lack interference. In contrast, for both group I and group II, repair during pachytene (disjunction pathway) is associated with interference and generates only two resolution types, whose structures suggest that the Holliday junctions of the repair intermediates are unligated. A crossover arises when such an intermediate is stabilized by a protein that prevents its default resolution to a noncrossover. The protein-binding pattern required for interference depends on clustering of sites that have received, or are normally about to receive, meiotic double-strand breaks.

Cell Cycle Proteins↗

PubMed2004

Competing crossover pathways act during meiosis in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae the MSH4-MSH5, MLH1-MLH3, and MUS81-MMS4 complexes act to promote crossing over during meiosis. MSH4-MSH5, but not MUS81-MMS4, promotes crossovers that display interference. A role for MLH1-MLH3 in crossover control is less clear partly because mlh1Delta mutants retain crossover interference yet display a decrease in crossing over that is only slightly less severe than that seen in msh4Delta and msh5Delta mutants. We analyzed the effects of msh5Delta, mlh1Delta, and mms4Delta single, double, and triple mutants on meiotic crossing over at four consecutive genetic intervals on chromosome XV using newly developed computer software. mlh1Delta mms4Delta double mutants displayed the largest decrease in crossing over (13- to 15-fold) of all mutant combinations, yet these strains displayed relatively high spore viability (42%). In contrast, msh5Delta mms4Delta and msh5Delta mms4Delta mlh1Delta mutants displayed smaller decreases in crossing over (4- to 6-fold); however, spore viability (18-19%) was lower in these strains than in mlh1Delta mms4Delta strains. These data suggest that meiotic crossing over can occur in yeast through three distinct crossover pathways. In one pathway, MUS81-MMS4 promotes interference-independent crossing over; in a second pathway, both MSH4-MSH5 and MLH1-MLH3 promote interference-dependent crossovers. A third pathway, which appears to be repressed by MSH4-MSH5, yields deleterious crossovers.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Cost-efficient higher-order crossover designs in comparative bioavailability studies.

BACKGROUND AND OBJECTIVE: Cost is an extremely important factor to consider when planning drug clinical trials. Higher-order crossover designs have recently drawn considerable attention in comparative bioavailability studies because of their desirable statistical properties. In this paper, we compared the cost efficiency of five commonly used higher-order crossover designs under certain cost function for comparative bioavailability studies. METHODS: Multivariate normal data were simulated under scenarios of a wide range of variability and correlations (coefficient of variation = 10-40%; correlation coefficient rho = 0.2-0.8). Monte Carlo simulations and mixed-effects models were carried out to obtain empirical sample sizes for each design using Schuirmann's two-one sided test procedure, under an 80% power and a 5% significance level, based on the US FDA bioequivalence criteria (80-125%). The five crossover designs studied were the two-period four-sequence (D2 x 4), the three-period two-sequence (D3 x 2), the three-period four-sequence (D3 x 4), the four-period two-sequence (D4 x 2), and the four-period four-sequence (D4 x 4). Costs for each design were then determined by a cost function, which takes into account costs for recruiting and screening, costs associated with period, and the overheads incurred for multiple sequences. Comparison of the costs for the above-mentioned designs was made under different scenarios. RESULTS: There was no single design uniformly dominating the others in terms of cost efficiency for comparative bioavailability studies. The designs D3 x 2 and D4 x 4 (especially the former) have the best overall performance in terms of cost efficiency for comparative bioavailability studies. They dominated the other designs under most of the scenarios. The design D2 x 4 showed the worst performance among the five crossover designs. CONCLUSIONS: A D3 x 2, and D4 x 2 crossover designs are recommended to achieve cost efficiency with a given power. The D2 x 4 crossover design is not recommended in general for comparative bioavailability studies.

Biological Availability↗

PubMed2000

The racial crossover in comorbidity, disability, and mortality.

This study analyzed one respondent per household who was age 70 or more at the time of the household's inclusion in Wave 1 (1993-1994) and whose survival status was determinable at Wave 2 (1995-1996) of the Survey on Asset and Health Dynamics Among the Oldest Old (AHEAD Survey). At age 76 at Wave 1, there was a racial crossover in the cumulative number of six potentially fatal diagnoses (chronic lung disease, cancer, heart disease, hypertension, diabetes, and stroke) from a higher cumulative average number for blacks to a higher average number for whites. Also, there was a racial crossover at age 86 in the cumulative average number of disabilities in the Advanced Activities of Daily Living (AADLs), from a higher average for blacks to a higher average for whites. Between Waves 1 and 2, there was a racial crossover in the odds of mortality from higher odds for blacks to higher odds for whites; this occurred at about age 81. The results are consistent with the interpretation that the racial crossover in comorbidity (but not the crossover in AADL disability) propelled the racial crossover in mortality.

Activities of Daily Living↗

PubMed1997

Case-crossover and case-time-control designs as alternatives in pharmacoepidemiologic research.

Standard cohort and case-control designs are suited to the study of cumulative effects of chronic exposures, but they are prone to confounding by indication. Case-crossover and case-time-control studies are especially useful for studying intermittent exposures with transient effects, and are less susceptible to confounding by indication. Each design has its strengths and weaknesses. Despite the increasing availability of automated databases, cohort studies are usually time consuming and expensive, and therefore not preferred for time-critical decisions. In case-control studies, the selection of appropriate controls can be difficult and time consuming, and sometimes impractical when the exposure is rare. Case-crossover studies use the exposure history of each case as his or her own control to examine the effect of transient exposures on acute events. It further allows to study the time relationship of immediate effects to the exposure. This design eliminates between-person confounding by constant characteristics, including chronic indications. Because exposure data for the case and control periods are provided by the same person, the problems of differential recall may be reduced in many but not all case-crossover studies. Bias can result from temporal changes in prescribing or within-person confounding, including transient indication or changes in disease severity. The case-time-control design is an elaboration of the case-crossover design, which uses exposure history data from a traditional control group to estimate and adjust for the bias from temporal changes in prescribing. This paper will present a structured decision table of when to use which design in pharmacoepidemiologic research. In conclusion, case-crossover and case-time-control studies are the designs of choice when separating acute effects from chronic effects of transient exposures and if confounding by indication is an outstanding problem.

Journal Article↗

PubMed2006

Fine-scale crossover rate heterogeneity in Drosophila pseudoobscura.

Broad-scale differences in crossover rate across the genome have been characterized in most genomes studied. Fine-scale differences, however, have only been examined in a few taxa, such as Arabidopsis, yeast, humans, and mice. No prior studies have directly looked for fine-scale recombination rate heterogeneity in Drosophila. We produced 370 Drosophila pseudoobscura containing a crossover event within the 2-megabase (MB) region between the genes yellow and white. We then examined 19 intervals within this region and determined where the crossovers occurred. We found that recombination events occur nonrandomly on a small scale and that mild "hotspots" of a few kilobases exist in Drosophila. Among the regions studied, recombination rates varied from 1.4 to 52 cM/MB. We also observed a trend toward high codon bias in regions of high recombination. Finally, we identified a significantly positive correlation between recombination rate and simple repeats, as well as the motif CACAC. These sequence features may contribute to broad-scale variation in crossover rate and, thus, shed light on features associated with crossover rate heterogeneity at a genome-wide scale.

Animals↗

PubMed2005

Homeopathic treatment of children with attention deficit hyperactivity disorder: a randomised, double blind, placebo controlled crossover trial.

UNLABELLED: An increasing number of parents turn to homeopathy for treatment of their hyperactive child. Two publications, a randomised, partially blinded trial and a clinical observation study, conclude that homeopathy has positive effects in patients with attention deficit hyperactivity disorder (ADHD). The aim of this study was to obtain scientific evidence of the effectiveness of homeopathy in ADHD. A total of 83 children aged 6-16 years, with ADHD diagnosed using the Diagnostic and Statistical Manual of Mental Disorders-IV criteria, were recruited. Prior to the randomised, double blind, placebo controlled crossover study, they were treated with individually prescribed homeopathic medications. 62 patients, who achieved an improvement of 50% in the Conners' Global Index (CGI), participated in the trial. Thirteen patients did not fulfill this eligibility criterion (CGI). The responders were split into two groups and received either verum for 6 weeks followed by placebo for 6 weeks (arm A), or vice-versa (arm B). At the beginning of the trial and after each crossover period, parents reported the CGI and patients underwent neuropsychological testing. The CGI rating was evaluated again at the end of each crossover period and twice in long-term follow-up. At entry to the crossover trial, cognitive performance such as visual global perception, impulsivity and divided attention, had improved significantly under open label treatment (P<0.0001). During the crossover trial, CGI parent-ratings were significantly lower under verum (average 1.67 points) than under placebo (P =0.0479). Long-term CGI improvement reached 12 points (63%, P <0.0001). CONCLUSION: The trial suggests scientific evidence of the effectiveness of homeopathy in the treatment of attention deficit hyperactivity disorder, particularly in the areas of behavioural and cognitive functions.

Adolescent↗

PubMed1989

Energy of stabilization of the right-handed beta alpha beta crossover in proteins.

An explanation in terms of conformational energies is provided for the observed nearly exclusive preference of the beta alpha beta structure for forming a right-handed, rather than a left-handed, crossover connection. Conformational energy computations have been carried out on a model beta alpha beta structure, consisting of two six-residue Val beta-strands and of a 12-residue Ala alpha-helix, connected by two flexible four-residue Ala links to the strands. The energy of the most favorable right-handed crossover is 15.51 kcal/mol lower than that of the corresponding left-handed cross-over. The right-handed crossover is a strain-free structure. Its energy of stabilization arises largely from the interactions of the two beta-strands with one another and with the alpha-helix. On the other hand, the left-handed crossover is either disrupted after energy minimization or it remains conformationally strained, as indicated by an energetically unfavorable left twisting of the beta-sheet and by the presence of high-energy local residue conformations. In the energetically most favorable right-handed crossover, the right twisting of the beta-sheet and its manner of interacting with the alpha-helix are identical with those computed earlier for isolated beta-sheets and for packed alpha/beta structures. This result supports a proposed principle that it is possible to account for the main features of frequently occurring structural arrangements in globular proteins in terms of the properties of their component structural elements.

Energy Metabolism↗

PubMed1984

Recombination in adenovirus: analysis of crossover sites in intertypic overlap recombinants.

Overlap recombination has been used as a means of generating intertypic recombinants with crossover sites located within a defined region of the adenovirus genome. Using terminal DNA fragments of adenovirus type 2 and type 5 that overlap within the vicinity of the hexon coding region (51.6-59.7 map units), two different crosses could be studied; in one the overlap entirely encompasses the hexon and there are homologous regions at either side of the overlap where recombination is expected, and in the other only one side of the overlap is capable of sustaining recombination. The overall distribution of crossover sites within the overlap has been determined by restriction endonuclease mapping, and analysed in terms of the extent of homology between Ad2 and Ad5 in this region as defined by the DNA sequences (R. Kinloch, N. Mackay, and V. Mautner (1984). J. Biol. Chem., 259, 6431-6436; G. Akusjärvi, P. Aleström, M. Pettersson, M. Lager, H. Jörnvall, and U. Pettersson (1984). Submitted). Crossovers are found only in regions of relatively high DNA homology, as previously shown for intertypic recombination between temperature-sensitive viruses (M. E. G. Boursnell and V. Mautner (1981). Virology 112, 198-209). The presence of a free DNA end within the heterologous zone is insufficient to overcome the barrier to recombination. In crosses where recombination is confined to a relatively small homologous zone (45.9-53.0 mu) there is no special distribution of crossovers within the interval; no "hot spot" is discernible at the free DNA end, suggesting that a free DNA end is not especially recombinogenic, nor at the junction between the homologous and heterologous zones, suggesting that branch migration up to the heterology does not always occur. A cross designed to furnish evidence for gene conversion gave rise to a "conventional" recombinant with a crossover located within a 21-nucleotide tract of homology.

Adenoviruses, Human↗

PubMed2006

The meiosis-specific zip4 protein regulates crossover distribution by promoting synaptonemal complex formation together with zip2.

We have characterized Zip4 (a.k.a. Spo22), a meiosis-specific protein essential for chromosome synapsis in budding yeast. In the absence of Zip4, the synaptonemal complex protein Zip1 fails to polymerize along chromosomes. Zip2 and Zip3 are previously characterized components of the synapsis initiation complex. Zip4 forms a functional unit with Zip2 that is distinct from Zip3. Zip2 and Zip4 are mutually dependent for their chromosomal localization; in polycomplexes, the pattern of Zip2/Zip4 localization is distinct from that of Zip3. Crossing-over is decreased in the zip4 mutant (as in zip1, zip2, and zip3); the remaining crossovers are largely dependent on a parallel pathway utilizing Mms4. zip4 displays a novel phenotype: negative crossover interference, meaning that crossovers tend to cluster. This clustering depends on Zip1. Our results suggest an interaction between crossover pathways such that a protein (Zip1) acting in one pathway influences the distribution of crossovers promoted by a parallel (Mms4-dependent) pathway.

Chromosomal Proteins, Non-Histone↗

PubMed2003

The flexibility of DNA double crossover molecules.

Double crossover molecules are DNA structures containing two Holliday junctions connected by two double helical arms. There are several types of double crossover molecules, differentiated by the relative orientations of their helix axes, parallel or antiparallel, and by the number of double helical half-turns (even or odd) between the two crossovers. They are found as intermediates in meiosis and they have been used extensively in structural DNA nanotechnology for the construction of one-dimensional and two-dimensional arrays and in a DNA nanomechanical device. Whereas the parallel double helical molecules are usually not well behaved, we have focused on the antiparallel molecules; antiparallel molecules with an even number of half-turns between crossovers (termed DAE molecules) produce a reporter strand when ligated, facilitating their characterization in a ligation cyclization assay. Hence, we have estimated the flexibility of antiparallel DNA double crossover molecules by means of ligation-closure experiments. We are able to show that these molecules are approximately twice as rigid as linear duplex DNA.

Amino Acid Sequence↗

PubMed1995

Effectiveness of crossover transseptal vasoepididymostomy in treating complex obstructive azoospermia.

OBJECTIVE: To review the indications, surgical technique, and results of crossover transseptal vasoepididymostomies for treatment of complex obstructive azoospermia and oligospermia. DESIGN: Retrospective review of our experience with crossover transseptal end-to-side vasoepididymostomies in 10 men. INTERVENTIONS: Ten men underwent crossover transseptal end-to-side vasoepididymostomies. Nine men had primary and one had secondary infertility. Seven men were azoospermic, and the remaining 3 had severe oligospermia (sperm density < 1 x 10(6)/mL). All had a combination of irreparable ipsilateral ductal obstruction or agenesis with a normal testis and a poorly functional or absent contralateral testis. Contralateral testicular atrophy was associated with a prior hernia repair in 3 men, varicocele-induced atrophy in 2, and severe orchitis in 2. Cryptorchidism, testicular torsion, and one unknown cause were reported for three others. Congenital absence of the vas deferens caused the ipsilateral ductal pathology in 5 men. Three men had a vas injury from pediatric inguinal surgery, and 2 had an idiopathic vas obstruction. RESULTS: Twelve microsurgical crossover transseptal vasoepididymostomies were performed (2 men had repeat procedures). Anastomosis was performed to the caput in five men, the corpus in two, and the cauda in three men. Eight of nine men followed for 6 months or more had sperm in their ejaculate. Two of seven couples have established pregnancies. Total sperm counts ranged from 18 to 201 x 10(6) (mean, 98.1 x 10(6)) with motility of 5% to 37% (mean, 13%). Men with congenital absence of the vas deferens had significantly lower postoperative total sperm counts than men with all other causes of ductal pathology: 37.8 x 10(6) versus 135 x 10(6). No other characteristics (type of infertility, preop semen analysis, cause of testicular pathology, site of epididymal anastomosis) were useful predictors of postoperative sperm counts. CONCLUSIONS: If there is a solitary functioning testis with irreparable excurrent ductal obstruction or agenesis, a crossover transseptal vasoepididymostomy can restore patency in most men.

Adult↗

PubMed1996

Empirical evidence of bias in infertility research: overestimation of treatment effect in crossover trials using pregnancy as the outcome measure.

OBJECTIVE: To determine whether crossover trials with simple pooling of data over different study periods leads to a different estimate of treatment effect compared with parallel group trials in infertility research using pregnancy as the outcome measure. DESIGN: An observational study using nine overviews that included trials with both crossover and parallel group designs. These overviews comprised 17 crossover and 17 parallel group trials. In total, there were 5,291 outcomes including 775 pregnancies. The association between study design and treatment effect estimate was analyzed using multiple logistic regression, controlling for differences in the therapeutic interventions and variations in the methodological quality of the trials. SETTING: Infertile patients in an academic research environment. PATIENTS: Infertile patients undergoing treatment efficacy evaluation in controlled trials. INTERVENTIONS: Random allocation to a variety of treatments including clomiphene citrate, hCG, IUI, tamoxifen, and bromocriptine. MAIN OUTCOME MEASURE: Estimate of bias between study designs, based on the interaction of study design and treatment in the logistic regression model. RESULTS: Crossover trials produced a larger average estimate of treatment effect compared with trials with a parallel group design, overestimating the odds ratio by 74% (95% confidence interval, 2% to 197%). CONCLUSION: The use of a crossover design for evaluating infertility treatments with outcomes that prevent patients from completing later phases of the trial should be avoided because it leads to exaggerated estimates of treatment effect and may result in erroneous inferences and clinical decisions. Furthermore, the type of study design should be taken into account when assessing the methodological quality of therapy trials in infertility.

Bias↗

PubMed2000

No correlation between germline mutation at repeat DNA and meiotic crossover in male mice exposed to X-rays or cisplatin.

To test the hypothesis that mouse germline expanded simple tandem repeat (ESTR) mutations are associated with recombination events during spermatogenesis, crossover frequencies were compared with germline mutation rates at ESTR loci in male mice acutely exposed to 1Gy of X-rays or to 10mg/kg of the anticancer drug cisplatin. Ionising radiation resulted in a highly significant 2.7-3.6-fold increase in ESTR mutation rate in males mated 4, 5 and 6 weeks after exposure, but not 3 weeks after exposure. In contrast, irradiation had no effect on meiotic crossover frequencies assayed on six chromosomes using 25 polymorphic microsatellite loci spaced at approximately 20cM intervals and covering 421cM of the mouse genome. Paternal exposure to cisplatin did not affect either ESTR mutation rates or crossover frequencies, despite a report that cisplatin can increase crossover frequency in mice. Correlation analysis did not reveal any associations between the paternal ESTR mutation rate and crossover frequency in unexposed males and in those exposed to X-rays or cisplatin. This study does not, therefore, support the hypothesis that mutation induction at mouse ESTR loci results from a general genome-wide increase in meiotic recombination rate.

Animals↗

PubMed2001

Differential timing and control of noncrossover and crossover recombination during meiosis.

Unitary models of meiotic recombination postulate that a central intermediate containing Holliday junctions is resolved to generate either noncrossover or crossover recombinants, both of which contain heteroduplex DNA. Contrary to this expectation, we find that during meiosis in Saccharomyces cerevisiae, noncrossover heteroduplex products are formed at the same time as Holliday junction intermediates. Crossovers appear later, when these intermediates are resolved. Furthermore, noncrossover and crossover recombination are regulated differently. ndt80 mutants arrest in meiosis with unresolved Holliday junction intermediates and very few crossovers, while noncrossover heteroduplex products are formed at normal levels and with normal timing. These results suggest that crossovers are formed by resolution of Holliday junction intermediates, while most noncrossover recombinants arise by a different, earlier pathway.

Base Sequence↗