Minimum Number Of Recombination Events Research Articles

Genetic polymorphism of circumsporozoite protein of Plasmodium falciparum among Chinese migrant workers returning from Africa to Henan Province

BackgroundPlasmodium falciparum malaria is recognized as a major global public health problem. The malaria vaccine was important because the case fatality rate of falciparum malaria was high. Plasmodium falciparum circumsporozoite protein (PfCSP) is one of the potential vaccine candidates, but the genetic polymorphism of PfCSP raises concerns regarding the efficacy of the vaccine. This study aimed to investigate the genetic polymorphism of PfCSP and provide data for the improvement of PfCSP-based vaccine (RTS,S malaria vaccine).MethodsBlood samples were collected from 287 Chinese migrant workers who were infected with P. falciparum and returning from Africa to Henan Province during 2016–2018. The Pfcsp genes were analysed to estimate the genetic diversity of this parasite.ResultsThe results showed that there were two mutations at the N-terminus of imported Pfcsp in Henan Province, including insertion amino acids (58.71%, 118/201) and A → G (38.81%, 78/201). The number of repeats of tetrapeptide motifs (NANP/NVDP/NPNP/NVDA) in the central repeat region ranged mainly from 39 to 42 (97.51%, 196/201). A total of 14 nonsynonymous amino acid changes were found at the C-terminus. The average nucleotide difference (K) of imported Pfcsp in Henan Province was 5.719, and the haplotype diversity (Hd) was 0.964 ± 0.004. The estimated value of dN-dS was 0.047, indicating that the region may be affected by positive natural selection. The minimum number of recombination events (Rm) of imported Pfcsp in Henan Province was close to that in Africa. The analysis of genetic differentiation showed that there may be moderate differentiation between East Africa and North Africa (Fst = 0.06484), and the levels of differentiation in the other regions were very small (Fst < 0.05).ConclusionsThe N-terminus of Pfcsp was relatively conserved, and the central repeat region and the Th2R and Th3R regions of the C-terminus were highly polymorphic. The gene polymorphism pattern among Chinese migrant workers returning from Africa to Henan Province was consistent with that in Africa. The geographical pattern of population differentiation and the evidence of natural selection and gene recombination suggested that the effect of polymorphism on the efficacy of PfCSP-based vaccines should be considered.

Natural selection and population genetic structure of domain-I of Plasmodium falciparum apical membrane antigen-1 in India

Development of a vaccine against Plasmodium falciparum infection is an urgent priority particularly because of widespread resistance to most traditionally used drugs. Multiple evidences point to apical membrane antigen-1(AMA-1) as a prime vaccine candidate directed against P. falciparum asexual blood-stages. To gain understanding of the genetic and demographic forces shaping the parasite sequence diversity in Kolkata, a part of Pfama-1 gene covering domain-I was sequenced from 100 blood samples of malaria patients. Statistical and phylogenetic analyses of the sequences were performed using DnaSP and MEGA. Very high haplotype diversity was detected both at nucleotide (0.998±0.002) and amino-acid (0.996±0.001) levels. An abundance of low frequency polymorphisms (Tajima’s D=−1.190, Fu & Li’s D∗ and F∗=−3.068 and −2.722), unimodal mismatch distribution and a star-like median-joining network of ama-1 haplotypes indicated a recent population expansion among Kolkata parasites. The high minimum number of recombination events (Rm=26) and a significantly high dN/dS of 3.705 (P<0.0001) in Kolkata suggested recombination and positive selection as major forces in the generation and maintenance of ama-1 allelic diversity. To evaluate the impact of observed non-synonymous substitutions in the context of AMA-1 functionality, PatchDock and FireDock protein–protein interaction solutions were mapped between PfAMA-1-PfRON2 and PfAMA-1-host IgNAR. Alterations in the desolvation and global energies of PfAMA-1-PfRON2 interaction complexes at the hotspot contact residues were observed together with redistribution of surface electrostatic potentials at the variant alleles with respect to referent Pf3D7 sequence. Finally, a comparison of P. falciparum subpopulations in five Indian regional isolates retrieved from GenBank revealed a significant level of genetic differentiation (FST=0.084–0.129) with respect to Kolkata sequences. Collectively, our results indicated a very high allelic and haplotype diversity, a high recombination rate and a signature of natural selection favoring accumulation of non-synonymous substitutions that facilitated PfAMA-1-PfRON2 interaction and hence parasite growth in Kolkata clinical isolates.

Genome-Wide Survey of Mutual Homologous Recombination in a Highly Sexual Bacterial Species

The nature of a species remains a fundamental and controversial question. The era of genome/metagenome sequencing has intensified the debate in prokaryotes because of extensive horizontal gene transfer. In this study, we conducted a genome-wide survey of outcrossing homologous recombination in the highly sexual bacterial species Helicobacter pylori. We conducted multiple genome alignment and analyzed the entire data set of one-to-one orthologous genes for its global strains. We detected mosaic structures due to repeated recombination events and discordant phylogenies throughout the genomes of this species. Most of these genes including the “core” set of genes and horizontally transferred genes showed at least one recombination event. Taking into account the relationship between the nucleotide diversity and the minimum number of recombination events per nucleotide, we evaluated the recombination rate in every gene. The rate appears constant across the genome, but genes with a particularly high or low recombination rate were detected. Interestingly, genes with high recombination included those for DNA transformation and for basic cellular functions, such as biosynthesis and metabolism. Several highly divergent genes with a high recombination rate included those for host interaction, such as outer membrane proteins and lipopolysaccharide synthesis. These results provide a global picture of genome-wide distribution of outcrossing homologous recombination in a bacterial species for the first time, to our knowledge, and illustrate how a species can be shaped by mutual homologous recombination.

Haplotype inference in general pedigrees with two sites

BackgroundGenetic disease studies investigate relationships between changes in chromosomes and genetic diseases. Single haplotypes provide useful information for these studies but extracting single haplotypes directly by biochemical methods is expensive. A computational method to infer haplotypes from genotype data is therefore important. We investigate the problem of computing the minimum number of recombination events for general pedigrees with two sites for all members.ResultsWe show that this NP-hard problem can be parametrically reduced to the Bipartization by Edge Removal problem and therefore can be solved by an O(2k · n2) exact algorithm, where n is the number of members and k is the number of recombination events.ConclusionsOur work can therefore be useful for genetic disease studies to track down how changes in haplotypes such as recombinations relate to genetic disease.

An FPT haplotyping algorithm on pedigrees with a small number of sites

BackgroundGenetic disease studies investigate relationships between changes in chromosomes and genetic diseases. Single haplotypes provide useful information for these studies but extracting single haplotypes directly by biochemical methods is expensive. A computational method to infer haplotypes from genotype data is therefore important. We investigate the problem of computing the minimum number of recombination events for general pedigrees with a small number of sites for all members.ResultsWe show that this NP-hard problem can be parametrically reduced to the Bipartization by Edge Removal problem with additional parity constraints. We solve this problem with an exact algorithm that runs in time, where n is the number of members, m is the number of sites, and k is the number of recombination events.ConclusionsThis algorithm infers haplotypes for a small number of sites, which can be useful for genetic disease studies to track down how changes in haplotypes such as recombinations relate to genetic disease.

Algorithms to estimate the lower bounds of recombination with or without recurrent mutations

BackgroundAn important method to quantify the effects of recombination on populations is to estimate the minimum number of recombination events, Rmin, in the history of a DNA sample. People have focused on estimating the lower bound of Rmin, because it is also a valid lower bound for the true number of recombination events occurred. Current approaches for estimating the lower bound are under the assumption of the infinite site model and do not allow for recurrent mutations. However, recurrent mutations are relatively common in genes with high mutation rates or mutation hot-spots, such as those in the genomes of bacteria or viruses.ResultsIn this paper two new algorithms were proposed for estimating the lower bound of Rmin under the infinite site model. Their performances were compared to other bounds currently in use. The new lower bounds were further extended to allow for recurrent mutations. Application of these methods were demonstrated with two haplotype data sets.ConclusionsThese new algorithms would help to obtain a better estimation of the lower bound of Rmin under the infinite site model. After extension to allow for recurrent mutations, they can produce robust estimations with the existence of high mutation rate or mutation hot-spots. They can also be used to show different combinations of recurrent mutations and recombinations that can produce the same polymorphic pattern in the sample.

An efficiently computed lower bound on the number of recombinations in phylogenetic networks: Theory and empirical study

Phylogenetic networks are models of sequence evolution that go beyond trees, allowing biological operations that are not tree-like. One of the most important biological operations is recombination between two sequences. An established problem [J. Hein, Reconstructing evolution of sequences subject to recombination using parsimony, Math. Biosci. 98 (1990) 185–200; J. Hein, A heuristic method to reconstruct the history of sequences subject to recombination, J. Molecular Evoluation 36 (1993) 396–405; Y. Song, J. Hein, Parsimonious reconstruction of sequence evolution and haplotype blocks: finding the minimum number of recombination events, in: Proceedings of 2003 Workshop on Algorithms in Bioinformatics, Berlin, Germany, 2003, Lecture Notes in Computer Science, Springer, Berlin; Y. Song, J. Hein, On the minimum number of recombination events in the evolutionary history of DNA sequences, J. Math. Biol. 48 (2003) 160–186; L. Wang, K. Zhang, L. Zhang, Perfect phylogenetic networks with recombination, J. Comput. Biol. 8 (2001) 69–78; S.R. Myers, R.C. Griffiths, Bounds on the minimum number of recombination events in a sample history, Genetics 163 (2003) 375–394; V. Bafna, V. Bansal, Improved recombination lower bounds for haplotype data, in: Proceedings of RECOMB, 2005; Y. Song, Y. Wu, D. Gusfield, Efficient computation of close lower and upper bounds on the minimum number of needed recombinations in the evolution of biological sequences, Bioinformatics 21 (2005) i413–i422. Bioinformatics (Suppl. 1), Proceedings of ISMB, 2005, D. Gusfield, S. Eddhu, C. Langley, Optimal, efficient reconstruction of phylogenetic networks with constrained recombination, J. Bioinform. Comput. Biol. 2(1) (2004) 173–213; D. Gusfield, Optimal, efficient reconstruction of root-unknown phylogenetic networks with constrained and structured recombination, J. Comput. Systems Sci. 70 (2005) 381–398] is to find a phylogenetic network that derives an input set of sequences, minimizing the number of recombinations used. No efficient, general algorithm is known for this problem. Several papers consider the problem of computing a lower bound on the number of recombinations needed. In this paper we establish a new, efficiently computed lower bound. This result is useful in methods to estimate the number of needed recombinations, and also to prove the optimality of algorithms for constructing phylogenetic networks under certain conditions [D. Gusfield, S. Eddhu, C. Langley, Optimal, efficient reconstruction of phylogenetic networks with constrained recombination, J. Bioinform. Comput. Biol. 2(1) (2004) 173–213; D. Gusfield, Optimal, efficient reconstruction of root-unknown phylogenetic networks with constrained and structured recombination, J. Comput. Systems Sci. 70 (2005) 381–398; D. Gusfield, Optimal, efficient reconstruction of root-unknown phylogenetic networks with constrained recombination, Technical Report, Department of Computer Science, University of California, Davis, CA, 2004]. The lower bound is based on a structural, combinatorial insight, using only the site conflicts and incompatibilities, and hence it is fundamental and applicable to many biological phenomena other than recombination, for example, when gene conversions or recurrent or back mutations or cross-species hybridizations cause the phylogenetic history to deviate from a tree structure. In addition to establishing the bound, we examine its use in more complex lower bound methods, and compare the bounds obtained to those obtained by other established lower bound methods.

Inference about Recombination from Haplotype Data: Lower Bounds and Recombination Hotspots

Recombination is an important evolutionary mechanism responsible for creating the patterns of haplotype variation observable in human populations. Recently, there has been extensive research on understanding the fine-scale variation in recombination across the human genome using DNA polymorphism data. Historical recombination events leave signature patterns in haplotype data. A nonparametric approach for estimating the number of historical recombination events is to compute the minimum number of recombination events in the history of a set of haplotypes. In this paper, we provide new and improved methods for computing lower bounds on the minimum number of recombination events. These methods are shown to detect a higher number of recombination events for a haplotype dataset from a region in the lipoprotein lipase gene than previous lower bounds. We apply our methods to two datasets for which recombination hotspots have been experimentally determined and demonstrate a high density of detectable recombination events in the regions annotated as recombination hotspots. The programs implementing the methods in this paper are available at www.cs.ucsd.edu/users/vibansal/RecBounds/.

Recombination hotspots as a point process

The variation of the recombination rate along chromosomal DNA is one of the important determinants of the patterns of linkage disequilibrium. A number of inferential methods have been developed which estimate the recombination rate and its variation from population genetic data. The majority of these methods are based on modelling the genealogical process underlying a sample of DNA sequences and thus explicitly include a model of the demographic process. Here we propose a different inferential procedure based on a previously introduced framework where recombination is modelled as a point process along a DNA sequence. The approach infers regions containing putative hotspots based on the inferred minimum number of recombination events; it thus depends only indirectly on the underlying population demography. A Poisson point process model with local rates is then used to infer patterns of recombination rate estimation in a fully Bayesian framework. We illustrate this new approach by applying it to several population genetic datasets, including a region with an experimentally confirmed recombination hotspot.

Constructing Minimal Ancestral Recombination Graphs

By viewing the ancestral recombination graph as defining a sequence of trees, we show how possible evolutionary histories consistent with given data can be constructed using the minimum number of recombination events. In contrast to previously known methods, which yield only estimated lower bounds, our method of detecting recombination always gives the minimum number of recombination events if the right kind of rooted trees are used in our algorithm. A new lower bound can be defined if rooted trees with fewer constraints are used. As well as studying how often it actually is equal to the minimum, we test how this new lower bound performs in comparison to some other lower bounds. Our study indicates that the new lower bound is an improvement on earlier bounds. Also, using simulated data, we investigate how well our method can recover the actual site-specific evolutionary relationships. In the presence of recombination, using a single tree to describe the evolution of the entire locus clearly leads to lower average recovery percentages than does our method. Our study shows that recovering the actual local tree topologies can be done more accurately than estimating the actual number of recombination events.

The number of recombination events in a sample history: conflict graph and lower bounds

We consider the following problem: Given a set of binary sequences, determine lower bounds on the minimum number of recombinations required to explain the history of the sample, under the infinite-sites model of mutation. The problem has implications for finding recombination hotspots and for the Ancestral Recombination Graph reconstruction problem. Hudson and Kaplan gave a lower bound based on the four-gamete test. In practice, their bound Rm often greatly underestimates the minimum number of recombinations. The problem was recently revisited by Myers and Griffiths, who introduced two new lower bounds Rh and Rs which are provably better, and also yield good bounds in practice. However, the worst-case complexities of their procedures for computing Rh and Rs are exponential and super-exponential, respectively. In this paper, we show that the number of nontrivial connected components, Rc, in the conflict graph for a given set of sequences, computable in time O(nm2), is also a lower bound on the minimum number of recombination events. We show that in many cases, Rc is a better bound than Rh. The conflict graph was used by Gusfield et al. to obtain a polynomial time algorithm for the galled tree problem, which is a special case of the Ancestral Recombination Graph (ARG) reconstruction problem. Our results also offer some insight into the structural properties of this graph and are of interest for the general Ancestral Recombination Graph reconstruction problem.

On the minimum number of recombination events in the evolutionary history of DNA sequences.

In representing the evolutionary history of a set of binary DNA sequences by a connected graph, a set theoretical approach is introduced for studying recombination events. We show that set theoretical constraints have direct implications on the number of recombination events. We define a new lower bound on the number of recombination events and demonstrate the usefulness of our new approach through several explicit examples.

Bounds on the minimum number of recombination events in a sample history.

Recombination is an important evolutionary factor in many organisms, including humans, and understanding its effects is an important task facing geneticists. Detecting past recombination events is thus important; this article introduces statistics that give a lower bound on the number of recombination events in the history of a sample, on the basis of the patterns of variation in the sample DNA. Such lower bounds are appropriate, since many recombination events in the history are typically undetectable, so the true number of historical recombinations is unobtainable. The statistics can be calculated quickly by computer and improve upon the earlier bound of Hudson and Kaplan 1985. A method is developed to combine bounds on local regions in the data to produce more powerful improved bounds. The method is flexible to different models of recombination occurrence. The approach gives recombination event bounds between all pairs of sites, to help identify regions with more detectable recombinations, and these bounds can be viewed graphically. Under coalescent simulations, there is a substantial improvement over the earlier method (of up to a factor of 2) in the expected number of recombination events detected by one of the new minima, across a wide range of parameter values. The method is applied to data from a region within the lipoprotein lipase gene and the amount of detected recombination is substantially increased. Further, there is strong clustering of detected recombination events in an area near the center of the region. A program implementing these statistics, which was used for this article, is available from http://www.stats.ox.ac.uk/mathgen/programs.html.

On the minimum number of topologies explaining a sample of DNA sequences

In this article I derive an alternative algorithm to Hudson and Kaplan's ( Genetics 111, 147–165) algorithm that gives a lower bound to the number of recombination events in a sample's history. It is shown that the number, T M , found by the algorithm is the least number of topologies required to explain a set of DNA sequences sampled under the infinite-site assumption. Let T=(T 1,…,T r) be a list of topologies compatible with the sequences, i.e., T k is compatible with an interval, I k , of sites in the alignment. A characterization of all lists having T M topologies is given and it is shown that T M relates to specific patterns in the alignment, here called chain series. Further, a number of theorems relating general lists of topologies to the number T M is presented. The results are discussed in relation to the true minimum number of recombination events required to explain an alignment.

Recombination is proportional to the number of chromosome arms in mammals.

Recombination is proportional to the number of chromosome arms in mammals.

Perfect Phylogenetic Networks with Recombination

The perfect phylogeny problem is a classical problem in evolutionary tree construction. In this paper, we propose a new model called phylogenetic network with recombination that takes recombination events into account. We show that the problem of finding a perfect phylogenetic network with the minimum number of recombination events is NP-hard; we also present an efficient polynomial time algorithm for an interesting restricted version of the problem.

Build Your Own Map

Biotech Software & Internet ReportVol. 1, No. 3 Views from the WebBuild Your Own MapDarryl NishimuraDarryl NishimuraSearch for more papers by this authorPublished Online:5 Jul 2004https://doi.org/10.1089/152791600414415AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetails Volume 1Issue 3Jun 2000 To cite this article:Darryl Nishimura.Build Your Own Map.Biotech Software & Internet Report.Jun 2000.68-70.http://doi.org/10.1089/152791600414415Published in Volume: 1 Issue 3: July 5, 2004PDF download

A Comparison of Estimators of the Population Recombination Rate

Three new estimators of the population recombination rate C = 4Nr are introduced. These estimators summarize the data using the number of distinct haplotypes and the estimated minimum number of recombination events, then calculate the value of C that maximizes the likelihood of obtaining the summarized data. They are compared with a number of previously proposed estimators of the recombination rate. One of the newly proposed estimators is generally better than the others for the parameter values considered here, while the three programs that calculate maximum-likelihood estimates give conflicting results.