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Functional constraints and frequency of deleterious mutations in noncoding DNA of rodents

Keightley, Peter D.; Gaffney, Daniel J.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
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46.48%
Selection against deleterious mutations imposes a mutation load on populations because individuals die or fail to reproduce. In vertebrates, estimates of genomic rates of deleterious mutations in protein-coding genes imply the existence of a substantial mutation load, but many functionally important regions of the genome are thought to reside in noncoding DNA, and the contribution of noncoding DNA to the mutation load has been unresolved. Here, we infer the frequency of deleterious mutations in noncoding DNA of rodents by comparing rates of substitution at noncoding nucleotides with rates of substitution at the fastest evolving intronic sites of adjacent genes sampled from the whole genome sequences of mouse and rat. We show that the major elements of selectively constrained noncoding DNA are within 2,500 bp upstream and downstream of coding sequences and in first introns. Our estimate of the genomic deleterious point mutation rate for noncoding DNA (0.22 per diploid per generation) is similar to that for coding DNA. Mammalian populations therefore experience a substantial genetic load associated with selection against deleterious mutations in noncoding DNA. Deleterious mutations in noncoding DNA have predominantly quantitative effects and could be an important source of the burden of complex genetic disease variation in human populations.

Deleterious Mutations, Apparent Stabilizing Selection and the Maintenance of Quantitative Variation

Kondrashov, A. S.; Turelli, M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1992 EN
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46.57%
Apparent stabilizing selection on a quantitative trait that is not causally connected to fitness can result from the pleiotropic effects of unconditionally deleterious mutations, because as N. Barton noted, ``... individuals with extreme values of the trait will tend to carry more deleterious alleles ....' We use a simple model to investigate the dependence of this apparent selection on the genomic deleterious mutation rate, U; the equilibrium distribution of K, the number of deleterious mutations per genome; and the parameters describing directional selection against deleterious mutations. Unlike previous analyses, we allow for epistatic selection against deleterious alleles. For various selection functions and realistic parameter values, the distribution of K, the distribution of breeding values for a pleiotropically affected trait, and the apparent stabilizing selection function are all nearly Gaussian. The additive genetic variance for the quantitative trait is kQa(2), where k is the average number of deleterious mutations per genome, Q is the proportion of deleterious mutations that affect the trait, and a(2) is the variance of pleiotropic effects for individual mutations that do affect the trait. In contrast, when the trait is measured in units of its additive standard deviation...

The Effect of Deleterious Mutations on Neutral Molecular Variation

Charlesworth, B.; Morgan, M. T.; Charlesworth, D.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1993 EN
Relevância na Pesquisa
46.46%
Selection against deleterious alleles maintained by mutation may cause a reduction in the amount of genetic variability at linked neutral sites. This is because a new neutral variant can only remain in a large population for a long period of time if it is maintained in gametes that are free of deleterious alleles, and hence are not destined for rapid elimination from the population by selection. Approximate formulas are derived for the reduction below classical neutral values resulting from such background selection against deleterious mutations, for the mean times to fixation and loss of new mutations, nucleotide site diversity, and number of segregating sites. These formulas apply to random-mating populations with no genetic recombination, and to populations reproducing exclusively asexually or by self-fertilization. For a given selection regime and mating system, the reduction is an exponential function of the total mutation rate to deleterious mutations for the section of the genome involved. Simulations show that the effect decreases rapidly with increasing recombination frequency or rate of outcrossing. The mean time to loss of new neutral mutations and the total number of segregating neutral sites are less sensitive to background selection than the other statistics...

Maintenance of Genetic Variability under the Pressure of Neutral and Deleterious Mutations in a Finite Population

Li, Wen-Hsiung
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1979 EN
Relevância na Pesquisa
46.54%
In order to assess the effect of deleterious mutations on various measures of genic variation, approximate formulas have been developed for the frequency spectrum, the mean number of alleles in a sample, and the mean homozygosity; in some particular cases, exact formulas have been obtained. The assumptions made are that two classes of mutations exist, neutral and deleterious, and that selection is strong enough to keep deleterious alleles in low frequencies, the mode of selection being either genic or recessive. The main findings are: (1) If the expected value (q) of the sum of the frequencies of deleterious alleles is about 10% or less, then the presence of deleterious alleles causes only a minor reduction in the mean number of neutral alleles in a sample, as compared to the case of q = 0. Also, the low- and intermediate-frequency parts of the frequency spectrum of neutral alleles are little affected by the presence of deleterious alleles, though the high-frequency part may be changed drastically. (2) The contribution of deleterious mutations to the expected total number of alleles in a sample can be quite large even if q is only 1 or 2%. (3) The mean homozygosity is roughly equal to (1—2q)/(1+θ1), where θ1 is twice the number of new neutral mutations occurring in each generation in the total population. Thus...

Deleterious mutations in small subunit ribosomal RNA identify functional sites and potential targets for antibiotics

Yassin, Aymen; Fredrick, Kurt; Mankin, Alexander S.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.44%
Many clinically useful antibiotics interfere with protein synthesis in bacterial pathogens by inhibiting ribosome function. The sites of action of known drugs are limited in number, are composed primarily of ribosomal RNA (rRNA), and coincide with functionally critical centers of the ribosome. Nucleotide alterations within such sites are often deleterious. To identify functional sites and potential sites of antibiotic action in the ribosome, we prepared a random mutant library of rRNA genes and selected dominant mutations in 16S rRNA that interfere with cell growth. Fifty-three 16S rRNA positions were identified whose mutation inhibits protein synthesis. Mutations were ranked according to the severity of the phenotype, and the detrimental effect of several mutations on translation was verified in a specialized ribosome system. Analysis of the polysome profiles of mutants suggests that the majority of the mutations directly interfered with ribosome function, whereas a smaller fraction of mutations affected assembly of the small ribosomal subunit. Twelve of the identified mutations mapped to sites targeted by known antibiotics, confirming that deleterious mutations can be used to identify antibiotic targets. About half of the mutations coincided with known functional sites in the ribosome...

The Effect of Antagonistic Pleiotropy on the Estimation of the Average Coefficient of Dominance of Deleterious Mutations

Fernández, B.; García-Dorado, A.; Caballero, A.
Fonte: Copyright © 2005 by the Genetics Society of America Publicador: Copyright © 2005 by the Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /12/2005 EN
Relevância na Pesquisa
46.43%
We investigate the impact of antagonistic pleiotropy on the most widely used methods of estimation of the average coefficient of dominance of deleterious mutations from segregating populations. A proportion of the deleterious mutations affecting a given studied fitness component are assumed to have an advantageous effect on another one, generating overdominance on global fitness. Using diffusion approximations and transition matrix methods, we obtain the distribution of gene frequencies for nonpleiotropic and pleiotropic mutations in populations at the mutation-selection-drift balance. From these distributions we build homozygous and heterozygous chromosomes and assess the behavior of the estimators of dominance. A very small number of deleterious mutations with antagonistic pleiotropy produces substantial increases on the estimate of the average degree of dominance of mutations affecting the fitness component under study. For example, estimates are increased three- to fivefold when 2% of segregating loci are overdominant for fitness. In contrast, strengthening pleiotropy, where pleiotropic effects are assumed to be also deleterious, has little effect on the estimates of the average degree of dominance, supporting previous results. The antagonistic pleiotropy model considered...

Antagonistic coevolution with parasites increases the cost of host deleterious mutations

Buckling, Angus; Wei, Yan; Massey, Ruth C; Brockhurst, Michael A; Hochberg, Michael E
Fonte: The Royal Society Publicador: The Royal Society
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.46%
The fitness consequences of deleterious mutations are sometimes greater when individuals are parasitized, hence parasites may result in the more rapid purging of deleterious mutations from host populations. The significance of host deleterious mutations when hosts and parasites antagonistically coevolve (reciprocal evolution of host resistance and parasite infectivity) has not previously been experimentally investigated. We addressed this by coevolving the bacterium Pseudomonas fluorescens and a parasitic bacteriophage in laboratory microcosms, using bacteria with high and low mutation loads. Directional coevolution between bacterial resistance and phage infectivity occurred in all populations. Bacterial population fitness, as measured by competition experiments with ancestral genotypes in the absence of phage, declined with time spent coevolving. However, this decline was significantly more rapid in bacteria with high mutation loads, suggesting the cost of bacterial resistance to phage was greater in the presence of deleterious mutations (synergistic epistasis). As such, resistance to phage was more costly to evolve in the presence of a high mutation load. Consistent with these data, bacteria with high mutation loads underwent less rapid directional coevolution with their phage populations...

From Bad to Good: Fitness Reversals and the Ascent of Deleterious Mutations

Cowperthwaite, Matthew C; Bull, J. J; Meyers, Lauren Ancel
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.51%
Deleterious mutations are considered a major impediment to adaptation, and there are straightforward expectations for the rate at which they accumulate as a function of population size and mutation rate. In a simulation model of an evolving population of asexually replicating RNA molecules, initially deleterious mutations accumulated at rates nearly equal to that of initially beneficial mutations, without impeding evolutionary progress. As the mutation rate was increased within a moderate range, deleterious mutation accumulation and mean fitness improvement both increased. The fixation rates were higher than predicted by many population-genetic models. This seemingly paradoxical result was resolved in part by the observation that, during the time to fixation, the selection coefficient (s) of initially deleterious mutations reversed to confer a selective advantage. Significantly, more than half of the fixations of initially deleterious mutations involved fitness reversals. These fitness reversals had a substantial effect on the total fitness of the genome and thus contributed to its success in the population. Despite the relative importance of fitness reversals, however, the probabilities of fixation for both initially beneficial and initially deleterious mutations were exceedingly small (on the order of 10−5 of all mutations).

Deleterious Mutations and Selection for Sex in Finite Diploid Populations

Roze, Denis; Michod, Richard E.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /04/2010 EN
Relevância na Pesquisa
46.44%
In diploid populations, indirect benefits of sex may stem from segregation and recombination. Although it has been recognized that finite population size is an important component of selection for recombination, its effects on selection for segregation have been somewhat less studied. In this article, we develop analytical two- and three-locus models to study the effect of recurrent deleterious mutations on a modifier gene increasing sex, in a finite diploid population. The model also incorporates effects of mitotic recombination, causing loss of heterozygosity (LOH). Predictions are tested using multilocus simulations representing deleterious mutations occurring at a large number of loci. The model and simulations show that excess of heterozygosity generated by finite population size is an important component of selection for sex, favoring segregation when deleterious alleles are nearly additive to dominant. Furthermore, sex tends to break correlations in homozygosity among selected loci, which disfavors sex when deleterious alleles are either recessive or dominant. As a result, we find that it is difficult to maintain costly sex when deleterious alleles are recessive. LOH tends to favor sex when deleterious mutations are recessive...

Evidence for Hitchhiking of Deleterious Mutations within the Human Genome

Chun, Sung; Fay, Justin C.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.54%
Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles.

The Influence of Deleterious Mutations on Adaptation in Asexual Populations

Jiang, Xiaoqian; Xu, Zhao; Li, Jingjing; Shi, Youyi; Wu, Wenwu; Tao, Shiheng
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 14/11/2011 EN
Relevância na Pesquisa
46.53%
We study the dynamics of adaptation in asexual populations that undergo both beneficial and deleterious mutations. In particular, how the deleterious mutations affect the fixation of beneficial mutations was investigated. Using extensive Monte Carlo simulations, we find that in the “strong-selection weak mutation (SSWM)” regime or in the “clonal interference (CI)” regime, deleterious mutations rarely influence the distribution of “selection coefficients of the fixed mutations (SCFM)”; while in the “multiple mutations” regime, the accumulation of deleterious mutations would lead to a decrease in fitness significantly. We conclude that the effects of deleterious mutations on adaptation depend largely on the supply of beneficial mutations. And interestingly, the lowest adaptation rate occurs for a moderate value of selection coefficient of deleterious mutations.

Relative Effectiveness of Mating Success and Sperm Competition at Eliminating Deleterious Mutations in Drosophila melanogaster

Clark, Sean C. A.; Sharp, Nathaniel P.; Rowe, Locke; Agrawal, Aneil F.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 25/05/2012 EN
Relevância na Pesquisa
46.49%
Condition-dependence theory predicts that sexual selection will facilitate adaptation by selecting against deleterious mutations that affect the expression of sexually selected traits indirectly via condition. Recent empirical studies have provided support for this prediction; however, their results do not elucidate the relative effects of pre- and postcopulatory sexual selection on deleterious mutations. We used the Drosophila melanogaster model system to discern the relative contributions of pre- and postcopulatory processes to selection against deleterious mutations. To assess second-male ejaculate competition success (P2; measured as the proportion of offspring attributable to the experimental male) and mating success, mutant and wild-type male D. melanogaster were given the opportunity to mate with females that were previously mated to a standard competitor male. This process was repeated for males subjected to a diet quality manipulation to test for effects of environmentally-manipulated condition on P2 and mating success. While none of the tested mutations affected P2, there was a clear effect of condition. Conversely, several of the mutations affected mating success, while condition showed no effect. Our results suggest that precopulatory selection may be more effective than postcopulatory selection at removing deleterious mutations. The opposite result obtained for our diet manipulation points to an interesting discrepancy between environmental and genetic manipulations of condition...

Experiments on the role of deleterious mutations as stepping stones in adaptive evolution

Covert, Arthur W.; Lenski, Richard E.; Wilke, Claus O.; Ofria, Charles
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.44%
It might seem obvious that deleterious mutations must impede evolution. However, a later mutation may interact with a deleterious predecessor, facilitating otherwise inaccessible adaptations. Although such interactions have been reported before, it is unclear whether they are rare and inconsequential or, alternatively, are important for sustaining adaptation. We studied digital organisms—computer programs that replicate and evolve—to compare adaptation in populations where deleterious mutations were disallowed with unrestricted controls. Control populations achieved higher fitness values because some deleterious mutations acted as stepping stones across otherwise impassable fitness valleys. Deleterious mutations can thus sometimes play a constructive role in adaptive evolution.

Population Growth Inflates the Per-Individual Number of Deleterious Mutations and Reduces Their Mean Effect

Gazave, Elodie; Chang, Diana; Clark, Andrew G.; Keinan, Alon
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /11/2013 EN
Relevância na Pesquisa
46.47%
This study addresses the question of how purifying selection operates during recent rapid population growth such as has been experienced by human populations. This is not a straightforward problem because the human population is not at equilibrium: population genetics predicts that, on the one hand, the efficacy of natural selection increases as population size increases, eliminating ever more weakly deleterious variants; on the other hand, a larger number of deleterious mutations will be introduced into the population and will be more likely to increase in their number of copies as the population grows. To understand how patterns of human genetic variation have been shaped by the interaction of natural selection and population growth, we examined the trajectories of mutations with varying selection coefficients, using computer simulations. We observed that while population growth dramatically increases the number of deleterious segregating sites in the population, it only mildly increases the number carried by each individual. Our simulations also show an increased efficacy of natural selection, reflected in a higher fraction of deleterious mutations eliminated at each generation and a more efficient elimination of the most deleterious ones. As a consequence...

Efficient Purging of Deleterious Mutations in Plants with Haploid Selfing

Szövényi, Péter; Devos, Nicolas; Weston, David J.; Yang, Xiaohan; Hock, Zsófia; Shaw, Jonathan A.; Shimizu, Kentaro K.; McDaniel, Stuart F.; Wagner, Andreas
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em 14/05/2014 EN
Relevância na Pesquisa
46.5%
In diploid organisms, selfing reduces the efficiency of selection in removing deleterious mutations from a population. This need not be the case for all organisms. Some plants, for example, undergo an extreme form of selfing known as intragametophytic selfing, which immediately exposes all recessive deleterious mutations in a parental genome to selective purging. Here, we ask how effectively deleterious mutations are removed from such plants. Specifically, we study the extent to which deleterious mutations accumulate in a predominantly selfing and a predominantly outcrossing pair of moss species, using genome-wide transcriptome data. We find that the selfing species purge significantly more nonsynonymous mutations, as well as a greater proportion of radical amino acid changes which alter physicochemical properties of amino acids. Moreover, their purging of deleterious mutation is especially strong in conserved regions of protein-coding genes. Our observations show that selfing need not impede but can even accelerate the removal of deleterious mutations, and do so on a genome-wide scale.

The Genomic Load of Deleterious Mutations: Relevance to Death in Infancy and Childhood

Morris, James Alfred
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 16/03/2015 EN
Relevância na Pesquisa
46.5%
The human diploid genome has approximately 40,000 functioning conserved genes distributed within 6 billion base pairs of DNA. Most individuals carry a few heterozygous deleterious mutations and this leads to an increased risk of recessive disease in the offspring of cousin unions. Rare recessive disease is more common in the children of cousin marriages than in the general population, even though <1% of marriages in the Western World are between first cousins. But more than 90% of the children of cousin marriages do not have recessive disease and are as healthy as the rest of the population. A mathematical model based on these observations generates simultaneous equations linking the mean number of deleterious mutations in the genome of adults (M), the mean number of new deleterious mutations arising in gametogenesis and passed to the next generation (N) and the number of genes in the human diploid genome (L). The best estimates are that M is <7 and N is approximately 1. The nature of meiosis indicates that deleterious mutations in zygotes will have a Poisson distribution with a mean of M + N. There must be strong selective pressure against zygotes at the upper end of the Poisson distribution otherwise the value of M would rise with each generation. It is suggested that this selection is based on synergistic interaction of heterozygous deleterious mutations acting in large complex highly redundant and robust genetic networks. To maintain the value of M in single figures over many thousands of generations means that the zygote loss must be of the order of 30%. Most of this loss will occur soon after conception but some will occur later; during fetal development...

Rate and effects of spontaneous mutations that affect fitness in mutator Escherichia coli

Gordo, I.; Perfeito, L.; Trindade, S.
Fonte: The Royal Society Publicador: The Royal Society
Tipo: Artigo de Revista Científica
Publicado em 27/04/2010 ENG
Relevância na Pesquisa
56.45%
Knowledge of the mutational parameters that affect the evolution of organisms is of key importance in understanding the evolution of several characteristics of many natural populations, including recombination and mutation rates. In this study, we estimated the rate and mean effect of spontaneous mutations that affect fitness in a mutator strain of Escherichia coli and review some of the estimation methods associated with mutation accumulation (MA) experiments. We performed an MA experiment where we followed the evolution of 50 independent mutator lines that were subjected to repeated bottlenecks of a single individual for approximately 1150 generations. From the decline in mean fitness and the increase in variance between lines, we estimated a minimum mutation rate to deleterious mutations of 0.005 (+0.001 with 95% confidence) and a maximum mean fitness effect per deleterious mutation of 0.03 (+0.01 with 95% confidence). We also show that any beneficial mutations that occur during the MA experiment have a small effect on the estimate of the rate and effect of deleterious mutations, unless their rate is extremely large. Extrapolating our results to the wild-type mutation rate, we find that our estimate of the mutational effects is slightly larger and the inferred deleterious mutation rate slightly lower than previous estimates obtained for non-mutator E. coli.

Identification of deleterious mutations within three human genomes

Chun, Sung; Fay, Justin C.
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /09/2009 EN
Relevância na Pesquisa
46.53%
Each human carries a large number of deleterious mutations. Together, these mutations make a significant contribution to human disease. Identification of deleterious mutations within individual genome sequences could substantially impact an individual's health through personalized prevention and treatment of disease. Yet, distinguishing deleterious mutations from the massive number of nonfunctional variants that occur within a single genome is a considerable challenge. Using a comparative genomics data set of 32 vertebrate species we show that a likelihood ratio test (LRT) can accurately identify a subset of deleterious mutations that disrupt highly conserved amino acids within protein-coding sequences, which are likely to be unconditionally deleterious. The LRT is also able to identify known human disease alleles and performs as well as two commonly used heuristic methods, SIFT and PolyPhen. Application of the LRT to three human genomes reveals 796–837 deleterious mutations per individual, ∼40% of which are estimated to be at <5% allele frequency. However, the overlap between predictions made by the LRT, SIFT, and PolyPhen, is low; 76% of predictions are unique to one of the three methods, and only 5% of predictions are shared across all three methods. Our results indicate that only a small subset of deleterious mutations can be reliably identified...

Effect of drift, selection and recombination on the equilibrium frequency of deleterious mutations

John, Sona; Jain, Kavita
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
46.49%
We study the stationary state of a population evolving under the action of random genetic drift, selection and recombination in which both deleterious and reverse beneficial mutations can occur. We find that the equilibrium fraction of deleterious mutations decreases as the population size is increased. We calculate exactly the steady state frequency in a nonrecombining population when population size is infinite and for a neutral finite population, and obtain bounds on the fraction of deleterious mutations. We also find that for small and very large populations, the number of deleterious mutations depends weakly on recombination, but for moderately large populations, recombination alleviates the effect of deleterious mutations. An analytical argument shows that recombination decreases disadvantageous mutations appreciably when beneficial mutations are rare as is the case in adapting microbial populations, whereas it has a moderate effect on codon bias where the mutation rates between the preferred and unpreferred codons are comparable.; Comment: Revised version, accepted in Journal of Theoretical Biology

The expected effect of deleterious mutations on within-host adaptation of pathogens

Fonville, Judith M.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Article; accepted version
EN
Relevância na Pesquisa
56.54%
This is the author accepted manuscript. The final version is available from American Society for Microbiology at http://jvi.asm.org/content/early/2015/06/23/JVI.00832-15.abstract?cited-by=yes&legid=jvi;JVI.00832-15v1.; Adaptation is a common theme in both pathogen emergence, for example in zoonotic cross-species transmission, and pathogen control, where adaptation might limit the effect of the immune response and antiviral treatment. When such evolution requires deleterious intermediate mutations, fitness ridges and valleys arise in the pathogen?s fitness landscape. The effect of deleterious intermediate mutations on within-host pathogen adaptation is examined with deterministic calculations, appropriate for pathogens replicating in large populations with high error rates. The effect of deleterious intermediates on pathogen adaptation is smaller than their name might suggest: when two mutations are required, and each individual single mutation is fully deleterious, the pathogen can jump across the fitness valley by obtaining two mutations at once, leading to a proportion of adapted mutant that is 20-fold lower than for the situation where all mutants are neutral. The negative effects of deleterious intermediates are typically substantially smaller...