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Transmission bottlenecks as determinants of virulence in rapidly evolving pathogens

Bergstrom, Carl T.; McElhany, Paul; Real, Leslie A.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 27/04/1999 EN
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26.99%
Transmission bottlenecks occur in pathogen populations when only a few individual pathogens are transmitted from one infected host to another in the initiation of a new infection. Transmission bottlenecks can dramatically affect the evolution of virulence in rapidly evolving pathogens such as RNA viruses. Characterizing pathogen diversity with the quasispecies concept, we use analytical and simulation methods to demonstrate that severe bottlenecks are likely to drive down the virulence of a pathogen because of stochastic loss of the most virulent pathotypes, through a process analogous to Muller’s ratchet. We investigate in this process the roles of host population size, duration of within-host viral replication, and transmission bottleneck size. We argue that the patterns of accumulation of deleterious mutation may explain differing levels of virulence in vertically and horizontally transmitted diseases.

Evaluation of Bottlenecks in the Late Stages of Protein Secretion in Bacillus subtilis

Bolhuis, Albert; Tjalsma, Harold; Smith, Hilde E.; de Jong, Anne; Meima, Rob; Venema, Gerard; Bron, Sierd; van Dijl, Jan Maarten
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /07/1999 EN
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27.16%
Despite a high capacity for secretion of homologous proteins, the secretion of heterologous proteins by Bacillus subtilis is frequently inefficient. In the present studies, we have investigated and compared bottlenecks in the secretion of four heterologous proteins: Bacillus lichenifomis α-amylase (AmyL), Escherichia coli TEM β-lactamase (Bla), human pancreatic α-amylase (HPA), and a lysozyme-specific single-chain antibody. The same expression and secretion signals were used for all four of these proteins. Notably, all identified bottlenecks relate to late stages in secretion, following translocation of the preproteins across the cytoplasmic membrane. These bottlenecks include processing by signal peptidase, passage through the cell wall, and degradation in the wall and growth medium. Strikingly, all translocated HPA was misfolded, its stability depending on the formation of disulfide bonds. This suggests that the disulfide bond oxidoreductases of B. subtilis cannot form the disulfide bonds in HPA correctly. As the secretion bottlenecks differed for each heterologous protein tested, it is anticipated that the efficient secretion of particular groups of heterologous proteins with the same secretion bottlenecks will require the engineering of specifically optimized host strains.

Hatching failure increases with severity of population bottlenecks in birds

Briskie, James V.; Mackintosh, Myles
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.16%
Severe bottlenecks can reduce genetic diversity and increase inbreeding as individuals are forced to mate with close relatives, but it is unknown at what minimum population size the negative fitness consequences of bottlenecks are expressed. The New Zealand avifauna contains a large number of species that have gone through bottlenecks of varying severity, providing an exceptional opportunity to test this question by using the comparative method. Using decreased hatchability as a measure of fitness costs, we found that hatching failure was significantly greater among both native and introduced species that had passed through bottlenecks of <150 individuals. Comparisons between pre- and postbottleneck populations of introduced species suggest that hatching problems arise even in populations founded by <600 individuals. Our study confirms that hatching failure is widespread and persistent among birds passing through severe bottlenecks and that the population sizes at which this fitness cost is expressed are several times greater than the number of individuals currently used to found most new populations of endangered species. We recommend that conservation managers revise the protocols they use for reintroductions or they may unwittingly reduce the long-term viability of the species they are trying to save.

Germline Bottlenecks, Biparental Inheritance and Selection on Mitochondrial Variants: A Two-Level Selection Model

Roze, Denis; Rousset, François; Michalakis, Yannis
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /07/2005 EN
Relevância na Pesquisa
27.16%
Selection on mitochondrial mutations potentially occurs at different levels: at the mitochondria, cell, and organism levels. Several factors affect the strength of selection at these different levels; in particular, mitochondrial bottlenecks during germline development and reduced paternal transmission decrease the genetic variance within cells, while they increase the variance between cells and between organisms, thus decreasing the strength of selection within cells and increasing the strength of selection between cells and organisms. However, bottlenecks and paternal transmission also affect the effective mitochondrial population size, thus affecting genetic drift. In this article, we use a simple model of a unicellular life cycle to investigate the effects of bottlenecks and paternal transmission on the probability of fixation of mitochondrial mutants and their frequency at mutation-selection equilibrium. We find that bottlenecks and reduced paternal transmission decrease the mean frequency of alleles with sm > sc (approximately), where sm and sc are the strengths of selection for an allele within and between cells, respectively, and increase the frequency of alleles with sm < sc. Effects on fixation probabilities are different; for example...

Evaluating the impact of population bottlenecks in experimental evolution.

Wahl, Lindi M; Gerrish, Philip J; Saika-Voivod, Ivan
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/2002 EN
Relevância na Pesquisa
27.09%
Experimental evolution involves severe, periodic reductions in population size when fresh media are inoculated during serial transfer. These bottlenecks affect the dynamics of evolution, reducing the probability that a beneficial mutation will reach fixation. We quantify the impact of these bottlenecks on the evolutionary dynamics, for populations that grow exponentially between transfers and for populations in which growth is curbed by a resource-limited environment. We find that in both cases, mutations that survive bottlenecks are equally likely to occur, per unit time, at all times during the growth phase. We estimate the total fraction of beneficial mutations that are lost due to bottlenecks during experimental evolution protocols and derive the "optimal" dilution ratio, the ratio that maximizes the number of surviving beneficial mutations. Although more severe dilution ratios are often used in the literature, we find that a ratio of 0.1-0.2 minimizes the chances that rare beneficial mutations are lost. Finally, we provide a number of useful approximate results and illustrate our approach with applications to experimental evolution protocols in the literature.

Impacts of genetic bottlenecks on soybean genome diversity

Hyten, David L.; Song, Qijian; Zhu, Youlin; Choi, Ik-Young; Nelson, Randall L.; Costa, Jose M.; Specht, James E.; Shoemaker, Randy C.; Cregan, Perry B.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
26.99%
Soybean has undergone several genetic bottlenecks. These include domestication in Asia to produce numerous Asian landraces, introduction of relatively few landraces to North America, and then selective breeding over the past 75 years. It is presumed that these three human-mediated events have reduced genetic diversity. We sequenced 111 fragments from 102 genes in four soybean populations representing the populations before and after genetic bottlenecks. We show that soybean has lost many rare sequence variants and has undergone numerous allele frequency changes throughout its history. Although soybean genetic diversity has been eroded by human selection after domestication, it is notable that modern cultivars have retained 72% of the sequence diversity present in the Asian landraces but lost 79% of rare alleles (frequency ≤0.10) found in the Asian landraces. Simulations indicated that the diversity lost through the genetic bottlenecks of introduction and plant breeding was mostly due to the small number of Asian introductions and not the artificial selection subsequently imposed by selective breeding. The bottleneck with the most impact was domestication; when the low sequence diversity present in the wild species was halved, 81% of the rare alleles were lost...

The Importance of Bottlenecks in Protein Networks: Correlation with Gene Essentiality and Expression Dynamics

Yu, Haiyuan; Kim, Philip M; Sprecher, Emmett; Trifonov, Valery; Gerstein, Mark
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
26.99%
It has been a long-standing goal in systems biology to find relations between the topological properties and functional features of protein networks. However, most of the focus in network studies has been on highly connected proteins (“hubs”). As a complementary notion, it is possible to define bottlenecks as proteins with a high betweenness centrality (i.e., network nodes that have many “shortest paths” going through them, analogous to major bridges and tunnels on a highway map). Bottlenecks are, in fact, key connector proteins with surprising functional and dynamic properties. In particular, they are more likely to be essential proteins. In fact, in regulatory and other directed networks, betweenness (i.e., “bottleneck-ness”) is a much more significant indicator of essentiality than degree (i.e., “hub-ness”). Furthermore, bottlenecks correspond to the dynamic components of the interaction network—they are significantly less well coexpressed with their neighbors than nonbottlenecks, implying that expression dynamics is wired into the network topology.

Population Bottlenecks Promote Cooperation in Bacterial Biofilms

Brockhurst, Michael A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 25/07/2007 EN
Relevância na Pesquisa
26.99%
Population bottlenecks are assumed to play a key role in the maintenance of social traits in microbes. Ecological parameters such as colonisation or disturbances can favour cooperation through causing population bottlenecks that enhance genetic structuring (relatedness). However, the size of the population bottleneck is likely to play a crucial role in determining the success of cooperation. Relatedness is likely to increase with decreasing bottleneck size thus favouring the evolution of cooperation. I used an experimental evolution approach to test this prediction with biofilm formation by the bacterium Pseudomonas fluorescens as the cooperative trait. Replicate populations were exposed to disturbance events every four days under one of six population bottleneck treatments (from 103 to 108 bacterial cells). In line with predictions, the frequency of evolved cheats within the populations increased with increasing bottleneck size. This result highlights the importance of ecologically mediated population bottlenecks in the maintenance of social traits in microbes.

Population Bottlenecks Increase Additive Genetic Variance But Do Not Break a Selection Limit in Rain Forest Drosophila

van Heerwaarden, Belinda; Willi, Yvonne; Kristensen, Torsten N.; Hoffmann, Ary A.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /08/2008 EN
Relevância na Pesquisa
27.09%
According to neutral quantitative genetic theory, population bottlenecks are expected to decrease standing levels of additive genetic variance of quantitative traits. However, some empirical and theoretical results suggest that, if nonadditive genetic effects influence the trait, bottlenecks may actually increase additive genetic variance. This has been an important issue in conservation genetics where it has been suggested that small population size might actually experience an increase rather than a decrease in the rate of adaptation. Here we test if bottlenecks can break a selection limit for desiccation resistance in the rain forest-restricted fly Drosophila bunnanda. After one generation of single-pair mating, additive genetic variance for desiccation resistance increased to a significant level, on average higher than for the control lines. Line crosses revealed that both dominance and epistatic effects were responsible for the divergence in desiccation resistance between the original control and a bottlenecked line exhibiting increased additive genetic variance for desiccation resistance. However, when bottlenecked lines were selected for increased desiccation resistance, there was only a small shift in resistance, much less than predicted by the released additive genetic variance. The small selection response in the bottlenecked lines was no greater than that observed in the control lines. Thus bottlenecks might produce a statistically detectable change in additive genetic variance but this change has no impact on the response to selection.

Travelling on a budget: predictions and ecological evidence for bottlenecks in the annual cycle of long-distance migrants

Buehler, Deborah M; Piersma, Theunis
Fonte: The Royal Society Publicador: The Royal Society
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.16%
Long-distance migration, and the study of the migrants who undertake these journeys, has fascinated generations of biologists. However, many aspects of the annual cycles of these migrants remain a mystery as do many of the driving forces behind the evolution and maintenance of the migrations themselves. In this article we discuss nutritional, energetic, temporal and disease-risk bottlenecks in the annual cycle of long-distance migrants, taking a sandpiper, the red knot Calidris canutus, as a focal species. Red knots have six recognized subspecies each with different migratory routes, well-known patterns of connectivity and contrasting annual cycles. The diversity of red knot annual cycles allows us to discuss the existence and the effects of bottlenecks in a comparative framework. We examine the evidence for bottlenecks focusing on the quality of breeding plumage and the timing of moult as indicators in the six subspecies. In terms of breeding plumage coloration, quality and timing of prealternate body moult (from non-breeding into breeding plumage), the longest migrating knot subspecies, Calidris canutus rogersi and Calidris canutus rufa, show the greatest impact of bottlenecking. The same is true in terms of prebasic body moult (from breeding into non-breeding plumage) which in case of both C. c. rogersi and C. c. rufa overlaps with southward migration and may even commence in the breeding grounds. To close our discussion of bottlenecks in long-distance migrants...

Estimation of the Size of Genetic Bottlenecks in Cell-to-Cell Movement of Soil-Borne Wheat Mosaic Virus and the Possible Role of the Bottlenecks in Speeding Up Selection of Variations in trans-Acting Genes or Elements▿ §

Miyashita, Shuhei; Kishino, Hirohisa
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.21%
Genetic bottlenecks facilitate the fixation and extinction of variants in populations, and viral populations are no exception to this theory. To examine the existence of genetic bottlenecks in cell-to-cell movement of plant RNA viruses, we prepared constructs for Soil-borne wheat mosaic virus RNA2 vectors carrying two different fluorescent proteins, yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP). Coinoculation of host plant leaves with the two RNA2 vectors and the wild-type RNA1 showed separation of the two vector RNA2s, mostly within seven to nine cell-to-cell movements from individual initially coinfected cells. Our statistical analysis showed that the number of viral RNA genomes establishing infection in adjacent cells after the first cell-to-cell movement from an initially infected cell was 5.97 ± 0.22 on average and 5.02 ± 0.29 after the second cell-to-cell movement. These results indicate that plant RNA viruses may generally face narrow genetic bottlenecks in every cell-to-cell movement. Furthermore, our model suggests that, rather than suffering from fitness losses caused by the bottlenecks, the plant RNA viruses are utilizing the repeated genetic bottlenecks as an essential element of rapid selection of their adaptive variants in trans-acting genes or elements to respond to host shifting and changes in the growth conditions of the hosts.

Linkage Disequilibrium Under Recurrent Bottlenecks

Schaper, E.; Eriksson, A.; Rafajlovic, M.; Sagitov, S.; Mehlig, B.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /01/2012 EN
Relevância na Pesquisa
26.99%
To model deviations from selectively neutral genetic variation caused by different forms of selection, it is necessary to first understand patterns of neutral variation. Best understood is neutral genetic variation at a single locus. But, as is well known, additional insights can be gained by investigating multiple loci. The resulting patterns reflect the degree of association (linkage) between loci and provide information about the underlying multilocus gene genealogies. The statistical properties of two-locus gene genealogies have been intensively studied for populations of constant size, as well as for simple demographic histories such as exponential population growth and single bottlenecks. By contrast, the combined effect of recombination and sustained demographic fluctuations is poorly understood. Addressing this issue, we study a two-locus Wright–Fisher model of a population subject to recurrent bottlenecks. We derive coalescent approximations for the covariance of the times to the most recent common ancestor at two loci in samples of two chromosomes. This covariance reflects the degree of association and thus linkage disequilibrium between these loci. We find, first, that an effective population-size approximation describes the numerically observed association between two loci provided that recombination occurs either much faster or much more slowly than the population-size fluctuations. Second...

Circulating Virus Load Determines the Size of Bottlenecks in Viral Populations Progressing within a Host

Gutiérrez, Serafín; Yvon, Michel; Pirolles, Elodie; Garzo, Eliza; Fereres, Alberto; Michalakis, Yannis; Blanc, Stéphane
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
26.99%
For any organism, population size, and fluctuations thereof, are of primary importance in determining the forces driving its evolution. This is particularly true for viruses—rapidly evolving entities that form populations with transient and explosive expansions alternating with phases of migration, resulting in strong population bottlenecks and associated founder effects that increase genetic drift. A typical illustration of this pattern is the progression of viral disease within a eukaryotic host, where such demographic fluctuations are a key factor in the emergence of new variants with altered virulence. Viruses initiate replication in one or only a few infection foci, then move through the vasculature to seed secondary infection sites and so invade distant organs and tissues. Founder effects during this within-host colonization might depend on the concentration of infectious units accumulating and circulating in the vasculature, as this represents the infection dose reaching new organs or “territories”. Surprisingly, whether or not the easily measurable circulating (plasma) virus load directly drives the size of population bottlenecks during host colonization has not been documented in animal viruses, while in plants the virus load within the sap has never been estimated. Here...

Bottlenecks of Motion Processing during a Visual Glance: The Leaky Flask Model

Öğmen, Haluk; Ekiz, Onur; Huynh, Duong; Bedell, Harold E.; Tripathy, Srimant P.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 31/12/2013 EN
Relevância na Pesquisa
27.16%
Where do the bottlenecks for information and attention lie when our visual system processes incoming stimuli? The human visual system encodes the incoming stimulus and transfers its contents into three major memory systems with increasing time scales, viz., sensory (or iconic) memory, visual short-term memory (VSTM), and long-term memory (LTM). It is commonly believed that the major bottleneck of information processing resides in VSTM. In contrast to this view, we show major bottlenecks for motion processing prior to VSTM. In the first experiment, we examined bottlenecks at the stimulus encoding stage through a partial-report technique by delivering the cue immediately at the end of the stimulus presentation. In the second experiment, we varied the cue delay to investigate sensory memory and VSTM. Performance decayed exponentially as a function of cue delay and we used the time-constant of the exponential-decay to demarcate sensory memory from VSTM. We then decomposed performance in terms of quality and quantity measures to analyze bottlenecks along these dimensions. In terms of the quality of information, two thirds to three quarters of the motion-processing bottleneck occurs in stimulus encoding rather than memory stages. In terms of the quantity of information...

Genome-wide signatures of population bottlenecks and diversifying selection in European wolves

Pilot, M; Greco, C; vonHoldt, B M; Jędrzejewska, B; Randi, E; Jędrzejewski, W; Sidorovich, V E; Ostrander, E A; Wayne, R K
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.16%
Genomic resources developed for domesticated species provide powerful tools for studying the evolutionary history of their wild relatives. Here we use 61K single-nucleotide polymorphisms (SNPs) evenly spaced throughout the canine nuclear genome to analyse evolutionary relationships among the three largest European populations of grey wolves in comparison with other populations worldwide, and investigate genome-wide effects of demographic bottlenecks and signatures of selection. European wolves have a discontinuous range, with large and connected populations in Eastern Europe and relatively smaller, isolated populations in Italy and the Iberian Peninsula. Our results suggest a continuous decline in wolf numbers in Europe since the Late Pleistocene, and long-term isolation and bottlenecks in the Italian and Iberian populations following their divergence from the Eastern European population. The Italian and Iberian populations have low genetic variability and high linkage disequilibrium, but relatively few autozygous segments across the genome. This last characteristic clearly distinguishes them from populations that underwent recent drastic demographic declines or founder events, and implies long-term bottlenecks in these two populations. Although genetic drift due to spatial isolation and bottlenecks seems to be a major evolutionary force diversifying the European populations...

The effect of population bottlenecks on mutation rate evolution in asexual populations

Raynes, Yevgeniy; Halstead, Angela L.; Sniegowski, Paul D.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.21%
In the absence of recombination, a mutator allele can spread through a population by hitchhiking with beneficial mutations that appear in its genetic background. Theoretical studies over the past decade have shown that the survival and fixation probability of beneficial mutations can be severely reduced by population size bottlenecks. Here we use computational modeling and evolution experiments with the yeast S. cerevisiae to examine whether population bottlenecks can affect mutator dynamics in adapting asexual populations. In simulation, we show that population bottlenecks can inhibit mutator hitchhiking with beneficial mutations and are most effective at lower beneficial mutation supply rates. We then subjected experimental populations of yeast propagated at the same effective population size to three different bottleneck regimes and observed that the speed of mutator hitchhiking was significantly slower at smaller bottlenecks, consistent with our theoretical expectations. Our results, thus, suggest that bottlenecks can be an important factor in mutation rate evolution and can in certain circumstances act to stabilize or, at least, delay the progressive elevation of mutation rates in asexual populations. Additionally, our findings provide the first experimental support for the theoretically postulated effect of population bottlenecks on beneficial mutations and demonstrate the usefulness of studying mutator frequency dynamics for understanding the underlying dynamics of fitness-effecting mutations.

Bottlenecks, Modules and Dynamic Architectural Capabilities

Baldwin, Carliss Young
Fonte: Harvard University Publicador: Harvard University
Tipo: Research Paper or Report
EN_US
Relevância na Pesquisa
27.09%
How do firms create and capture value in large technical systems? In this paper, I argue that the points of both value creation and value capture are the system’s bottlenecks. Bottlenecks arise first as important technical problems to be solved. Once the problem is solved, the solution in combination with property rights can be used to capture a stream of rents. The tools a firm can use to manage bottlenecks are, first, an understanding of the technical architecture of the system; and, second, an understanding of the industry architecture in which the technical system is embedded. Although these tools involve disparate bodies of knowledge, they must be used in tandem to achieve maximum effect. Architectural capabilities provide managers with the ability to see a complex technical system in an abstract way and change the system’s structure to manage bottlenecks and modules in conjunction with the firm’s organizational boundaries and property rights.

Economic Analysis of Production Bottlenecks

Lawrence, Stephen R.; Buss, Arnold H.
Fonte: Escola de Pós-Graduação Naval Publicador: Escola de Pós-Graduação Naval
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
37.25%
The management of bottlenecks has become a central topic in the planning and control of production systems. In this paper, we critically analyze bottlenecks from an economic perspective. Using a queueing network model, we demonstrate that bottlenecks are inevitable when there are differences in job arrival rates, processing rates, or costs of productive resources. These differences naturally lead to the creation of bottlenecks both for facilities design and demand planning problems. To evaluate bottlenecks from an economic perspective, we develop the notion of an "economic bottleneck," which defines resources as bottlenecks based on economic, rather than physical, characteristics.

New insights into pedestrian flow through bottlenecks

Seyfried, Armin; Rupprecht, Tobias; Passon, Oliver; Steffen, Bernhard; Klingsch, Wolfram; Boltes, Maik
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
27.09%
Capacity estimation is an important tool for the design and dimensioning of pedestrian facilities. The literature contains different procedures and specifications which show considerable differences with respect to the estimated flow values. Moreover do new experimental data indicate a stepwise growing of the capacity with the width and thus challenge the validity of the specific flow concept. To resolve these differences we have studied experimentally the unidirectional pedestrian flow through bottlenecks under laboratory conditions. The time development of quantities like individual velocities, density and individual time gaps in bottlenecks of different width is presented. The data show a linear growth of the flow with the width. The comparison of the results with experimental data of other authors indicates that the basic assumption of the capacity estimation for bottlenecks has to be revised. In contradiction with most planning guidelines our main result is, that a jam occurs even if the incoming flow does not overstep the capacity defined by the maximum of the flow according to the fundamental diagram.; Comment: Traffic flow, pedestrian traffic, crowd dynamics, capacity of bottlenecks (16 pages, 8 figures); (+ 3 new figures and minor revisions)

Linkage disequilibrium under recurrent bottlenecks

Schaper, E.; Eriksson, A.; Rafajlovic, M.; Sagitov, S.; Mehlig, B.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 03/05/2011
Relevância na Pesquisa
27.09%
Understanding patterns of selectively neutral genetic variation is essential in order to model deviations from neutrality, caused for example by different forms of selection. Best understood is neutral genetic variation at a single locus, but additional insights can be gained by investigating genetic variation at multiple loci. The corresponding patterns of variation reflect linkage disequilibrium and provide information about the underlying multi-locus gene genealogies. The statistical properties of two-locus genealogies have been intensively studied for populations of constant census size, as well as for simple demographic histories such as exponential population growth, and single bottlenecks. By contrast, the combined effect of recombination and sustained demographic fluctuations is poorly understood. Addressing this issue, we study a two-locus Wright-Fisher model of a population subject to recurrent bottlenecks. We derive coalescent approximations for the covariance of the times to the most recent common ancestor at two loci. We find, first, that an effective population-size approximation describes the numerically observed linkage disequilibrium provided that recombination occurs either much faster or much more slowly than the population size changes. Second...