Evidence for Nonindependent Evolution of Adjacent Microsatellites in the Human Genome

Microsatellites are short tandem repeats that evolve predominantly through a stepwise mutation model. Despite intensive study, many aspects of their evolution remain unresolved, particularly the question of how compound microsatellites containing two different motifs evolve. Previous work described profound asymmetries in the probability that any given second motif lies either 3′ or 5′ of an AC repeat tract. Here we confirm and extend this analysis to examine the length dependence of these asymmetries. We then use the differences in length between homologous human and chimpanzee microsatellites as a surrogate measure of the slippage-based mutation rate to explore factors that influence this process. We find that the dominant predictor of mutation rate is the length of the tract being considered, which is a stronger predictor than the length of the two tracts combined, but other factors also have a significant impact, including the length of the second tract and which of the two tracts lies upstream. We conclude that compound microsatellites rarely arise through random point mutations generating a second motif within a previously pure tract. Instead, our analyses point toward a model in which poorly understood mutation biases, probably affecting both slippage and point mutations and often showing 3′-5′ polarity, promote the formation of compound microsatellites. The result is convergent evolution. We suggest that, although their exact nature remains unclear, these biases are likely attributable to structural features, such as the propensity of AC tracts to form Z-DNA.     

微卫星序列及其应用

微卫星序列广泛存在于各类真核生物基因组中,一般为散在分布的中等程度重复序列。不同物种中,微卫星序列的含量以及占优势的微卫星序列类型各不相同。复制时,微卫星序列易于发生长度突变,这种突变与微卫星序列的复制滑移有关,同时也受多种因素的影响。微卫星序列可能是原微卫星序列通过复制滑移使序列长度扩增形成的。进化过程中,微卫星序列的长度变化维持在一定的范围内。由于微卫星标记多态性高、重复性好,并且操作简单,因此在基因的定位、人类疾病诊断及预测、亲权分析、品种鉴定、进化研究,以及动植物分子标记辅助选择育种研究等领域中都有着重要的应用价值。 Abstract:Microsatellites,simple sequence repeats (SSR),are abundant and distributed throughout the eukaryote genome.The contents of microsatellites are variant in different creatures.There are also different types of microsatellites,which are dominant in different creatures.One of the most noticeable characters of microsatellites is that they are easy to expand during DNA replication.It is thought to attribute to DNA slippage.This kind of mutation is affected by many factors.It is guessed that microsatellites come from pro-microsatellites,while the pro-microsatellites origin from random point mutations.The length of microsatellites can be maintained under relative conservative ranges during species evolution.As they are abundant,codominatnt,distributed over the euchromatic part of the genome,and have the character of highly polimorphic,microsatellites are useful tools for gene mapping,clinical diagnosis and predicting,paternity or pedigree analysis,evolution study,and marker-assisted breeding.     

Human APOBEC3 Induced Mutation of Human Immunodeficiency Virus Type-1 Contributes to Adaptation and Evolution in Natural Infection

Human APOBEC3 proteins are cytidine deaminases that contribute broadly to innate immunity through the control of exogenous retrovirus replication and endogenous retroelement retrotransposition. As an intrinsic antiretroviral defense mechanism, APOBEC3 proteins induce extensive guanosine-to-adenosine (G-to-A) mutagenesis and inhibit synthesis of nascent human immunodeficiency virus-type 1 (HIV-1) cDNA. Human APOBEC3 proteins have additionally been proposed to induce infrequent, potentially non-lethal G-to-A mutations that make subtle contributions to sequence diversification of the viral genome and adaptation though acquisition of beneficial mutations. Using single-cycle HIV-1 infections in culture and highly parallel DNA sequencing, we defined trinucleotide contexts of the edited sites for APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H. We then compared these APOBEC3 editing contexts with the patterns of G-to-A mutations in HIV-1 DNA in cells obtained sequentially from ten patients with primary HIV-1 infection. Viral substitutions were highest in the preferred trinucleotide contexts of the edited sites for the APOBEC3 deaminases. Consistent with the effects of immune selection, amino acid changes accumulated at the APOBEC3 editing contexts located within human leukocyte antigen (HLA)-appropriate epitopes that are known or predicted to enable peptide binding. Thus, APOBEC3 activity may induce mutations that influence the genetic diversity and adaptation of the HIV-1 population in natural infection.     

Microsatellites: consensus and controversy

Microsatellite DNA loci have recently been adopted for many biological applications. Comparative studies across a wide range of species has revealed many details of their mutational properties and evolutionary life cycles. Experience shows that a full understanding of these processes is essential to ensure the effective use of microsatellites as analytical tools. In this article, we review the controversies that have arisen as biologists have taken up this new technology and the emerging consensus that has resulted from their debates. We point to the need for comparative DNA sequencing studies to produce input data for a new generation of theoretical models of microsatellite behaviour. We conclude by presenting our own conceptual model, ‘Snakes and Ladders’, as an aid to theory development.     

Mutation and Human Exceptionalism: Our Future Genetic Load

Although the human germline mutation rate is higher than that in any other well-studied species, the rate is not exceptional once the effective genome size and effective population size are taken into consideration. Human somatic mutation rates are substantially elevated above those in the germline, but this is also seen in other species. What is exceptional about humans is the recent detachment from the challenges of the natural environment and the ability to modify phenotypic traits in ways that mitigate the fitness effects of mutations, e.g., precision and personalized medicine. This results in a relaxation of selection against mildly deleterious mutations, including those magnifying the mutation rate itself. The long-term consequence of such effects is an expected genetic deterioration in the baseline human condition, potentially measurable on the timescale of a few generations in westernized societies, and because the brain is a particularly large mutational target, this is of particular concern. Ultimately, the price will have to be covered by further investment in various forms of medical intervention. Resolving the uncertainties of the magnitude and timescale of these effects will require the establishment of stable, standardized, multigenerational measurement procedures for various human traits.MUTATION, the production of heritable changes in DNA, is one of the most fundamental concepts in genetics. Yet, a broad phylogenetic understanding of the rate and molecular spectrum of mutations and the mechanisms driving the evolution of these key parameters has only recently begun to emerge (Baer et al. 2007; Lynch 2010, 2011). Of special concern is the rate at which mutations are arising in our own lineage and their long-term consequences. In terms of cognitive abilities and proclivity for dominating the global ecosystem, humans are clearly exceptional. But how exceptional are we with respect to the genetic machinery that is the key to long-term genome stability and evolutionary flexibility? And in light of our unusual behavioral features, what are the long-term genetic consequences of being a modern human? Will the miracles of molecular biology and modern medicine reduce the incidence and/or effects of genetic afflictions to negligible levels, or might such applications have the opposite effect?Two issues are of central relevance here. First, few other species willingly expose themselves to environmental mutagens to the extent that humans do. Presumably, there is some room for reducing the human mutation rate by minimizing negative environmental effects, e.g., through reductions in exposure to smoke from tobacco and other sources, harmful food additives, radon gas, UV irradiation, etc. What, however, is the lower bound to the achievable mutation rate at both the germline and somatic levels? And do factors that influence the somatic mutation rate also have germline effects and vice versa?Second, owing to the remarkable advances in living conditions and medicine over the past century, and many more likely to come, humans uniquely modify the environment in ways that minimize the consequences of acquired genetic afflictions. Today’s ethical imperative for maximizing individual reproductive potential and longevity independent of genetic background raises significant questions about the future of the human gene pool. Specifically, what are the long-term consequences of the accumulation of mutations whose phenotypic consequences can be transiently minimized through medical intervention and/or a sheltering environment?It is fitting to review both of these issues in the year 2016, as this would have been the 100th birthday of James Crow, who played a central role in the Genetics Society of America and had a long-standing interest in human mutation (Crow 1993, 1997, 2000, 2006). Many of the issues addressed below were raised by Crow prior to the genomics revolution and can now be evaluated in a more quantitative way.     

Mutation Rate Evolution in Replicator Dynamics

The mutation rate of an organism is itself evolvable. In stable environments, if faithful replication is costless, theory predicts that mutation rates will evolve to zero. However, positive mutation rates can evolve in novel or fluctuating environments, as analytical and empirical studies have shown. Previous work on this question has focused on environments that fluctuate independently of the evolving population. Here we consider fluctuations that arise from frequency-dependent selection in the evolving population itself. We investigate how the dynamics of competing traits can induce selective pressure on the rates of mutation between these traits. To address this question, we introduce a theoretical framework combining replicator dynamics and adaptive dynamics. We suppose that changes in mutation rates are rare, compared to changes in the traits under direct selection, so that the expected evolutionary trajectories of mutation rates can be obtained from analysis of pairwise competition between strains of different rates. Depending on the nature of frequency-dependent trait dynamics, we demonstrate three possible outcomes of this competition. First, if trait frequencies are at a mutation–selection equilibrium, lower mutation rates can displace higher ones. Second, if trait dynamics converge to a heteroclinic cycle—arising, for example, from “rock-paper-scissors” interactions—mutator strains succeed against non-mutators. Third, in cases where selection alone maintains all traits at positive frequencies, zero and nonzero mutation rates can coexist indefinitely. Our second result suggests that relatively high mutation rates may be observed for traits subject to cyclical frequency-dependent dynamics.     

有尾噬菌体目中微卫星和复合型微卫星的发生及分析

简单重复序列亦称微卫星,被成功应用于许多真核生物、原核生物和病毒的基因组和进化研究,但是噬菌体中的微卫星目前很少被研究。因此对60条尾病毒目基因组中的微卫星和和复合型微卫星(由两个或两个以上直接相邻的微卫星组成)做综合性分析,在这60个基因组中总共观察到11 874个微卫星和449个复合型微卫星。相关性分析表明微卫星个数与基因组大小成正线性相关(ρ=0.899, P<0.01)。参考序列中的微卫星个数少于对应的随机序列中微卫星个数,这种反常现象主要是因为参考序列含有较少的单核苷酸和二核苷酸重复。A/T和AT/TA重复是单核苷酸和二核苷酸重复中最主要的类型,因此单核苷酸重复中的GC含量明显低于相应的序列中的GC含量;相比之下,微卫星中的二核苷酸和三核苷酸重复的GC含量与对应的参考序列的GC含量无明显区别。尾病毒目基因组中的这些结果与其它生物体基因组存在一定的差别。有助于了解尾病毒目中微卫星的分布、进化和生物学功能。     

Microsatellites and kinship

Many evolutionary studies, particularly kinship studies, have been limited by the availability of segregating genetic marker loci. Microsatellites promise to alleviate these problems. Microsatellite loci are segments of DNA with very short sequence motifs repeated in tandem; their often numerous alleles differ in the number of these repeat units. They are very common in eukaryotic DNA and can be amplified by the polymerase chain reaction, which allows the use of minute or degraded DNA samples. The alleles can be scored consistently and compared unambiguously, even across different gels.     

Evolution of Microsatellites in the Yeast Saccharomyces cerevisiae: Role of Length and Number of Repeated Units

The observed and expected frequencies of occurrence of microsatellites in the yeast Saccharomyces cerevisiae were investigated. In all cases, the observed frequencies exceeded the expected ones. In contrast to predictions by Messier et al. (1996), there is no critical number of repeats beyond which the observed frequencies of microsatellites significantly exceed the frequencies expected in a random DNA sequence of the same size. Rather, the degree of deviation from expectation was found to be dependent on the length of the microsatellite. That is, a fourfold concatemeric repeat of 3 bp was found to deviate from expectation as much as threefold concatemeric repeat of 4 bp, unlike the deviation of a fourfold concatemeric repeat of 4 bp. These findings suggest that microsatellites evolve through strand-slippage events, rather than recombination events. This, in turn, suggests that the chances of erroneous hybridizations leading to strand-slippage are length dependent. Received: 1 June 1998 / Accepted: 16 September 1998     

Controlling Mutation: Intervening in Evolution as a Therapeutic Strategy

ABSTRACT

Mutation is the driving force behind many processes linked to human disease, including cancer, aging, and the evolution of drug resistance. Mutations have traditionally been considered the inevitable consequence of replicating large genomes with polymerases of finite fidelity. Observations over the past several decades, however, have led to a new perspective on the process of mutagenesis. It has become clear that, under some circumstances, mutagenesis is a regulated process that requires the induction of pro-mutagenic enzymes and that, at least in bacteria, this induction may facilitate evolution. Herein, we review what is known about induced mutagenesis in bacteria as well as evidence that it contributes to the evolution of antibiotic resistance. Finally, we discuss the possibility that components of induced mutation pathways might be targeted for inhibition as a novel therapeutic strategy to prevent the evolution of antibiotic resistance.     

Meat-Eating and Human Evolution

Meat-Eating and Human Evolution. Craig B. Stanford and Henry T. Bunn. eds. New York: Oxford University Press, 2001.384 pp.     

Modeling Within-Host Evolution of HIV: Mutation,Competition and Strain Replacement

Virus evolution during infection of a single individual is a well-known feature of disease progression in chronic viral diseases. However, the simplest models of virus competition for host resources show the existence of a single dominant strain that grows most rapidly during the initial period of infection and competitively excludes all other virus strains. Here, we examine the dynamics of strain replacement in a simple model that includes a convex trade-off between rapid virus reproduction and long-term host cell survival. Strains are structured according to their within-cell replication rate. Over the course of infection, we find a progression in the dominant strain from fast- to moderately-replicating virus strains featuring distinct jumps in the replication rate of the dominant strain over time. We completely analyze the model and provide estimates for the replication rate of the initial dominant strain and its successors. Our model lays the groundwork for more detailed models of HIV selection and mutation. We outline future directions and application of related models to other biological situations.