How strong is the mutagenicity of recombination in mammals?

It is commonly believed that a high recombination rate such as that in a pseudoautosomal region (PAR) greatly increases the mutation rate because a 170-fold increase was estimated for the mouse PAR region. However, sequencing PAR and non-PAR introns of the Fxy gene in four Mus taxa, we found an increase of only twofold to fivefold. Furthermore, analyses of sequence data from human and orangutan PAR and X-linked regions and from autosomal regions showed a weak effect of recombination on mutation rate (a slope of less than 0.2% per cM/Mb), although a much stronger effect on GC content (1% to 2% per cM/Mb). Because typical recombination rates in mammals are much lower than those in PARs, the mutagenicity of recombination is weak or, at best, moderate, although its effect on GC% is much stronger. In addition, contrary to a previous study, we found no Fxy duplicate in Mus spretus.     

人类性染色体拟常染色体区的研究进展

拟常染色体区是性染色体上的重要区域,对于维持性染色体结构与功能、保证性染色体在减数分裂过程中正常配对与分离具有重要意义。拟常染色体区与常染色体结构与功能的异同点也为了解性染色体的起源与进化提供了很好的材料。人类的拟常染色体区由PAR1和PAR2两个区域组成,这两个区域在结构上有明显不同。位于其上的基因虽然不多,但与许多遗传疾病相关,详细研究该区的基因与疾病的关系还有助于尽早诊断并防治与之相关的遗传疾病。本文全面综述了人类性染色体拟常染色体区的最新研究进展。     

Molecular evolution of recombination hotspots and highly recombining pseudoautosomal regions in hominoids

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.     

An examination of phylogenetic models of substitution rate variation among lineages

Molecular evolutionary rates can show significant variation among lineages, complicating the task of estimating substitution rates and divergence times using phylogenetic methods. Accordingly, relaxed molecular clock models have been developed to accommodate such rate heterogeneity, but these often make the assumption of rate autocorrelation among lineages. In this paper, I examine the validity of this assumption.     

Evolution of hominoid mitochondrial DNA with special reference to the silent substitution rate over the genome

Summary Focusing on the synonymous substitution rate, we carried out detailed sequence analyses of hominoid mitochondrial (mt) DNAs of ca. 5-kb length. Owing to the outnumbered transitions and strong biases in the base compositions, synonymous substitutions in mtDNA reach rapidly a rather low saturation level. The extent of the compositional biases differs from gene to gene. Such changes in base compositions, even if small, can bring about considerable variation in observed synonymous differences and may result in the region-dependent estimate of the synonymous substitution rate. We demonstrate that such a region dependency is due to a failure to take proper account of heterogeneous compositional biases from gene to gene but that the actual synonymous substitution rate is rather uniform. The synonymous substitution rate thus estimated is 2.37 ± 0.11 × 10^–8 per site per year and comparable to the overall rate for the noncoding region. On the other hand, the rate of nonsynonymous substitutions differs considerably from gene to gene, as expected under the neutral theory of molecular evolution. The lowest rate is 0.8 × 10^–9 per site per year forCOI and the highest rate is 4.5 × 10^–9 forATPase 8, the degree of functional constraints (measured by the ratio of the nonsynonymous to the synonymous substitution rate) being 0.03 and 0.19, respectively. Transfer RNA (tRNA) genes also show variability in the base contents and thus in the nucleotide differences. The average rate for 11 tRNAs contained in the 5-kb region is 3.9 × 10^–9 per site per year. The nucleotide substitutions in the genome suggest that the transition rate is about 17 times faster than the transversion rate.     

A physical map of the human pseudoautosomal region.

A physical map of the human pseudoautosomal region has been constructed using pulsed field gel electrophoresis and the infrequently cutting restriction enzymes BssHIII, EagI, SstII, NotI, MluI and NruI. This map extends 2.3 Mbp from the telomere to sex-chromosome-specific DNA, includes at least seven CpG islands and locates four genetically mapped loci. Five of the CpG islands are organized into two clusters. One cluster is adjacent to the telomere, the other extends into sex-chromosome-specific DNA. There is congruence between the genetic and physical maps which implies that the frequency of recombination is approximately uniform throughout the DNA.     

Characterizing the time dependency of human mitochondrial DNA mutation rate estimates

Previous research has established a discrepancy of nearly anorder of magnitude between pedigree-based and phylogeny-based(human vs. chimpanzee) estimates of the mitochondrial DNA (mtDNA)control region mutation rate. We characterize the time dependencyof the human mitochondrial hypervariable region one mutationrate by generating 14 new phylogeny-based mutation rate estimatesusing within-human comparisons and archaeological dates. Rateestimates based on population events between 15,000 and 50,000years ago are at least 2-fold lower than pedigree-based estimates.These within-human estimates are also higher than estimatesgenerated from phylogeny-based human–chimpanzee comparisons.Our new estimates establish a rapid decay in evolutionary mutationrate between approximately 2,500 and 50,000 years ago and aslow decay from 50,000 to 6 Ma. We then extend this analysisto the mtDNA-coding region. Our within-human coding region mutationrate estimates display a similar, though less rapid, time-dependentdecay. We explore the possibility that multiple hits explainthe discrepancy between pedigree-based and phylogeny-based mutationrates. We conclude that whereas nucleotide substitution modelsincorporating multiple hits do provide a possible explanationfor the discrepancy between pedigree-based and human–chimpanzeemutation rate estimates, they do not explain the rapid declineof within-human rate estimates. We propose that demographicprocesses such as serial bottlenecks prior to the Holocene couldexplain the difference between rates estimated before and after15,000 years ago. Our findings suggest that human mtDNA estimatesof dates of population and phylogenetic events should be adjustedin light of this time dependency of the mutation rate estimates.     

Time dependency of molecular rate estimates and systematic overestimation of recent divergence times

Studies of molecular evolutionary rates have yielded a wide range of rate estimates for various genes and taxa. Recent studies based on population-level and pedigree data have produced remarkably high estimates of mutation rate, which strongly contrast with substitution rates inferred in phylogenetic (species-level) studies. Using Bayesian analysis with a relaxed-clock model, we estimated rates for three groups of mitochondrial data: avian protein-coding genes, primate protein-coding genes, and primate d-loop sequences. In all three cases, we found a measurable transition between the high, short-term (< 1-2 Myr) mutation rate and the low, long-term substitution rate. The relationship between the age of the calibration and the rate of change can be described by a vertically translated exponential decay curve, which may be used for correcting molecular date estimates. The phylogenetic substitution rates in mitochondria are approximately 0.5% per million years for avian protein-coding sequences and 1.5% per million years for primate protein-coding and d-loop sequences. Further analyses showed that purifying selection offers the most convincing explanation for the observed relationship between the estimated rate and the depth of the calibration. We rule out the possibility that it is a spurious result arising from sequence errors, and find it unlikely that the apparent decline in rates over time is caused by mutational saturation. Using a rate curve estimated from the d-loop data, several dates for last common ancestors were calculated: modern humans and Neandertals (354 ka; 222-705 ka), Neandertals (108 ka; 70-156 ka), and modern humans (76 ka; 47-110 ka). If the rate curve for a particular taxonomic group can be accurately estimated, it can be a useful tool for correcting divergence date estimates by taking the rate decay into account. Our results show that it is invalid to extrapolate molecular rates of change across different evolutionary timescales, which has important consequences for studies of populations, domestication, conservation genetics, and human evolution.     

Contrasting rates of nucleotide substitution in the X-Linked and Y-Linked zinc finger genes

We have sequenced the entire exon (1,180 bp) encoding the zinc finger domain of the X-linked and Y-linked zinc finger genes (ZFX and ZFY, respectively) in the orangutan, the baboon, the squirrel monkey, and the rat; a total of 9,442 by were sequenced. The ratio of the rates of synonymous substitution in the ZFY and ZFX genes is estimated to be 2.1 in primates. This is close to the ratio of 2.3 estimated from primate ZFY and ZFX intron sequences and supports the view that the male-to-female ratio of mutation rate in humans is considerably higher than 1 but not extremely large. The ratio of synonymous substitution rates in ZFY and ZFX is estimated to be 1.3 in the rat lineage but 4.2 in the mouse lineage. The former is close to the estimate (1.4) from introns. The much higher ratio in the mouse lineage (not statistically significant) might have arisen from relaxation of selective constraints. The synonymous divergence between mouse and rat ZFX is considerably lower than that between mouse and rat autosomal genes, agreeing with previous observations and providing some evidence for stronger selective constraints on synonymous changes in X-linked genes than in autosomal genes. At the protein level ZFX has been highly conserved in all placental mammals studied while ZFY has been well conserved in primates and foxes but has evolved rapidly in mice and rats, possibly due to relaxation of functional constraints as a result of the development of X-inactivation of ZFX in rodents. The long persistence of the ZFY-ZFX gene pair in mammals provides some insight into the process of degeneration of Y-linked genes.Correspondence to: W.-H. Li     

Low base‐substitution mutation rate and predominance of insertion‐deletion events in the acidophilic bacterium Acidobacterium capsulatum

Analyses of spontaneous mutation have shown that total genome‐wide mutation rates are quantitatively similar for most prokaryotic organisms. However, this view is mainly based on organisms that grow best around neutral pH values (6.0–8.0). In particular, the whole‐genome mutation rate has not been determined for an acidophilic organism. Here, we have determined the genome‐wide rate of spontaneous mutation in the acidophilic Acidobacterium capsulatum using a direct and unbiased method: a mutation‐accumulation experiment followed by whole‐genome sequencing. Evaluation of 69 mutation accumulation lines of A. capsulatum after an average of ~2900 cell divisions yielded a base‐substitution mutation rate of 1.22 × 10⁻¹⁰ per site per generation or 4 × 10⁻⁴ per genome per generation, which is significantly lower than the consensus value (2.5−4.6 × 10⁻³) of mesothermophilic (~15–40°C) and neutrophilic (pH 6–8) prokaryotic organisms. However, the insertion‐deletion rate (0.43 × 10⁻¹⁰ per site per generation) is high relative to the base‐substitution mutation rate. Organisms with a similar effective population size and a similar expected effect of genetic drift should have similar mutation rates. Because selection operates on the total mutation rate, it is suggested that the relatively high insertion‐deletion rate may be balanced by a low base‐substitution rate in A. capsulatum, with selection operating on the total mutation rate.     

Loss of the IR region in conifer plastomes: Changes in the selection pressure and substitution rate of protein‐coding genes

Plastid genomes (plastomes) have a quadripartite structure, but some species have drastically reduced or lost inverted repeat (IR) regions. IR regions are important for genome stability and the evolution rate. In the evolutionary process of gymnosperms, the typical IRs of conifers were lost, possibly affecting the evolutionary rate and selection pressure of genomic protein‐coding genes. In this study, we selected 78 gymnosperm species (51 genera, 13 families) for evolutionary analysis. The selection pressure analysis results showed that negative selection effects were detected in all 50 common genes. Among them, six genes in conifers had higher ω values than non‐conifers, and 12 genes had lower ω values. The evolutionary rate analysis results showed that 9 of 50 common genes differed between conifers and non‐conifers. It is more obvious that in non‐conifers, the rates of psbA (trst, trsv, ratio, dN, dS, and ω) were 2.6‐ to 3.1‐fold of conifers. In conifers, trsv, ratio, dN, dS, and ω of ycf2 were 1.2‐ to 3.6‐fold of non‐conifers. In addition, the evolution rate of ycf2 in the IR was significantly reduced. psbA is undergoing dynamic change, with an abnormally high evolution rate as a small portion of it enters the IR region. Although conifers have lost the typical IR regions, we detected no change in the substitution rate or selection pressure of most protein‐coding genes due to gene function, plant habitat, or newly acquired IRs.     

Significant positive correlation between the recombination rate and GC content in the human pseudoautosomal region.

This paper establishes that recombination drives the evolution of GC content in a significant way. Because the human P-arm pseudoautosomal region (PAR1) has been shown to have a high recombination rate, at least 20-fold more frequent than the genomic average of approximately 1 cM/Mb, this region provides an ideal system to study the role of recombination in the evolution of base composition. Nine non-coding regions of PAR1 are analyzed in this study. We have observed a highly significant positive correlation between the recombination rate and GC content (rho = 0.837, p < or = 0.005). Five regions that lie in the distal part of PAR1 are shown to be significantly higher than genomic average divergence. By comparing the intra- and inter-specific AT->GC -GC->AT ratios, we have detected no fixation bias toward GC alleles except for L254915, which has excessive AT-->GC changes in the human lineage. Thus, we conclude that the high GC content of the PAR1 genes better fits the biased gene conversion (BGC) model.     

Generation time,life history and the substitution rate of neutral mutations

Our understanding of molecular evolution is hampered by a lack of quantitative predictions about how life-history (LH) traits should correlate with substitution rates. Comparative studies have shown that neutral substitution rates vary substantially between species, and evidence shows that much of this diversity is associated with variation in LH traits. However, while these studies often agree, some unexplained and contradictory results have emerged. Explaining these results is difficult without a clear theoretical understanding of the problem. In this study, we derive predictions for the relationships between LH traits and substitution rates in iteroparous species by using demographic theory to relate commonly measured life-history traits to genetic generation time, and by implication to neutral substitution rates. This provides some surprisingly simple explanations for otherwise confusing patterns, such as the association between fecundity and substitution rates. The same framework can be applied to more complex life histories if full life-tables are available.     

Strong regional biases in nucleotide substitution in the chicken genome

Interspersed repeats have emerged as a valuable tool for studying neutral patterns of molecular evolution. Here we analyze variation in the rate and pattern of nucleotide substitution across all autosomes in the chicken genome by comparing the present-day CR1 repeat sequences with their ancestral copies and reconstructing nucleotide substitutions with a maximum likelihood model. The results shed light on the origin and evolution of large-scale heterogeneity in GC content found in the genomes of birds and mammals--the isochore structure. In contrast to mammals, where GC content is becoming homogenized, heterogeneity in GC content is being reinforced in the chicken genome. This is also supported by patterns of substitution inferred from alignments of introns in chicken, turkey, and quail. Analysis of individual substitution frequencies is consistent with the biased gene conversion (BGC) model of isochore evolution, and it is likely that patterns of evolution in the chicken genome closely resemble those in the ancestral amniote genome, when it is inferred that isochores originated. Microchromosomes and distal regions of macrochromosomes are found to have elevated substitution rates and a more GC-biased pattern of nucleotide substitution. This can largely be accounted for by a strong correlation between GC content and the rate and pattern of substitution. The results suggest that an interaction between increased mutability at CpG motifs and fixation biases due to BGC could explain increased levels of divergence in GC-rich regions.     

基于地形梯度的赣南地区生态系统服务价值对人为干扰的空间响应

赣南地区是我国南方山地丘陵带的重要组成部分,属于我国重要的生态屏障带,生态保护意义重大。以赣南为研究区域,基于1990—2015年间的6期遥感影像,利用遥感、地理信息技术和空间统计的方法,研究了赣南地区基于地形梯度变化的土地利用结构及生态系统服务价值的时空分异,基于网格法分析了全区人为干扰度空间分布及其与地形梯度的关系,并对人为干扰度与生态系统服务价值的空间相关性进行了分析。研究结果表明:(1)随着地形梯度的上升,赣南地区的林地面积比例逐渐上升,其他用地类型的面积比例逐渐下降;其中林地和耕地的变化最为显著;(2) 1990—2015年间赣南地区的生态系统服务价值均随着地形梯度的上升而下降;在地形位指数为0.2164—0.6826的梯度1区域下降最为显著;(3)人为干扰分析显示,90%的高人为干扰度网格分布在低海拔和低坡度的地形梯度1区域,在其他地形梯度分布较少;(4)赣南地区生态系统服务价值和人为干扰度值存在极为显著的空间集聚现象,高-低型集聚区主要分布在地形梯度1的大余县、南康市、赣州市区、信丰县、瑞金市、会昌县、兴国县、于都县等8个县市,低-高型集聚区主要分布在地形梯度较高的崇义县和上犹县。分析了赣南地区生态系统服务价值的地形梯度变化及其与人为干扰度的空间聚类效应,为合理布局和保护我国南方丘陵的生态用地,发挥赣南地区的生态屏障作用提供了理论依据和决策支持。     

Variation in mutation rate and polymorphism among mitochondrial genes of Silene vulgaris

The prevailing wisdom of the plant mitochondrial genome is that it has very low substitution rates, thus it is generally assumed that nucleotide diversity within species will also be low. However, recent evidence suggests plant mitochondrial genes may harbor variable and sometimes high levels of within-species polymorphism, a result attributed to variance in the influence of selection. However, insufficient attention has been paid to the effect of among-gene variation in mutation rate on varying levels of polymorphism across loci. We measured levels of polymorphism in seven mitochondrial gene regions across a geographically wide sample of the plant Silene vulgaris to investigate whether individual mitochondrial genes accumulate polymorphisms equally. We found that genes vary significantly in polymorphism. Tests based on coalescence theory show that the genes vary significantly in their scaled mutation rate, which, in the absence of differences among genes in effective population size, suggests these genes vary in their underlying mutation rate. Further evidence that among-gene variance in polymorphism is due to variation in the underlying mutation rate comes from a significant positive relationship between the number of segregating sites and silent site divergence from an outgroup. Contrary to recent studies, we found unconvincing evidence of recombination in the mitochondrial genome, and generally confirm the standard model of plant mitochondria characterized by low substitution rates and no recombination. We also show no evidence of significant variation in the strength or direction of selection among genes; this result may be expected if there is no recombination. The present study provides some of the most thorough data on plant mitochondrial polymorphism, and provides compelling evidence for mutation rate variation among genes. The study also demonstrates the difficulty in establishing a null model of mitochondrial genome polymorphism, and thus the difficulty, in the absence of a comparative approach, in testing the assumption that low substitution rates in plant mitochondria lead to low polymorphism.     

人类基因组中突变对紧邻碱基的依赖性与重组率

减数分裂重组通过基因转变、碱基替换等方式影响基因组进化。紧邻碱基对突变偏好性有很强的影响,但该“紧邻碱基效应”如何随重组率变化有待深入研究。本文提出基于条件互信息(Conditional mutual information)量化突变对紧邻碱基依赖性的方法,并利用人类SNP等相关数据,分析重组率如何影响突变对紧邻碱基的依赖性。结果表明:在全基因组水平上, SNP位点上的突变对紧邻碱基的依赖性(即平均条件互信息)随着重组率的增加而增加;具体而言,当SNPs两侧碱基为A/G、C/G或C/T时,随着重组率的增加突变偏向性增强,但两侧碱基为A/A或T/T时,重组率对SNP突变偏向性产生抑制作用;另外,重组率越高,外显子与基因间区SNP的突变偏好性越强;而内含子区域SNP的突变偏好受到高重组率的抑制。结果有助于深入理解减数分裂重组如何影响基因组进化。