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1.
Regional biases in substitution pattern are likely to be responsible for the large-scale variation in base composition observed in vertebrate genomes. However, the evolutionary forces responsible for these biases are still not clearly defined. In order to study the processes of mutation and fixation across the entire human genome, we analyzed patterns of substitution in Alu repeats since their insertion. We also studied patterns of human polymorphism within the repeats. There is a highly significant effect of recombination rate on the pattern of substitution, whereas no such effect is seen on the pattern of polymorphism. These results suggest that regional biases in substitution are caused by biased gene conversion, a process that increases the probability of fixation of mutations that increase GC content. Furthermore, the strongest correlate of substitution patterns is found to be male recombination rates rather than female or sex-averaged recombination rates. This indicates that in addition to sexual dimorphism in recombination rates, the sexes also differ in the relative rates of crossover and gene conversion.  相似文献   

2.
Regional variations of DNA GC content are observed in species as different as S.cerevisiae and humans. In vertebrates and yeast they are correlated with replication timing; late replicating chromosomal regions are more AT-rich than early replicating regions. We show here that gene composition in E.coli also has long range variations which are similarly correlated with replication timing. We suggest that the enrichment in AT base pairs in late replicating DNA reflects differences in DNA repair modes. These sequences, which are in single copy for a greater part of the cell cycle than origin-linked genes, have less opportunity to engage in repair via homologous recombination and therefore may resort more often to translesion synthesis involving the misincorporation of adenine opposite modified nucleotides.  相似文献   

3.
In human genetics, two loci are declared to be linked when the lod score at the maximum likelihood recombination fraction theta exceeds the threshold of 3.0. Since recombination rates differ between the sexes, one can alternatively detect linkage by estimating separate recombination rates, theta m and theta f, for male and female meiosis and examining the corresponding sex-specific lod scores. The question arises: In order to maintain the same chance of falsely declaring linkage, what is the correct threshold for declaring linkage when sex-specific lod scores are used? We show here that the appropriate threshold is about 3.5. If the restriction that theta f greater than theta m is added, the appropriate threshold falls to about 3.25. We also discuss the relative efficiency of detecting linkage by using sex-specific and sex-averaged lod scores.  相似文献   

4.
The mammalian genome is organized as a mosaic of isochores, stretches of DNA with a distinct sequence composition. Isochores form the basis of the chromosomal banding pattern, which is tightly correlated with a number of structural and functional features. We have recently demonstrated that the transition from a GC-poor isochore to a GC-rich one in the NF1 gene region occurs within 5 kb and demarcates genomic regions with high and low recombination frequency. We now report that the same transition zone separates early replicating from late replicating chromatin on the molecular level. At the isochore transition the replication fork is stalled in mid-S phase and can be visualized by fiber-FISH techniques as a Y-shaped structure. The switch in GC content and in replication timing is conserved between human and mouse, emphasizing the importance of the transition zones as landmarks of chromosome organization and function.  相似文献   

5.
Several reports from mammals indicate that an increase in the mutation rate in late-replicating regions may, in part, be responsible for the observed genomic heterogeneity in neutral substitution rates and levels of diversity, although the mechanisms for this remain poorly understood. Recent evidence also suggests that late replication is associated with high mutability in yeast. This then raises the question as to whether a similar effect is operating across all eukaryotes. Limited evidence from one chromosome arm in Drosophila melanogaster suggests the opposite pattern, with regions overlapping early-firing origins showing increased levels of diversity and divergence. Given the availability of genome-wide replication timing profiles for D. melanogaster, we now return to this issue. Consistent with what is seen in other taxa, we find that divergence at synonymous sites in exon cores, as well as divergence at putatively unconstrained intronic sites, is elevated in late-replicating regions. Analysis of genes with low codon usage bias suggests a ~30% difference in mutation rate between the earliest and the latest replicating sequence. Intronic sequence suggests a more modest difference. We additionally show that an increase in diversity in late-replicating sequences is not owing to replication timing covarying with the local recombination rate. If anything, the effects of recombination mask the impact of replication timing. We conclude that, contrary to prior reports and consistent with what is seen in mammals and yeast, there is indeed a relationship between rates of nucleotide divergence and diversity and replication timing that is consistent with an increase in the mutation rate during late S-phase in D. melanogaster. It is therefore plausible that such an effect might be common among eukaryotes. The result may have implications for the inference of positive selection.  相似文献   

6.
We examined the effects of recombination on the molecular evolution of noncoding regions in pseudoautosomal regions (PARs) and recombination hotspots in hominoids. The PAR-linked regions analyzed had on average longer branch lengths than those of the recombination hotspots. Moreover, contrary to previous observations, we found no correlation between recombination rate and silent site divergence in our data set and little change in the GC content during recent hominoid evolution. This suggests that the current rate of recombination is not a good indicator of the past rates of recombination for these highly recombining regions. Furthermore, human recombination hotspots show increased AT to GC substitutions in the human lineage, while no such pattern is detected for PAR-linked regions. Together, these observations suggest that recombination hotspots in hominoids are transient in the evolutionary time-scale. Interestingly, the 16p13.3 recombination hotspot locus violates a local molecular clock, though the locus appears to be noncoding and should evolve neutrally. We hypothesize that sudden changes in recombination rate have caused the changes in substitution rate at this locus.  相似文献   

7.
MOTIVATION: Sex-specific marker maps have become increasingly available. We have implemented the usage of sex-specific recombination frequencies in the GENEHUNTER-MODSCORE program that performs multipoint linkage analysis. Furthermore, we have devised a consistent method to choose the combinations of male and female genetic positions at which linkage scores should be calculated. Marker coordinates can be read automatically from publicly available genetic maps. RESULTS: In a MOD-score analysis of the COGA dataset provided for Genetic Analysis Workshop 14, the highest linkage peak on chromosome 1 further increases when using sex-specific maps, while some smaller peaks are decreased. Simulations confirm that the MOD score can be biased when a sex-averaged instead of the correct sex-specific map is employed. This shows that an adequate modeling of the female:male ratio of genetic distances is important, especially for complex traits. AVAILABILITY: The new version of GENEHUNTER-MODSCORE can be downloaded from the following website: http://www.staff.uni-marburg.de/~strauchk/software.html  相似文献   

8.
W. Schempp  M. Schmid 《Chromosoma》1981,83(5):697-710
A modified BrdU-Hoechst-Giemsa technique permitted the demonstration of easily reproducible replication patterns in the somatic chromosomes of Amphibia. These banding patterns allow for the first time a precise identification of all chromosomes and the analysis of the patterns of replication in the various stages of S-phase in Amphibia. Several possibilities for the use of this technique were demonstrated on three frog species of the family Ranidae, all differing greatly in their DNA-content. With this method, the homomorphic chromosome pair No. 4 in Rana esculenta could be identified as sex-specific chromosomes of the XX/XY-type. All male animals exhibit an extremely late replicating region in the Y-chromosome, which is lacking in the X-chromosome; in the female animals, both X-chromosomes replicate synchronously. These sex-specific chromosomes cannot be distinguished by other banding techniques. In the highly heteromorphic ZZ/ZW-sex chromosome system of Pyxicephalus adspersus a synchronous replication of the two Z-chromosomes of male animals and a very late replication of the short arm of the W-chromosome of female animals was demonstrated. These results support the assumption that there is no dosage compensation for Z-linked or X-linked genes by the sex chromosome inactivation mechanism in the sex chromosomes of Amphibia.  相似文献   

9.
DNA replication is spatially and temporally regulated during S-phase. DNA replication timing is established in early-G1-phase at a point referred to as timing decision point. However, how the genome-wide replication timing domains are established is unknown. Here, we show that Rif1 (Rap1-interacting-factor-1), originally identified as a telomere-binding factor in yeast, is a critical determinant of the replication timing programme in human cells. Depletion of Rif1 results in specific loss of mid-S replication foci profiles, stimulation of initiation events in early-S-phase and changes in long-range replication timing domain structures. Analyses of replication timing show replication of sequences normally replicating early is delayed, whereas that normally replicating late is advanced, suggesting that replication timing regulation is abrogated in the absence of Rif1. Rif1 tightly binds to nuclear-insoluble structures at late-M-to-early-G1 and regulates chromatin-loop sizes. Furthermore, Rif1 colocalizes specifically with the mid-S replication foci. Thus, Rif1 establishes the mid-S replication domains that are restrained from being activated at early-S-phase. Our results indicate that Rif1 plays crucial roles in determining the replication timing domain structures in human cells through regulating higher-order chromatin architecture.  相似文献   

10.
OBJECTIVE: We continue statistical development of the posterior probability of linkage (PPL). We present a two-point PPL allowing for unequal male and female recombination fractions, thetaM and thetaF, and consider alternative priors on thetaM, thetaF. METHODS: We compare the sex-averaged PPL (PPLSA), assuming thetaM = thetaF, to the sex-specific PPL (PPLSS) in (thetaM, thetaF), in a series of simulations; we also compute the PPLSS using alternative priors on (thetaM, thetaF). RESULTS: The PPLSS based on a prior that ignores prior genomic information on sex specific recombination rates performs essentially identically to the PPLSA, even in the presence of large thetaM, thetaF differences. Moreover, adaptively skewing the prior, to incorporate (correct) genomic information on thetaM, thetaF differences, actually worsens performance of the PPLSS. We demonstrate that this has little to do with the PPLSS per se, but is rather due to extremely high levels of variability in the location of the maximum likelihood estimates of (thetaM, thetaF) in realistic data sets. CONCLUSIONS: Incorporating (correct) prior genomic information is not always helpful. We recommend that the PPLSA be used as the standard form of the PPL regardless of the sex-specific recombination rates in the region of the marker in question.  相似文献   

11.
12.
In many instances, there are large sex differences in mutation rates, recombination rates, selection, rates of gene flow, and genetic drift. Mutation rates are often higher in males, a difference that has been estimated both directly and indirectly. The higher male mutation rate appears related to the larger number of cell divisions in male lineages but mutation rates also appear gene- and organism-specific. When there is recombination in only one sex, it is always the homogametic sex. When there is recombination in both sexes, females often have higher recombination but there are many exceptions. There are a number of hypotheses to explain the sex differences in recombination. Sex-specific differences in selection may result in stable polymorphisms or for sex chromosomes, faster evolutionary change. In addition, sex-dependent selection may result in antagonistic pleiotropy or sexually antagonistic genes. There are many examples of sex-specific differences in gene flow (dispersal) and a number of adaptive explanations for these differences. The overall effective population size (genetic drift) is dominated by the lower sex-specific effective population size. The mean of the mutation, recombination, and gene flow rates over the two sexes can be used in a population genetics context unless there are sex-specific differences in selection or genetic drift. Sex-specific differences in these evolutionary factors appear to be unrelated to each other. The evolutionary explanations for sex-specific differences for each factor are multifaceted and, in addition, explanations may include chance, nonadaptive differences, or mechanistic, nonevolutionary factors.  相似文献   

13.
14.
15.
The mammalian genome is not a random sequence but shows a specific, evolutionarily conserved structure that becomes manifest in its isochore pattern. Isochores, i.e. stretches of DNA with a distinct sequence composition and thus a specific GC content, cause the chromosomal banding pattern. This fundamental level of genome organization is related to several functional features like the replication timing of a DNA sequence. GC richness of genomic regions generally corresponds to an early replication time during S phase. Recently, we demonstrated this interdependency on a molecular level for an abrupt transition from a GC-poor isochore to a GC-rich one in the NF1 gene region; this isochore boundary also separates late from early replicating chromatin. Now, we analyzed another genomic region containing four isochores separated by three sharp isochore transitions. Again, the GC-rich isochores were found to be replicating early, the GC-poor isochores late in S phase; one of the replication time zones was discovered to consist of one single replicon. At the boundaries between isochores, that all show no special sequence elements, the replication machinery stopped for several hours. Thus, our results emphasize the importance of isochores as functional genomic units, and of isochore transitions as genomic landmarks with a key function for chromosome organization and basic biological properties.  相似文献   

16.
Mating systems and recombination are thought to have a deep impact on the organization and evolution of genomes. Because of the decline in effective population size and the interference between linked loci, the efficacy of selection is expected to be reduced in regions with low recombination rates and in the whole genome of self-fertilizing species. At the molecular level, relaxed selection is expected to result in changes in the rate of protein evolution and the pattern of codon bias. It is increasingly recognized that recombination also affects non-selective processes such as the biased gene conversion towards GC alleles (bGC). Like selection, this kind of meiotic drive in favour of GC over AT alleles is expected to be reduced in weakly recombining regions and genomes. Here, we investigated the effect of mating system and recombination on molecular evolution in four Triticeae species: two outcrossers (Secale cereale and Aegilops speltoides) and two selfers (Triticum urartu and Triticum monococcum). We found that GC content, possibly driven by bGC, is affected by mating system and recombination as theoretically predicted. Selection efficacy, however, is only weakly affected by mating system and recombination. We investigated the possible reasons for this discrepancy. A surprising one is that, in outcrossing lineages, selection efficacy could be reduced because of high substitution rates in favour of GC alleles. Outcrossers, but not selfers, would thus suffer from a 'GC-induced' genetic load. This result sheds new light on the evolution of mating systems.  相似文献   

17.
Current linkage analysis methods for quantitative traits do not usually incorporate imprinting effects. Here, we carried out genome-wide linkage analysis for loci influencing adult height in the Framingham Heart Study subjects using variance components while allowing for imprinting effects. We used a sex-averaged map for the 22 autosomes, while chromosomes 6, 14, 18, and 19 were also analyzed using sex-specific maps. We compared results from these four analyses: 1) non-imprinted with sex-averaged maps, 2) imprinted with sex-averaged maps, 3) non-imprinted with sex-specific maps, and 4) imprinted with sex-specific maps. We found four regions on three chromosomes (14q32, 18p11-q21, 18q21-22, and 19q13) with LOD scores above 2.0, with a maximum LOD score of 3.12, allowing for imprinting and sex-specific maps, at D18S1364 on 18q21. While we obtained significant evidence of imprinting effects in both the 18p11-q21 and 19q13 regions when using sex-averaged maps, there were no significant differences between the imprinted and non-imprinted LOD scores when we used sex-specific maps. Our results illustrate the importance of allowing for gender-specific effects in linkage analyses, whether these are in the form of gender-specific recombination frequencies, or in the form of imprinting effects.  相似文献   

18.
The intranuclear arrangement of human chromosome 12 in G0(G1) nuclei from human myeloid leukemia HL60 cells was analyzed by multicolor fluorescence in situ hybridization (FISH) using band-specific cosmid clones as probes. Pairs of differently colored cosmids were detected on paraformaldehyde-fixed HL60 nuclei, and their relative positions, internal or peripheral, in individual nuclei were scored. Our results suggest that the intranuclear arrangement of human chromosome 12 is not random. Some chromosomal domains, including the centromere, were located in the periphery of the nucleus, while other domains, including the telomeres, were positioned in the internal areas of the nucleus in G0(G1) cells. Based on the replication banding patterns of metaphase spreads, human chromosome 12 was divided roughly into five large domains. Interestingly, the clones in late replicating domains were preferentially localized in the nuclear periphery, whereas clones in early replicating domains were arranged in the internal areas of the nuclei. The DNA replication timing of each cosmid determined by FISH-based assay did not reflect the replication bands, but an overall profile of the replication timing was relatively correlated with these domains on chromosome 12. These results suggest that the intranuclear arrangement of a human chromosome is correlated with the large-scale replication domains, even before DNA replication. Received: 23 January 1999; in revised form: 6 September 1999 / Accepted: 11 September 1999  相似文献   

19.
During S-phase of the cell cycle, chromosomal DNA is replicated according to a complex replication timing program, with megabase-sized domains replicating at different times. DNA fibre analysis reveals that clusters of adjacent replication origins fire near-synchronously. Analysis of replicating cells by light microscopy shows that DNA synthesis occurs in discrete foci or factories. The relationship between timing domains, origin clusters and replication foci is currently unclear. Recent work, using a hybrid Xenopus/hamster replication system, has shown that when CDK levels are manipulated during S-phase the activation of replication factories can be uncoupled from progression through the replication timing program. Here, we use data from this hybrid system to investigate potential relationships between timing domains, origin clusters and replication foci. We suggest that each timing domain typically comprises several replicon clusters, which are usually processed sequentially by replication factories. We discuss how replication might be regulated at different levels to create this complex organisation and the potential involvement of CDKs in this process.  相似文献   

20.
The introduction and persistence of novel, sexually antagonistic alleles can depend upon factors that differ between males and females. Understanding the conditions for invasion in a two‐locus model can elucidate these processes. For instance, selection can act differently upon the sexes, or sex linkage can facilitate the invasion of genetic variation with opposing fitness effects between the sexes. Two factors that deserve further attention are recombination rates and allele frequencies – both of which can vary substantially between the sexes. We find that sex‐specific recombination rates in a two‐locus diploid model can affect the invasion outcome of sexually antagonistic alleles and that the sex‐averaged recombination rate is not necessarily sufficient to predict invasion. We confirm that the range of permissible recombination rates is smaller in the sex benefitting from invasion and larger in the sex harmed by invasion. However, within the invasion space, male recombination rate can be greater than, equal to or less than female recombination rate in order for a male‐benefit, female‐detriment allele to invade (and similarly for a female‐benefit, male‐detriment allele). We further show that a novel, sexually antagonistic allele that is also associated with a lowered recombination rate can invade more easily when present in the double heterozygote genotype. Finally, we find that sexual dimorphism in resident allele frequencies can impact the invasion of new sexually antagonistic alleles at a second locus. Our results suggest that accounting for sex‐specific recombination rates and allele frequencies can determine the difference between invasion and non‐invasion of novel, sexually antagonistic alleles in a two‐locus model.  相似文献   

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