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Saturday, April 20, 2019

Horizontal gene transfer

From Wikipedia, the free encyclopedia

Tree of life showing vertical and horizontal gene transfers
 
Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between unicellular and/or multicellular organisms other than by the ("vertical") transmission of DNA from parent to offspring (reproduction). HGT is an important factor in the evolution of many organisms.

Horizontal gene transfer is the primary mechanism for the spread of antibiotic resistance in bacteria, and plays an important role in the evolution of bacteria that can degrade novel compounds such as human-created pesticides and in the evolution, maintenance, and transmission of virulence. It often involves temperate bacteriophages and plasmids. Genes responsible for antibiotic resistance in one species of bacteria can be transferred to another species of bacteria through various mechanisms of HGT such as transformation, transduction and conjugation, subsequently arming the antibiotic resistant genes' recipient against antibiotics. The rapid spread of antibiotic resistance genes in this manner is becoming medically challenging to deal with. Ecological factors may also play a role in the LGT of antibiotic resistant genes. It is also postulated that HGT promotes the maintenance of a universal life biochemistry and, subsequently, the universality of the genetic code.

Most thinking in genetics has focused upon vertical transfer, but the importance of horizontal gene transfer among single-cell organisms is beginning to be acknowledged.

Gene delivery can be seen as an artificial horizontal gene transfer, and is a form of genetic engineering.

History

Griffith's experiment, reported in 1928 by Frederick Griffith, was the first experiment suggesting that bacteria are capable of transferring genetic information through a process known as transformation. Griffith's findings were followed by research in the late 1930s and early 40s that isolated DNA as the material that communicated this genetic information. 

Horizontal genetic transfer was then described in Seattle in 1951, in a paper demonstrating that the transfer of a viral gene into Corynebacterium diphtheriae created a virulent strain from a non-virulent strain, also simultaneously solving the riddle of diphtheria (that patients could be infected with the bacteria but not have any symptoms, and then suddenly convert later or never), and giving the first example for the relevance of the lysogenic cycle. Inter-bacterial gene transfer was first described in Japan in a 1959 publication that demonstrated the transfer of antibiotic resistance between different species of bacteria. In the mid-1980s, Syvanen predicted that lateral gene transfer existed, had biological significance, and was involved in shaping evolutionary history from the beginning of life on Earth. 

As Jian, Rivera and Lake (1999) put it: "Increasingly, studies of genes and genomes are indicating that considerable horizontal transfer has occurred between prokaryotes". The phenomenon appears to have had some significance for unicellular eukaryotes as well. As Bapteste et al. (2005) observe, "additional evidence suggests that gene transfer might also be an important evolutionary mechanism in protist evolution."

Grafting of one plant to another can transfer chloroplasts (organelles in plant cells that conduct photosynthesis), mitochondrial DNA, and the entire cell nucleus containing the genome to potentially make a new species. Some Lepidoptera (e.g. monarch butterflies and silkworms) have been genetically modified by horizontal gene transfer from the wasp bracovirus. Bites from the insect Reduviidae (assassin bug) can, via a parasite, infect humans with the trypanosomal Chagas disease, which can insert its DNA into the human genome. It has been suggested that lateral gene transfer to humans from bacteria may play a role in cancer.

Aaron Richardson and Jeffrey D. Palmer state: "Horizontal gene transfer (HGT) has played a major role in bacterial evolution and is fairly common in certain unicellular eukaryotes. However, the prevalence and importance of HGT in the evolution of multicellular eukaryotes remain unclear."

Due to the increasing amount of evidence suggesting the importance of these phenomena for evolution molecular biologists such as Peter Gogarten have described horizontal gene transfer as "A New Paradigm for Biology".

Mechanisms

There are several mechanisms for horizontal gene transfer:
  • Transformation, the genetic alteration of a cell resulting from the introduction, uptake and expression of foreign genetic material (DNA or RNA). This process is relatively common in bacteria, but less so in eukaryotes. Transformation is often used in laboratories to insert novel genes into bacteria for experiments or for industrial or medical applications. See also molecular biology and biotechnology.
  • Transduction, the process in which bacterial DNA is moved from one bacterium to another by a virus (a bacteriophage, or phage).
  • Bacterial conjugation, a process that involves the transfer of DNA via a plasmid from a donor cell to a recombinant recipient cell during cell-to-cell contact.
  • Gene transfer agents, virus-like elements encoded by the host that are found in the alphaproteobacteria order Rhodobacterales.

Horizontal transposon transfer

A transposable element (TE) (also called a transposon or jumping gene) is a mobile segment of DNA that can sometimes pick up a resistance gene and insert it into a plasmid or chromosome, thereby inducing horizontal gene transfer of antibiotic resistance.

Horizontal transposon transfer (HTT) refers to the passage of pieces of DNA that are characterized by their ability to move from one locus to another between genomes by means other than parent-to-offspring inheritance. Horizontal gene transfer has long been thought to be crucial to prokaryotic evolution, but there is a growing amount of data showing that HTT is a common and widespread phenomenon in eukaryote evolution as well. On the transposable element side, spreading between genomes via horizontal transfer may be viewed as a strategy to escape purging due to purifying selection, mutational decay and/or host defense mechanisms.

HTT can occur with any type of transposable elements, but DNA transposons and LTR retroelements are more likely to be capable of HTT because both have a stable, double-stranded DNA intermediate that is thought to be sturdier than the single-stranded RNA intermediate of non-LTR retroelements, which can be highly degradable. Non-autonomous elements may be less likely to transfer horizontally compared to autonomous elements because they do not encode the proteins required for their own mobilization. The structure of these non-autonomous elements generally consists of an intronless gene encoding a transposase protein, and may or may not have a promoter sequence. Those that do not have promoter sequences encoded within the mobile region rely on adjacent host promoters for expression. Horizontal transfer is thought to play an important role in the TE life cycle.

HTT has been shown to occur between species and across continents in both plants and animals (Ivancevic et al. 2013), though some TEs have been shown to more successfully colonize the genomes of certain species over others. Both spatial and taxonomic proximity of species has been proposed to favor HTTs in plants and animals. It is unknown how the density of a population may affect the rate of HTT events within a population, but close proximity due to parasitism and cross contamination due to crowding have been proposed to favor HTT in both plants and animals. Successful transfer of a transposable element requires delivery of DNA from donor to host cell (and to the germ line for multi-cellular organisms), followed by integration into the recipient host genome. Though the actual mechanism for the transportation of TEs from donor cells to host cells is unknown, it is established that naked DNA and RNA can circulate in bodily fluid. Many proposed vectors include arthropods, viruses, freshwater snails (Ivancevic et al. 2013), endosymbiotic bacteria, and intracellular parasitic bacteria. In some cases, even TEs facilitate transport for other TEs.

The arrival of a new TE in a host genome can have detrimental consequences because TE mobility may induce mutation. However, HTT can also be beneficial by introducing new genetic material into a genome and promoting the shuffling of genes and TE domains among hosts, which can be co-opted by the host genome to perform new functions. Moreover, transposition activity increases the TE copy number and generates chromosomal rearrangement hotspots. HTT detection is a difficult task because it is an ongoing phenomenon that is constantly changing in frequency of occurrence and composition of TEs inside host genomes. Furthermore, few species have been analyzed for HTT, making it difficult to establish patterns of HTT events between species. These issues can lead to the underestimation or overestimation of HTT events between ancestral and current eukaryotic species.

Methods of detection

A speciation event produces orthologs of a gene in the two daughter species. A horizontal gene transfer event from one species to another adds a xenolog of the gene to the receiving genome.

Horizontal gene transfer is typically inferred using bioinformatics methods, either by identifying atypical sequence signatures ("parametric" methods) or by identifying strong discrepancies between the evolutionary history of particular sequences compared to that of their hosts. The transferred gene (xenolog) found in the receiving species is more closely related to the genes of the donor species than would be expected.

Viruses

The virus called Mimivirus infects amoebae. Another virus, called Sputnik, also infects amoebae, but it cannot reproduce unless mimivirus has already infected the same cell. "Sputnik's genome reveals further insight into its biology. Although 13 of its genes show little similarity to any other known genes, three are closely related to mimivirus and mamavirus genes, perhaps cannibalized by the tiny virus as it packaged up particles sometime in its history. This suggests that the satellite virus could perform horizontal gene transfer between viruses, paralleling the way that bacteriophages ferry genes between bacteria." Horizontal transfer is also seen between geminiviruses and tobacco plants.

Prokaryotes

Horizontal gene transfer is common among bacteria, even among very distantly related ones. This process is thought to be a significant cause of increased drug resistance when one bacterial cell acquires resistance, and the resistance genes are transferred to other species. Transposition and horizontal gene transfer, along with strong natural selective forces have led to multi-drug resistant strains of S. aureus and many other pathogenic bacteria. Horizontal gene transfer also plays a role in the spread of virulence factors, such as exotoxins and exoenzymes, amongst bacteria. A prime example concerning the spread of exotoxins is the adaptive evolution of Shiga toxins in E. coli through horizontal gene transfer via transduction with Shigella species of bacteria. Strategies to combat certain bacterial infections by targeting these specific virulence factors and mobile genetic elements have been proposed. For example, horizontally transferred genetic elements play important roles in the virulence of E. coli, Salmonella, Streptococcus and Clostridium perfringens.

In prokaryotes, restriction-modification systems are known to provide immunity against horizontal gene transfer and in stabilizing mobile genetic elements. Genes encoding restriction modification systems have been reported to move between prokaryotic genomes within mobile genetic elements such as plasmids, prophages, insertion sequences/transposons, integrative conjugative elements (ICEs), and integrons. Still, they are more frequently a chromosomal-encoded barrier to MGEs than an MGE-encoded tool for cell infection.

Bacterial transformation

1: Donor bacteria 2: Bacteria who will receive the gene 3: The red portion represents the gene that will be transferred. Transformation in bacteria in a certain environment.
 
Natural transformation is a bacterial adaptation for DNA transfer (HGT) that depends on the expression of numerous bacterial genes whose products are responsible for this process. In general, transformation is a complex, energy-requiring developmental process. In order for a bacterium to bind, take up and recombine exogenous DNA into its chromosome, it must become competent, that is, enter a special physiological state. Competence development in Bacillus subtilis requires expression of about 40 genes. The DNA integrated into the host chromosome is usually (but with infrequent exceptions) derived from another bacterium of the same species, and is thus homologous to the resident chromosome. The capacity for natural transformation occurs in at least 67 prokaryotic species. Competence for transformation is typically induced by high cell density and/or nutritional limitation, conditions associated with the stationary phase of bacterial growth. Competence appears to be an adaptation for DNA repair. Transformation in bacteria can be viewed as a primitive sexual process, since it involves interaction of homologous DNA from two individuals to form recombinant DNA that is passed on to succeeding generations. Although transduction is the form of HGT most commonly associated with bacteriophages, certain phages may also be able to promote transformation.

Bacterial conjugation

1: Donor bacteria cell (F+ cell) 2: Bacteria that receives the plasmid (F- cell) 3: Plasmid that will be moved to the other bacteria 4: Pilus. Conjugation in bacteria using a sex pilus; then the bacteria that received the plasmid can go give it to other bacteria as well.
 
Conjugation in Mycobacterium smegmatis, like conjugation in E. coli, requires stable and extended contact between a donor and a recipient strain, is DNase resistant, and the transferred DNA is incorporated into the recipient chromosome by homologous recombination. However, unlike E. coli high frequency of recombination conjugation (Hfr), mycobacterial conjugation is a type of HGT that is chromosome rather than plasmid based. Furthermore, in contrast to E. coli (Hfr) conjugation, in M. smegmatis all regions of the chromosome are transferred with comparable efficiencies. Substantial blending of the parental genomes was found as a result of conjugation, and this blending was regarded as reminiscent of that seen in the meiotic products of sexual reproduction.

Archaeal DNA transfer

The archaeon Sulfolobus solfataricus, when UV irradiated, strongly induces the formation of type IV pili which then facilitates cellular aggregation. Exposure to chemical agents that cause DNA damage also induces cellular aggregation. Other physical stressors, such as temperature shift or pH, do not induce aggregation, suggesting that DNA damage is a specific inducer of cellular aggregation.

UV-induced cellular aggregation mediates intercellular chromosomal HGT marker exchange with high frequency, and UV-induced cultures display recombination rates that exceed those of uninduced cultures by as much as three orders of magnitude. S. solfataricus cells aggregate preferentially with other cells of their own species. Frols et al. and Ajon et al. suggested that UV-inducible DNA transfer is likely an important mechanism for providing increased repair of damaged DNA via homologous recombination. This process can be regarded as a simple form of sexual interaction. 

Another thermophilic species, Sulfolobus acidocaldarius, is able to undergo HGT. S. acidocaldarius can exchange and recombine chromosomal markers at temperatures up to 84oC. UV exposure induces pili formation and cellular aggregation. Cells with the ability to aggregate have greater survival than mutants lacking pili that are unable to aggregate. The frequency of recombination is increased by DNA damage induced by UV-irradiation and by DNA damaging chemicals.

The ups operon, containing five genes, is highly induced by UV irradiation. The proteins encoded by the ups operon are employed in UV-induced pili assembly and cellular aggregation leading to intercellular DNA exchange and homologous recombination. Since this system increases the fitness of S. acidocaldarius cells after UV exposure, Wolferen et al. considered that transfer of DNA likely takes place in order to repair UV-induced DNA damages by homologous recombination.

Eukaryotes

"Sequence comparisons suggest recent horizontal transfer of many genes among diverse species including across the boundaries of phylogenetic 'domains'. Thus determining the phylogenetic history of a species can not be done conclusively by determining evolutionary trees for single genes."

Organelle to nuclear genome

Bacteria to fungi

Bacteria to plants

  • Agrobacterium, a pathogenic bacterium that causes cells to proliferate as crown galls and proliferating roots is an example of a bacterium that can transfer genes to plants and this plays an important role in plant evolution.

Endosymbiont to insects and nematodes

  • The adzuki bean beetle has acquired genetic material from its (non-beneficial) endosymbiont Wolbachia. New examples have recently been reported demonstrating that Wolbachia bacteria represent an important potential source of genetic material in arthropods and filarial nematodes.

Organelle to organelle

Plant to plant

  • Striga hermonthica, a parasitic eudicot, has received a gene from sorghum (Sorghum bicolor) to its nuclear genome. The gene's functionality is unknown.
  • A gene that allowed ferns to survive in dark forests came from the hornwort, which grows in mats on streambanks or trees. The neochrome gene arrived about 180 million years ago.

Fungi to insects

  • Pea aphids (Acyrthosiphon pisum) contain multiple genes from fungi. Plants, fungi, and microorganisms can synthesize carotenoids, but torulene made by pea aphids is the only carotenoid known to be synthesized by an organism in the animal kingdom.

Human to protozoan

Bacteria to insects

  • HhMAN1 is a gene in the genome of the coffee borer beetle (Hypothenemus hampei) that resembles bacterial genes, and is thought to be transferred from bacteria in the beetle's gut.

Viruses to plants

  • Plants are capable of receiving genetic information from viruses by horizontal gene transfer.

Human genome

  • One study identified approximately 100 of humans' approximately 20,000 total genes which likely resulted from horizontal gene transfer, but this number has been challenged by several researchers arguing these candidate genes for HGT are more likely the result of gene loss combined with differences in the rate of evolution.

Bacteria to animals

  • Bdelloid rotifers currently hold the 'record' for HGT in animals with ~8% of their genes from bacterial origins. Tardigrades were thought to break the record with 17.5% HGT, but that finding was an artifact of bacterial contamination.
  • A study found the genomes of 40 animals (including 10 primates, four Caenorhabditis worms, and 12 Drosophila insects) contained genes which the researchers concluded had been transferred from bacteria and fungi by horizontal gene transfer. The researchers estimated that for some nematodes and Drosophilia insects these genes had been acquired relatively recently.
  • A bacteriophage-mediated mechanism transfers genes between prokaryotes and eukaryotes. Nuclear localization signals in bacteriophage terminal proteins (TP) prime DNA replication and become covalently linked to the viral genome. The role of virus and bacteriophages in HGT in bacteria, suggests that TP-containing genomes could be a vehicle of inter-kingdom genetic information transference all throughout evolution.

Plants to animals

  • The eastern emerald sea slug Elysia chlorotica has been suggested by FISH analysis to contain photosynthesis-supporting genes obtained from an algae (Vaucheria litorea) in their diet. LGT in Sacoglossa is now thought to be an artifact and no trace of LGT was found upon sequencing the genome of Elysia chlorotica.

Plant-fungus

  • Gene transfer between plants and fungi has been posited for a number of cases, including rice (Oryza sativa).

Artificial horizontal gene transfer

Before it is transformed, a bacterium is susceptible to antibiotics. A plasmid can be inserted when the bacteria is under stress, and be incorporated into the bacterial DNA creating antibiotic resistance. When the plasmids are prepared they are inserted into the bacterial cell by either making pores in the plasma membrane with temperature extremes and chemical treatments, or making it semi permeable through the process of electrophoresis, in which electric currents create the holes in the membrane. After conditions return to normal the holes in the membrane close and the plasmids are trapped inside the bacteria where they become part of the genetic material and their genes are expressed by the bacteria.
 
Genetic engineering is essentially horizontal gene transfer, albeit with synthetic expression cassettes. The Sleeping Beauty transposon system (SB) was developed as a synthetic gene transfer agent that was based on the known abilities of Tc1/mariner transposons to invade genomes of extremely diverse species. The SB system has been used to introduce genetic sequences into a wide variety of animal genomes.

Importance in evolution

Horizontal gene transfer is a potential confounding factor in inferring phylogenetic trees based on the sequence of one gene. For example, given two distantly related bacteria that have exchanged a gene a phylogenetic tree including those species will show them to be closely related because that gene is the same even though most other genes are dissimilar. For this reason it is often ideal to use other information to infer robust phylogenies such as the presence or absence of genes or, more commonly, to include as wide a range of genes for phylogenetic analysis as possible.

For example, the most common gene to be used for constructing phylogenetic relationships in prokaryotes is the 16S ribosomal RNA gene since its sequences tend to be conserved among members with close phylogenetic distances, but variable enough that differences can be measured. However, in recent years it has also been argued that 16s rRNA genes can also be horizontally transferred. Although this may be infrequent, the validity of 16s rRNA-constructed phylogenetic trees must be reevaluated.

Biologist Johann Peter Gogarten suggests "the original metaphor of a tree no longer fits the data from recent genome research" therefore "biologists should use the metaphor of a mosaic to describe the different histories combined in individual genomes and use the metaphor of a net to visualize the rich exchange and cooperative effects of HGT among microbes". There exist several methods to infer such phylogenetic networks

Using single genes as phylogenetic markers, it is difficult to trace organismal phylogeny in the presence of horizontal gene transfer. Combining the simple coalescence model of cladogenesis with rare HGT horizontal gene transfer events suggest there was no single most recent common ancestor that contained all of the genes ancestral to those shared among the three domains of life. Each contemporary molecule has its own history and traces back to an individual molecule cenancestor. However, these molecular ancestors were likely to be present in different organisms at different times."

Challenge to the tree of life

Horizontal gene transfer poses a possible challenge to the concept of the last universal common ancestor (LUCA) at the root of the tree of life first formulated by Carl Woese, which led him to propose the Archaea as a third domain of life. Indeed, it was while examining the new three-domain view of life that horizontal gene transfer arose as a complicating issue: Archaeoglobus fulgidus was seen as an anomaly with respect to a phylogenetic tree based upon the encoding for the enzyme HMGCoA reductase—the organism in question is a definite Archaean, with all the cell lipids and transcription machinery that are expected of an Archaean, but whose HMGCoA genes are of bacterial origin. Scientists are broadly agreed on symbiogenesis, that mitochondria in eukaryotes derived from alpha-proteobacterial cells and that chloroplasts came from ingested cyanobacteria, and other gene transfers may have affected early eukaryotes. (In contrast, multicellular eukaryotes have mechanisms to prevent horizontal gene transfer, including separated germ cells.) If there had been continued and extensive gene transfer, there would be a complex network with many ancestors, instead of a tree of life with sharply delineated lineages leading back to a LUCA. However, a LUCA can be identified, so horizontal transfers must have been relatively limited.

Phylogenetic information in HGT

On the opposite, it has been remarked that the detection of Horizontal Gene Transfers could bring valuable phylogenetic and dating information.

The potential of HGT to be used for dating phylogenies has recently been confirmed.

The chromosomal organization of Horizontal Gene Transfer

The acquisition of new genes has the potential to disorganize the other genetic elements and hinder the function of the bacterial cell, thus affecting the competitiveness of bacteria. Consequently, bacterial adaptation lies in a conflict between the advantages of acquiring beneficial genes, and the need to maintain the organization of the rest of its genome. Horizontally transferred genes are typically concentrated in only ~1% of the chromosome (in regions called hotspots). This concentration increases with genome size and with the rate of transfer. Hotspots diversify by rapid gene turnover; their chromosomal distribution depends on local contexts (neighboring core genes), and content in mobile genetic elements. Hotspots concentrate most changes in gene repertoires, reduce the trade-off between genome diversification and organization, and should be treasure troves of strain-specific adaptive genes. Most mobile genetic elements and antibiotic resistance genes are in hotspots, but many hotspots lack recognizable mobile genetic elements and exhibit frequent homologous recombination at flanking core genes. Overrepresentation of hotspots with fewer mobile genetic elements in naturally transformable bacteria suggests that homologous recombination and horizontal gene transfer are tightly linked in genome evolution.

Genes

There is evidence for historical horizontal transfer of the following genes:

Agrobacterium

From Wikipedia, the free encyclopedia

Agrobacterium
Agrobacterium-tumefaciens.png
Scientific classification
Kingdom:
Phylum:
Class:
Order:
Family:
Genus:
Agrobacterium
Type species
Agrobacterium tumefaciens
(Smith and Townsend 1907) Conn 1942
Species
Synonyms
  • Polymonas Lieske 1928

Agrobacterium is a genus of Gram-negative bacteria established by H. J. Conn that uses horizontal gene transfer to cause tumors in plants. Agrobacterium tumefaciens is the most commonly studied species in this genus. Agrobacterium is well known for its ability to transfer DNA between itself and plants, and for this reason it has become an important tool for genetic engineering.

The genus Agrobacterium is quite heterogeneous. Recent taxonomic studies have reclassified all of the Agrobacterium species into new genera, such as Ahrensia, Pseudorhodobacter, Ruegeria, and Stappia, but most species have been controversially reclassified as Rhizobium species.

Plant pathogen

The large growths on these roots are galls induced by Agrobacterium sp.
 
Agrobacterium tumefaciens causes crown-gall disease in plants. The disease is characterised by a tumour-like growth or gall on the infected plant, often at the junction between the root and the shoot. Tumors are incited by the conjugative transfer of a DNA segment (T-DNA) from the bacterial tumour-inducing (Ti) plasmid. The closely related species, Agrobacterium rhizogenes, induces root tumors, and carries the distinct Ri (root-inducing) plasmid. Although the taxonomy of Agrobacterium is currently under revision it can be generalised that 3 biovars exist within the genus, Agrobacterium tumefaciens, Agrobacterium rhizogenes, and Agrobacterium vitis. Strains within Agrobacterium tumefaciens and Agrobacterium rhizogenes are known to be able to harbour either a Ti or Ri-plasmid, whilst strains of Agrobacterium vitis, generally restricted to grapevines, can harbour a Ti-plasmid. Non-Agrobacterium strains have been isolated from environmental samples which harbour a Ri-plasmid whilst laboratory studies have shown that non-Agrobacterium strains can also harbour a Ti-plasmid. Some environmental strains of Agrobacterium possess neither a Ti nor Ri-plasmid. These strains are avirulent.

The plasmid T-DNA is integrated semi-randomly into the genome of the host cell, and the tumor morphology genes on the T-DNA are expressed, causing the formation of a gall. The T-DNA carries genes for the biosynthetic enzymes for the production of unusual amino acids, typically octopine or nopaline. It also carries genes for the biosynthesis of the plant hormones, auxin and cytokinins, and for the biosynthesis of opines, providing a carbon and nitrogen source for the bacteria that most other micro-organisms can't use, giving Agrobacterium a selective advantage. By altering the hormone balance in the plant cell, the division of those cells cannot be controlled by the plant, and tumors form. The ratio of auxin to cytokinin produced by the tumor genes determines the morphology of the tumor (root-like, disorganized or shoot-like).

In humans

Although generally seen as an infection in plants, Agrobacterium can be responsible for opportunistic infections in humans with weakened immune systems, but has not been shown to be a primary pathogen in otherwise healthy individuals. One of the earliest associations of human disease caused by Agrobacterium radiobacter was reported by Dr. J. R. Cain in Scotland (1988). A later study suggested that Agrobacterium attaches to and genetically transforms several types of human cells by integrating its T-DNA into the human cell genome. The study was conducted using cultured human tissue and did not draw any conclusions regarding related biological activity in nature.

Uses in biotechnology

The ability of Agrobacterium to transfer genes to plants and fungi is used in biotechnology, in particular, genetic engineering for plant improvement. A modified Ti or Ri plasmid can be used. The plasmid is 'disarmed' by deletion of the tumor inducing genes; the only essential parts of the T-DNA are its two small (25 base pair) border repeats, at least one of which is needed for plant transformation. The genes to be introduced into the plant are cloned into a plant transformation vector that contains the T-DNA region of the disarmed plasmid, together with a selectable marker (such as antibiotic resistance) to enable selection for plants that have been successfully transformed. Plants are grown on media containing antibiotic following transformation, and those that do not have the T-DNA integrated into their genome will die. An alternative method is agroinfiltration.

Plant (S. chacoense) transformed using Agrobacterium. Transformed cells start forming calluses on the side of the leaf pieces
 
Transformation with Agrobacterium can be achieved in multiple ways. Protoplasts or alternatively leaf-discs can be incubated with the Agrobacterium and whole plants regenerated using plant tissue culture. In agroinfiltration the Agrobacterium may be injected directly into the leaf tissue of a plant. This method transforms only cells in immediate contact with the bacteria, and results in transient expression of plasmid DNA.

Agroinfiltration is commonly used to transform tobacco (Nicotiana). A common transformation protocol for Arabidopsis is the floral dip method: inflorescence are dipped in a suspension of Agrobacterium, and the bacterium transforms the germline cells that make the female gametes. The seeds can then be screened for antibiotic resistance (or another marker of interest), and plants that have not integrated the plasmid DNA will die when exposed to the correct condition of antibiotic.

Agrobacterium does not infect all plant species, but there are several other effective techniques for plant transformation including the gene gun

Agrobacterium is listed as being the vector of genetic material that was transferred to these USA GMOs:

Genomics

The sequencing of the genomes of several species of Agrobacterium has permitted the study of the evolutionary history of these organisms and has provided information on the genes and systems involved in pathogenesis, biological control and symbiosis. One important finding is the possibility that chromosomes are evolving from plasmids in many of these bacteria. Another discovery is that the diverse chromosomal structures in this group appear to be capable of supporting both symbiotic and pathogenic lifestyles. The availability of the genome sequences of Agrobacterium species will continue to increase, resulting in substantial insights into the function and evolutionary history of this group of plant-associated microbes.

History

Marc Van Montagu and Jozef Schell at the University of Ghent (Belgium) discovered the gene transfer mechanism between Agrobacterium and plants, which resulted in the development of methods to alter Agrobacterium into an efficient delivery system for gene engineering in plants. A team of researchers led by Dr Mary-Dell Chilton were the first to demonstrate that the virulence genes could be removed without adversely affecting the ability of Agrobacterium to insert its own DNA into the plant genome (1983).

Wars of the Roses

From Wikipedia, the free encyclopedia

Wars of the Roses
Plucking the Red and White Roses, by Henry Payne.jpg
Framed print after 1908 painting by Henry Payne of the scene in the Temple Garden from Shakespeare's play Henry VI, Part 1, where supporters of the rival factions pick either red or white roses
Date22 May 145516 June 1487
(32 years, 3 weeks and 4 days)
Location
Result Initial Yorkist victory
Eventual Lancastrian victory
Belligerents
Red Rose Badge of Lancaster.svg House of Lancaster Tudor Rose.svg House of Tudor
Supported by:
Royal Arms of the Kingdom of Scotland.svg Kingdom of Scotland
Arms of France (France Moderne).svg Kingdom of France
White Rose Badge of York.svg House of York
Supported by:
Arms of the Duke of Burgundy (1364-1404).svg Duchy of Burgundy
Commanders and leaders
Royal Arms of England (1470-1471).svg Henry VI Surrendered Executed Arms of Edmund Tudor, Earl of Richmond.svg Henry VII Arms of Margaret of Anjou.svg Margaret of Anjou Surrendered # Arms of the Prince of Wales (Modern).svg Prince of Wales  Beaufort Arms (France modern).svg Duke of Somerset Executed Arms of John Holland, 2nd Duke of Exeter.svg Duke of Exeter # SIr Andrew Trollope's coat of arms.svg Andrew Trollope  Modern arms of Percy.svg E. of Northumberland  Coat of arms of Sir John de Vere, 13th Earl of Oxford.png Earl of Oxford Arms of Jasper Tudor, Duke of Bedford.svg Jasper Tudor Arms of Owen Tudor.svg Owen Tudor Executed Stafford Coat of Arms.jpg Duke of Buckingham  De Ros arms.svg Baron de Ros Executed Talbot arms.svg Earl of Shrewsbury  COA Tuchet.svg Lord Audley  Arms of Clifford.svg Baron Clifford  Neville arms.svg Baron Neville  Coat of Arms of Sir James Butler, 1st Earl of Wiltshire, KG.png Earl of Wiltshire Executed Courtenay of Devon.svg Earl of Devon  Neville Warwick Arms.svg Earl of Warwick  Neville arms.svg Marquess of Montagu  Neville arms.svg Thomas Neville Executed

Coat of Arms of Sir John Conyers, KG.png Robin of Redesdale
WilloughbyArms.png Baron Willoughby Executed
Royal Arms of England (1399-1603).svg Edward IV # Arms of Thomas of Lancaster, 1st Duke of Clarence.svg Richard III  Arms of Richard of York, 3rd Duke of York.svg Duke of York  Neville Warwick Arms.svg Earl of Warwick Neville arms.svg Lord Montagu Neville arms.svg Earl of Salisbury Executed Neville arms.svg Earl of Kent # Neville arms.svg Thomas Neville Arms of Thomas of Brotherton, 1st Earl of Norfolk.svg Duke of Norfolk # Arms of Edmund, Earl of Rutland.svg Earl of Rutland  Arms of George Plantagenet, 1st Duke of Clarence.svg Duke of Clarence Executed Coat of Arms of Sir William Hastings, 1st Baron Hastings, KG.png Lord Hastings Executed Howard arms (John, duke of Norfolk).svg Baron Howard 
John de la Pole, 1st Earl of Lincoln.svg Earl of Lincoln 
Coat of Arms of Sir Francis Lovell, 1st Viscount Lovell, KG.png Viscount Lovell

The Wars of the Roses were a series of English civil wars for control of the throne of England fought between supporters of two rival branches of the royal House of Plantagenet: the House of Lancaster, associated with a red rose, and the House of York, whose symbol was a white rose. Eventually, the wars eliminated the male lines of both families. The conflict lasted through many sporadic episodes between 1455 and 1487, but there was related fighting before and after this period between the parties. The power struggle ignited around social and financial troubles following the Hundred Years' War, unfolding the structural problems of feudalism, combined with the mental infirmity and weak rule of King Henry VI which revived interest in Richard of York's claim to the throne. Historians disagree on which of these factors to identify as the main reason for the wars.

With the Duke of York's death in 1460, the claim transferred to his heir, Edward. After a series of Yorkist victories from January–February 1461, Edward claimed the throne on March 4, 1461, and the last serious Lancastrian resistance ended at decisive Battle of Towton. Edward was thus unopposed as the first Yorkist king of England, as Edward IV. Resistance smoldered in the North until 1464, but the early part of his reign remained relatively peaceful.

A new phase of the wars broke out in 1469 after The Earl of Warwick, the most powerful noble in the country, withdrew his support for Edward and threw it behind the Lancastrian cause. Fortunes changed many times as the Yorkist and Lancastrian forces exchanged victories throughout 1469–1470 (and Edward was even captured for a time in 1469). When Edward fled to Flanders in 1470, Henry VI was re-installed as king on 3 October 1470, but his resumption of rule was short lived, and he was deposed again following the defeat of his forces at the Battle of Tewkesbury, and on 21 May 1471, Edward entered London unopposed, resumed the throne, and probably had Henry killed that same day. With all significant Lancastrian leaders now banished or killed, Edward ruled unopposed until his sudden death in 1483. His son reigned for 78 days as Edward V, but was then deposed by his uncle, who became Richard III.

The ascension of Richard III occurred under a cloud of controversy, and shortly after assuming the throne, the wars sparked anew with Buckingham's rebellion, as many die-hard Yorkists abandoned Richard to join Lancastrians. While the rebellions lacked much central coordination, in the chaos the exiled Henry Tudor, son of Henry VI's half-brother Edmund Earl of Richmond, and the leader of the Lancastrian cause, returned to the country from exile in Brittany at the head of an army of combined Breton and English forces. Richard avoided direct conflict with Henry until the Battle of Bosworth Field on 22 August 1485. After Richard III was killed and his forces defeated at Bosworth Field, Henry assumed the throne as Henry VII and married Elizabeth of York, the eldest daughter and heir of Edward IV, thereby uniting the two claims. The House of Tudor ruled the Kingdom of England until 1603, with the death of Elizabeth I, granddaughter of Henry VII and Elizabeth of York. 

Shortly after Henry took the throne, the Earl of Lincoln, a Yorkist sympathizer, put forward Lambert Simnel as an imposter Richard of York, younger brother of Edward V. Lincoln's forces were defeated, and he was killed at the Battle of Stoke Field on 16 June 1487, bringing a close to the Wars of the Roses.

Name and symbols

 
The name "Wars of the Roses" refers to the heraldic badges associated with two rival branches of the same royal house, the White Rose of York and the Red Rose of Lancaster. Wars of the Roses came into common use in the 19th century after the publication in 1829 of Anne of Geierstein by Sir Walter Scott. Scott based the name on a scene in William Shakespeare's play Henry VI, Part 1 (Act 2, Scene 4), set in the gardens of the Temple Church, where a number of noblemen and a lawyer pick red or white roses to show their loyalty to the Lancastrian or Yorkist faction respectively. It is often suggested by literary critics that Lewis Carroll's Alice's Adventures in Wonderland has strong allegorical references to the conflict with York represented by the White Queen and Lancaster represented by the Red Queen

The Yorkist faction used the symbol of the white rose from early in the conflict, but the Lancastrian red rose was introduced only after the victory of Henry Tudor at the Battle of Bosworth in 1485, when it was combined with the Yorkist white rose to form the Tudor rose, which symbolised the union of the two houses; the origins of the Rose as a cognizance itself stem from Edward I's use of "a golden rose stalked proper." Often, owing to nobles holding multiple titles, more than one badge was used: Edward IV, for example, used both his sun in splendour as Earl of March, but also his father's falcon and fetterlock as Duke of York. Badges were not always distinct; at the Battle of Barnet, Edward's 'sun' was very similar to the Earl of Oxford's Vere star, which caused fateful confusion.

Most, but not all, of the participants in the wars wore livery badges associated with their immediate lords or patrons under the prevailing system of bastard feudalism; the wearing of livery was by now confined to those in "continuous employ of a lord", thus excluding, for example, mercenaries. Another example: Henry Tudor's forces at Bosworth fought under the banner of a red dragon while the Yorkist army used Richard III's personal device of a white boar.

Although the names of the rival houses derive from the cities of York and Lancaster, the corresponding duchy and dukedom had little to do with these cities. The lands and offices attached to the Duchy of Lancaster were mainly in Gloucestershire, North Wales, Cheshire, and (ironically) in Yorkshire, while the estates and castles of the Duke of York were spread throughout England and Wales, many in the Welsh Marches.

Summary of events

Important locations in the Wars of the Roses
 
Tensions within England during the 1450s centered on the mental state of Henry VI and on his inability to produce an heir with his wife, Margaret of Anjou. In the absence of a direct heir, there were two rival branches with claims to the throne should Henry die without issue, being the Beaufort family, led by Edmund Beaufort, 2nd Duke of Somerset, and the House of York, headed by Richard of York. By 1453, issues had come to a head: though Margaret of Anjou was pregnant, Henry VI was descending into increasing mental instability, by August becoming completely non-responsive and unable to govern. A Great Council of nobles was called, and through shrewd political machinations, Richard had himself declared Lord Protector and chief regent during the mental incapacity of Henry. In the interlude, Margaret gave birth to a healthy son and heir, Edward of Westminster

By 1455, Henry had regained his faculties, and open warfare came at the First Battle of St Albans. Several prominent Lancastrians died at the hands of the Yorkists. Henry was again imprisoned, and Richard of York resumed his role as Lord Protector. Although peace was temporarily restored, the Lancastrians were inspired by Margaret of Anjou to contest York's influence, and a deadly feud between the two branches of the royal family ensued.

Fighting resumed more violently in 1459. York and his supporters were forced to flee the country, and Henry was once again restored to direct rule, but one of York's most prominent supporters, the Earl of Warwick, invaded England from Calais in October 1460 and captured Henry VI yet again at the Battle of Northampton. York returned to the country and for the third time became Protector of England, but was dissuaded from claiming the throne, though it was agreed that he would become heir to the throne (thus displacing Henry and Margaret's son, Edward of Westminster, from the line of succession). Margaret and the remaining Lancastrian nobles gathered their army in the north of England

When York moved north to engage them, he and his second son Edmund were killed at the Battle of Wakefield in December 1460. The Lancastrian army advanced south and released Henry at the Second Battle of St Albans but failed to occupy London and subsequently retreated to the north. York's eldest son Edward, Earl of March, was proclaimed King Edward IV. He gathered the Yorkist armies and won a crushing victory at the Battle of Towton in March 1461. 

After Lancastrian revolts in the north were suppressed in 1464, Henry was captured once again and placed in the Tower of London. Edward fell out with his chief supporter and adviser, the Earl of Warwick (known as the "Kingmaker"), after Edward's unpopular and secretly conducted marriage with the widow of a Lancastrian supporter, Elizabeth Woodville. Within a few years, it became clear that Edward was favouring his wife's family and alienating a number of friends closely aligned with Warwick as well. 

A near-contemporary Flemish picture of the Battle of Barnet in 1471
 
Furious, Warwick tried first to supplant Edward with his younger brother George, Duke of Clarence, establishing the alliance by marriage to his daughter, Isabel Neville. When that plan failed, due to lack of support from Parliament, Warwick sailed to France with his family and made an alliance with the former Lancastrian Queen, Margaret of Anjou, to restore Henry VI to the throne. 

This resulted in two years of rapid changes of fortune before Edward IV once again won complete victories at Barnet (14 April 1471), where Warwick was killed, and Tewkesbury (4 May 1471), where the Lancastrian heir, Edward of Westminster, Prince of Wales was killed or perhaps executed after the battle. Queen Margaret was escorted to London as a prisoner, and Henry was murdered in the Tower of London several days later, ending the direct Lancastrian line of succession.

A period of comparative peace followed, ending with the unexpected death of King Edward in 1483. His surviving brother Richard, Duke of Gloucester, first moved to prevent the unpopular Woodville family of Edward's widow from participating in the government during the minority of Edward's son, Edward V, and then seized the throne for himself, using the suspect legitimacy of Edward IV's marriage as pretext. 

Henry Tudor, a distant relative of the Lancastrian kings who had inherited their claim, defeated Richard III at Bosworth in 1485. He was crowned Henry VII and married Elizabeth of York, daughter of Edward IV, to unite and reconcile the two houses. Yorkist revolts, directed by John de la Pole, 1st Earl of Lincoln and others, flared up in 1487 under the banner of the pretender Lambert Simnel—who claimed he was Edward, Earl of Warwick (son of George of Clarence), resulting in the last pitched battles.

Though most surviving descendants of Richard of York were imprisoned, sporadic rebellions continued until 1497, when Perkin Warbeck, who claimed he was the younger brother of Edward V, one of the two disappeared Princes in the Tower, was imprisoned and later executed.

Origins of the conflict

Disputed succession

In the early middle ages, the succession to the crown was open to any member (Ætheling) of the royal family. From the 9th century, the term was used in a much narrower context and came to refer exclusively to members of the house of Cerdic of Wessex, the ruling dynasty of Wessex, most particularly the sons or brothers of the reigning king. According to historian Richard Abels "King Alfred transformed the very principle of royal succession. Before Alfred, any nobleman who could claim royal descent, no matter how distant, could strive for the throne. After him, throne-worthiness would be limited to the sons and brothers of the reigning king." Alfred himself succeeded to the throne in preference to the sons of his brother the previous king, who were under age at the time. In the reign of Edward the Confessor, Edgar the Ætheling received the appellation as the grandson of Edmund Ironside, but that was at a time when for the first time in 250 years there was no living ætheling according to the strict definition.

William the Conqueror's son King Henry I of England died in 1135 after William Adelin (William Ætheling), his only male heir, was killed aboard the White Ship. Following the White Ship disaster, England entered a period of prolonged instability known as The Anarchy. However, following the ascension of Henry of Anjou to the throne in 1154 as Henry II, the crown passed from father to son or brother to brother with little difficulty until 1399.

The question of succession after Edward III's death in 1377 is said to be the cause of the Wars of Roses. He had five surviving legitimate sons: Edward, the Black Prince (1330–1376); Lionel, Duke of Clarence (called 'Lionel of Antwerp' 1338–1368); John, Duke of Lancaster (called 'John of Gaunt'; 1340–1399); Edmund, Duke of York (called 'Edmund of Langley' 1341–1402); and Thomas, Duke of Gloucester (1355–1397). Although Edward III's succession seemed secure, there was a "sudden narrowing in the direct line of descent" near the end of his reign. His eldest son Edward, the Black Prince, had died the year before. Edward III was succeeded on the throne by the Black Prince's only surviving son Richard II, who was only 10 years old. Richard's claim to the throne was based on the principle that the son of an elder brother had priority in the succession over his uncles. Since Richard was a minor, had no siblings, and had three living uncles at the time of Edward III's death, there was considerable uncertainty about who was next in line for the succession after Richard.

If Richard II died without legitimate offspring, his successors by primogeniture would be the descendants of Lionel of Antwerp, Edward III's second son. Clarence's only daughter, Philippa, 5th Countess of Ulster, married into the Mortimer family and had a son, Roger Mortimer, 4th Earl of March (1374–1398), who technically had the best claim to succeed. However, a legal decree issued by Edward III in 1376 introduced some complexity into the question of who would ultimately take the throne. The letters patent he issued limited the right of succession to male heirs, which placed his third son, John of Gaunt, ahead of Clarence's descendants because the Mortimer line of descent passed through a daughter.

Richard II's reign was marked by increasing dissension between the King and several of the most powerful nobles. In 1399, he exiled Gaunt's son Henry of Bolingbroke. Richard's government had become highly unpopular beyond his strongholds in Cheshire and Wales. Throughout his reign, Richard had repeatedly switched his choice of heir in order to keep his political enemies at bay and perhaps to reduce the chances of deposition. Nevertheless, when Bolingbroke returned from exile in 1399, initially to reclaim his rights as Duke of Lancaster, he took advantage of the support of most of the nobles to depose Richard and was crowned King Henry IV, establishing the House of Lancaster on the throne.

House of Lancaster

 
The House of Lancaster descended from John of Gaunt, third surviving son of Edward III of England. Their name derives from John of Gaunt's primary title of Duke of Lancaster, which he held by right of his spouse, Blanche of Lancaster. They had received explicit preference from Edward III in the line of succession because they formed the most senior unbroken male line of descent from him.

Henry IV's claim to the throne was through his father, John of Gaunt. At the onset of Richard II's reign, Gaunt was the official heir presumptive, but due to the intrigues of his turbulent rule, the succession was unclear by the time of his deposition. Therefore, an argument could be made that the legitimate king of England was not Henry IV, but instead was Edmund Mortimer, 5th Earl of March, the son of Roger Mortimer, 4th Earl of March. However, there was little support at the time for his counter-claim. Certainly many people believed it to be the case. As Henry's initial popularity waned, the Mortimer family's claim to the throne was a pretext for the major rebellion of Owain Glyndŵr in Wales, and other, less successful, revolts in Cheshire and Northumberland. There were uprisings in support of the Mortimers' claim throughout Henry IV's reign, which lasted until 1413.

A peculiarity of Henry IV's seizure of the throne is demonstrated in the way he announced his claim. He was vague, and he resigned himself to mentioning that he was the rightful heir of Henry III, who had died more than a century before, perhaps subtly implying that all English kings ever since (Edward I, Edward II, Edward III and Richard II) had not been rightful monarchs. Henry IV seems to have been exploiting a legend that Henry III's second son Edmund "Crouchback", 1st Earl of Lancaster, was in fact his eldest son but had been removed from succession because he had a physical deformity, which gave origin to his nickname. Since Henry IV was Edmund's descendant and heir through his mother Blanche of Lancaster, he was in fact the rightful king. There is no evidence for this legend, and Edmund's nickname did not stem from a deformity.

An important branch of the House of Lancaster was the House of Beaufort, whose members were descended from Gaunt by his mistress, Katherine Swynford. Originally illegitimate, they were made legitimate by an Act of Parliament when Gaunt and Katherine later married. However, Henry IV excluded them from the line of succession to the throne.

Henry IV's son and successor, Henry V, inherited a temporarily pacified nation, and his military success against France in the Hundred Years' War bolstered his popularity, enabling him to strengthen the Lancastrian hold on the throne. Nevertheless, one notable conspiracy against Henry, the Southampton Plot, took place during his nine-year reign. This was led by Richard, Earl of Cambridge, who attempted to place Edmund Mortimer, his brother-in-law, in the throne. Cambridge was executed for treason in 1415, at the start of the campaign that led to the Battle of Agincourt.

House of York

The founder of the House of York was Edmund of Langley, the fourth son of Edward III and the younger brother of John of Gaunt. Their family name comes from Edmund's title Duke of York, which he acquired in 1385. However, the superiority of their claim is not based on the male line, but on the female line, as descendants of Edward III's second son Lionel of Antwerp. Edmund's second son, Richard, Earl of Cambridge, who was executed by Henry V, had married Anne de Mortimer, daughter of Roger Mortimer and sister of Edmund Mortimer. Anne's grandmother, Philippa of Clarence, was the daughter of Lionel of Antwerp. The Mortimers were the most powerful marcher family of the fourteenth century. G.M. Trevelyan has written that "the Wars of the Roses were to a large extent a quarrel between Welsh Marcher Lords, who were also great English nobles, closely related to the English throne."

Anne Mortimer's husband Richard, Earl of Cambridge
 
Anne de Mortimer had died in 1411. When her brother Edmund Mortimer, 5th Earl of March, who had loyally supported Henry, died childless in 1425, the title and extensive estates of the Earldom of March and the Mortimer claim to the throne thus passed to Anne's descendants.

Richard of York, the son of Cambridge and Anne Mortimer, was four years old at the time of his father's execution. Although Cambridge was attainted, Henry V later allowed Richard to inherit the title and lands of Cambridge's elder brother Edward, Duke of York, who had died fighting alongside Henry at Agincourt and had no issue. Henry, who had three younger brothers and was himself in his prime and recently married to the French princess, Catherine of Valois, had no doubt that the Lancastrian right to the crown was secure. 

Henry's premature death in 1422, at the age of 36, led to his only son Henry VI coming to the throne as an infant and the country being ruled by a divided Council of regency. Henry V's younger brothers produced no surviving legitimate issue, leaving only distant cousins (the Beauforts) as alternative Lancaster heirs. As Richard of York grew into maturity and questions were raised over Henry VI's fitness to rule, Richard's claim to the throne thus became more significant. The revenue from the York and March estates also made him the wealthiest magnate in the land.

Henry VI

From early childhood, Henry VI was surrounded by quarrelsome councillors and advisors. His younger surviving paternal uncle, Humphrey, Duke of Gloucester, sought to be named Lord Protector and deliberately courted the popularity of the common people for his own ends but was opposed by his half-uncle Cardinal Henry Beaufort. On several occasions, Beaufort called on John, Duke of Bedford, Humphrey's older brother, to return from his post as Henry VI's regent in France, either to mediate or to defend him against Humphrey's accusations of treason. Henry VI's coming of age in 1437 brought no end to the noblemen's scheming, as his weak personality made him prone to being swayed and influenced by select courtiers, especially those whom he deemed his favourites. Some time after, Cardinal Beaufort withdrew from public affairs, partly due to old age and partly because William de la Pole, 1st Duke of Suffolk, rose to become the dominant personality at court. Suffolk and the Beauforts were widely held to be enriching themselves through their influence on Henry, and were blamed for mismanaging the government and poorly executing the continuing Hundred Years' War with France. Under Henry VI, all the land in France won by Henry V and even the provinces of Guienne and Gascony, which had been held since the reign of Henry II three centuries previously, were lost. 

Opposition to Suffolk and Beaufort was led by Humphrey of Gloucester, and Richard of York. Humphrey felt that the lifetime efforts of his brothers, of himself, and of many Englishmen in the war against France were being wasted as the French territories slipped from English hands, especially since Suffolk and his supporters were trying to make large diplomatic and territorial concessions to the French in a desperate attempt for peace. In this, Gloucester enjoyed little influence, as Henry VI tended to favour Suffolk and Beaufort's faction at court due to its less hawkish and more conciliatory inclinations. The Duke of York, Bedford's successor in France, and at times also described as a skeptic of the peace policy, became entangled in this dispute as Suffolk and the Beauforts were frequently granted large money and land grants from the king, as well as important government and military positions, redirecting much needed resources away from York's campaigns in France. 

Suffolk eventually succeeded in having Humphrey of Gloucester arrested for treason. Humphrey died while awaiting trial in prison at Bury St Edmunds in 1447. Some authorities date the start of the War of the Roses from the death of Humphrey. At the same time, Richard of York was stripped of the prestigious military command in France and sent to govern the relatively distant Ireland, whereby he could not interfere in the proceedings of the court. However, with severe reverses in France, Suffolk was stripped of office and was murdered on his way to exile. Edmund Beaufort, 2nd Duke of Somerset (Cardinal Beaufort's nephew), succeeded him as leader of the party seeking peace with France. The Duke of York meanwhile represented those who wished to prosecute the war more vigorously, and criticised the court, and Somerset in particular, for starving him of funds and men during his campaigns in France.

In all these quarrels, Henry VI had taken little part. He was seen as a weak, ineffectual king. In addition, he displayed several symptoms of mental illness that he may have inherited from his maternal grandfather, Charles VI of France. By 1450 many considered Henry incapable of carrying out the duties and responsibilities of a king. 

In 1450, there was a violent popular revolt in Kent, Jack Cade's Rebellion, which is often seen as the prelude to the Wars of the Roses. The rebel manifesto, The Complaint of the Poor Commons of Kent written under Cade's leadership, accused the crown of extortion, perversion of justice, and election fraud. The rebels occupied parts of London, and executed James Fiennes, 1st Baron Saye and Sele, the unpopular Lord High Treasurer, after a hasty trial. After some of them fell to looting, they were driven out of London by the citizens. They dispersed after they were supposedly pardoned but several, including Cade, were later executed. After the rebellion the rebels' grievances formed the basis of Richard of York's opposition to a royal government from which he felt excluded.

Two years later, in 1452, Richard of York returned to England from his new post as Lieutenant of Ireland and marched on London, demanding Somerset's removal and reform of the government. At this stage, few of the nobles supported such drastic action, and York was forced to submit to superior force at Blackheath. He was imprisoned for much of 1452 and 1453 but was released after swearing not to take arms against the court. 

The increasing discord at court was mirrored in the country as a whole, where noble families engaged in private feuds and showed increasing disrespect for the royal authority and for the courts of law. In many cases feuds were fought between old-established families, and formerly minor nobility raised in power and influence by Henry IV in the aftermath of the rebellions against him. The quarrel between the Percys—long the Earls of Northumberland—and the comparatively upstart Nevilles was the best-known of these private wars and followed this pattern, as did the Bonville–Courtenay feud in Cornwall and Devon. A factor in these feuds was the presence of large numbers of soldiers discharged from the English armies that had been defeated in France. Nobles engaged many of these to mount raids, or to pack courts of justice with their supporters, intimidating suitors, witnesses and judges.

This growing civil discontent, the abundance of feuding nobles with private armies, and corruption in Henry VI's court formed a political climate ripe for civil war. With the king so easily manipulated, power rested with those closest to him at court, in other words, Somerset and the Lancastrian faction. Richard and the Yorkist faction, who tended to be physically placed further away from the seat of power, found their power slowly being stripped away. Royal power and finances also started to slip, as Henry was persuaded to grant many royal lands and estates to the Lancastrians, thereby losing their revenue. 

In 1453, Henry suffered the first of several bouts of complete mental collapse, during which he failed even to recognise his new-born son, Edward of Westminster. On 22 March 1454, Cardinal John Kemp, the Chancellor, died. Henry was incapable of nominating a successor. To ensure that the country could be governed, a Council of Regency was set up, headed by the Duke of York, who still remained popular with the people, as Lord Protector. York soon asserted his power with ever-greater boldness (although there is no proof that he had aspirations to the throne at this early stage). He imprisoned Somerset and backed his Neville allies (his brother-in-law, the Earl of Salisbury, and Salisbury's son, the Earl of Warwick), in their continuing feud with the Earl of Northumberland, a powerful supporter of Henry.

Henry recovered in 1455 and once again fell under the influence of those closest to him at court. Directed by Henry's queen, the powerful and aggressive Margaret of Anjou, who emerged as the de facto leader of the Lancastrians, Richard was forced out of court. Margaret built up an alliance against Richard and conspired with other nobles to reduce his influence. An increasingly thwarted Richard (who feared arrest for treason) finally resorted to armed hostilities in 1455.

Start of the war

The Lancastrian siege of London in 1471 is attacked by a Yorkist sally.
 
Richard, Duke of York, led a small force toward London and was met by Henry's forces at St Albans, north of London, on 22 May 1455. The relatively small First Battle of St Albans was the first open conflict of the civil war. Richard's aim was ostensibly to remove "poor advisors" from King Henry's side. The result was a Lancastrian defeat. Several prominent Lancastrian leaders, including Somerset and Northumberland, were killed. After the battle, the Yorkists found Henry hiding in a local tanner's shop, abandoned by his advisers and servants, apparently having suffered another bout of mental illness. (He had also been slightly wounded in the neck by an arrow.) York and his allies regained their position of influence. With the king indisposed, York was again appointed Protector, and Margaret was shunted aside, charged with the king's care.

For a while, both sides seemed shocked that an actual battle had been fought and did their best to reconcile their differences, but the problems that caused conflict soon re-emerged, particularly the issue of whether the Duke of York, or Henry and Margaret's infant son, Edward, would succeed to the throne. Margaret refused to accept any solution that would disinherit her son, and it became clear that she would only tolerate the situation for as long as the Duke of York and his allies retained the military ascendancy. 

Henry recovered and in February 1456 he relieved York of his office of Protector. In the autumn of that year, Henry went on royal progress in the Midlands, where the king and queen were popular. Margaret did not allow him to return to London where the merchants were angry at the decline in trade and the widespread disorder. The king's court was set up at Coventry. By then, the new Duke of Somerset was emerging as a favourite of the royal court. Margaret persuaded Henry to revoke the appointments York had made as Protector, while York was made to return to his post as lieutenant in Ireland. 

Disorder in the capital and the north of England (where fighting between the Nevilles and Percys had resumed ) and piracy by French fleets on the south coast were growing, but the king and queen remained intent on protecting their own positions, with the queen introducing conscription for the first time in England. Meanwhile, York's ally, Warwick (later dubbed "The Kingmaker"), was growing in popularity in London as the champion of the merchants; as Captain of Calais he had fought piracy in the Channel.

In the spring of 1458, Thomas Bourchier, the Archbishop of Canterbury, attempted to arrange a reconciliation. The lords had gathered in London for a Grand Council and the city was full of armed retainers. The Archbishop negotiated complex settlements to resolve the blood-feuds that had persisted since the Battle of St. Albans. Then, on Lady Day (25 March), the King led a "love day" procession to St. Paul's Cathedral, with Lancastrian and Yorkist nobles following him, hand in hand. No sooner had the procession and the Council dispersed than plotting resumed.

Act of Accord

Ludlow Castle, South Shropshire
 
The next outbreak of fighting was prompted by Warwick's high-handed actions as Captain of Calais. He led his ships in attacks on neutral Hanseatic League and Spanish ships in the Channel on flimsy grounds of sovereignty. He was summoned to London to face enquiries, but he claimed that attempts had been made on his life, and returned to Calais. York, Salisbury and Warwick were summoned to a royal council at Coventry, but they refused, fearing arrest when they were isolated from their own supporters.

York summoned the Nevilles to join him at his stronghold at Ludlow Castle in the Welsh Marches. On 23 September 1459, at the Battle of Blore Heath in Staffordshire, a Lancastrian army failed to prevent Salisbury from marching from Middleham Castle in Yorkshire to Ludlow. Shortly afterwards the combined Yorkist armies confronted the much larger Lancastrian force at the Battle of Ludford Bridge. Warwick's contingent from the garrison of Calais under Andrew Trollope defected to the Lancastrians, and the Yorkist leaders fled. York returned to Ireland, and his eldest son, Edward, Earl of March, Salisbury and Warwick fled to Calais.

The Lancastrians were back in total control. York and his supporters were attainted at the Parliament of Devils as traitors. Somerset was appointed Governor of Calais and was dispatched to take over the vital fortress on the French coast, but his attempts to evict Warwick were easily repulsed. Warwick and his supporters even began to launch raids on the English coast from Calais, adding to the sense of chaos and disorder. Being attainted, only by a successful invasion could the Yorkists recover their lands and titles. Warwick travelled to Ireland to concert plans with York, evading the royal ships commanded by the Duke of Exeter. In late June 1460, Warwick, Salisbury and Edward of March crossed the Channel and rapidly established themselves in Kent and London, where they enjoyed wide support. Backed by a papal emissary who had taken their side, they marched north. King Henry led an army south to meet them while Margaret remained in the north with Prince Edward. At the Battle of Northampton on 10 July, the Yorkist army under Warwick defeated the Lancastrians, aided by treachery in the king's ranks. For the second time in the war, King Henry was found by the Yorkists in a tent, abandoned by his retinue, having apparently suffered another breakdown. With the king in their possession, the Yorkists returned to London. 

In the light of this military success, Richard of York moved to press his claim to the throne based on the illegitimacy of the Lancastrian line. Landing in north Wales, he and his wife Cecily entered London with all the ceremony usually reserved for a monarch. Parliament was assembled, and when York entered he made straight for the throne, which he may have been expecting the Lords to encourage him to take for himself as they had acclaimed Henry IV in 1399. Instead, there was stunned silence. York announced his claim to the throne, but the Lords, even Warwick and Salisbury, were shocked by his presumption; they had no desire at this stage to overthrow King Henry. Their ambition was still limited to the removal of his councillors.

The next day, York produced detailed genealogies to support his claim based on his descent from Lionel of Antwerp, Duke of Clarence. York's claim was through a daughter of a second son, Henry's through the son of a third son. The judges felt that Common law principles could not determine who had priority in the royal succession, and declared the matter "above the law and passed ther lernyng." Parliament agreed to consider the matter and accepted that York's claim was better, but by a majority of five, they voted that Henry VI should remain as king. A compromise was struck in October 1460 with the Act of Accord, which recognised York as Henry's successor, disinheriting Henry's six-year-old son, Edward. York accepted this compromise as the best offer. It gave him much of what he wanted, particularly since he was also made Protector of the Realm and was able to govern in Henry's name.

Death of Richard, Duke of York

Ruins of Sandal Castle, near Wakefield, West Yorkshire
 
Queen Margaret and her son had fled to north Wales, parts of which were still in Lancastrian hands. They later travelled by sea to Scotland to negotiate for Scottish assistance. Mary of Gueldres, Queen Consort to James II of Scotland, agreed to give Margaret an army on condition that she cede the town of Berwick to Scotland and Mary's daughter be betrothed to Prince Edward. Margaret agreed, although she had no funds to pay her army and could only promise booty from the riches of southern England, as long as no looting took place north of the River Trent.

The Duke of York left London later that year with the Earl of Salisbury to consolidate his position in the north against the Lancastrians who were reported to be massing near the city of York. He took up a defensive position at Sandal Castle near Wakefield over Christmas 1460. Then on 30 December, his forces left the castle and attacked the Lancastrians in the open, although outnumbered. The ensuing Battle of Wakefield was a complete Lancastrian victory. Richard of York was slain in the battle, and both Salisbury and York's 17-year-old second son, Edmund, Earl of Rutland, were captured and executed. Margaret ordered the heads of all three placed on the gates of York.

Edward's claim to the throne

Parhelion at sunset
 
The Act of Accord and the events of Wakefield left the 18-year-old Edward, Earl of March, York's eldest son, as Duke of York and heir to his claim to the throne. With an army from the pro-Yorkist Marches (the border area between England and Wales), he met Jasper Tudor's Lancastrian army arriving from Wales, and he defeated them soundly at the Battle of Mortimer's Cross in Herefordshire. He inspired his men with a "vision" of three suns at dawn (a phenomenon known as "parhelion"), telling them that it was a portent of victory and represented the three surviving York sons; himself, George and Richard. This led to Edward's later adoption of the sign of the sunne in splendour as his personal device

Margaret's army was moving south, supporting itself by looting as it passed through the prosperous south of England. In London, Warwick used this as propaganda to reinforce Yorkist support throughout the south – the town of Coventry switched allegiance to the Yorkists. Warwick's army established fortified positions north of the town of St Albans to block the main road from the north but was outmanoeuvred by Margaret's army, which swerved to the west and then attacked Warwick's positions from behind. At the Second Battle of St Albans, the Lancastrians won another big victory. As the Yorkist forces fled they left behind King Henry, who was found unharmed, sitting quietly beneath a tree. 

Henry knighted thirty Lancastrian soldiers immediately after the battle. In an illustration of the increasing bitterness of the war, Queen Margaret instructed her seven-year-old son Edward of Westminster to determine the manner of execution of the Yorkist knights who had been charged with keeping Henry safe and had stayed at his side throughout the battle.

As the Lancastrian army advanced southwards, a wave of dread swept London, where rumours were rife about savage northerners intent on plundering the city. The people of London shut the city gates and refused to supply food to the queen's army, which was looting the surrounding counties of Hertfordshire and Middlesex.

Yorkist triumph

Edward of March, having joined with Warwick's surviving forces, advanced towards London from the west at the same time that the queen retreated northwards to Dunstable; as a result, Edward and Warwick were able to enter London with their army. They found considerable support there, as the city was largely Yorkist-supporting. It was clear that Edward was no longer simply trying to free the king from bad councillors, but that his goal was to take the crown. Thomas Kempe, the Bishop of London, asked the people of London their opinion and they replied with shouts of "King Edward". The request was quickly approved by Parliament, and Edward was unofficially appointed king in an impromptu ceremony at Westminster Abbey; Edward vowed that he would not have a formal coronation until Henry VI and his wife were removed from the scene. Edward claimed Henry had forfeited his right to the crown by allowing his queen to take up arms against his rightful heirs under the Act of Accord. Parliament had already accepted that Edward's victory was simply a restoration of the rightful heir to the throne. 

Edward and Warwick marched north, gathering a large army as they went, and met an equally impressive Lancastrian army at Towton. The Battle of Towton, near York, was the biggest battle of the Wars of the Roses. Both sides agreed beforehand that the issue would be settled that day, with no quarter asked or given. An estimated 40,000–80,000 men took part, with over 20,000 men being killed during (and after) the battle, an enormous number for the time and the greatest recorded single day's loss of life on English soil. Edward and his army won a decisive victory, and the Lancastrians were routed, with most of their leaders slain. Henry and Margaret, who were waiting in York with their son Edward, fled north when they heard the outcome. Many of the surviving Lancastrian nobles switched allegiance to King Edward, and those who did not were driven back to the northern border areas and a few castles in Wales. Edward advanced to take York, where he replaced the rotting heads of his father, his brother, and Salisbury with those of defeated Lancastrian lords such as the notorious John Clifford, 9th Baron de Clifford of Skipton-Craven, who was blamed for the execution of Edward's brother Edmund, Earl of Rutland, after the Battle of Wakefield.

Edward IV

Harlech Castle, Gwynedd, Wales
 
The official coronation of Edward IV took place in June 1461 in London, where he received a rapturous welcome from his supporters.

After the Battle of Towton, Henry VI and Margaret had fled to Scotland, where they stayed with the court of James III and followed through on their promise to cede Berwick to Scotland. Later in the year, they mounted an attack on Carlisle, but, lacking money, they were easily repulsed by Edward's men, who were rooting out the remaining Lancastrian forces in the northern counties. Several castles under Lancastrian commanders held out for years: Dunstanburgh, Alnwick (the Percy family seat), and Bamburgh were some of the last to fall.

There was also some fighting in Ireland. At the Battle of Piltown in 1462, the Yorkish supporter Thomas FitzGerald, 7th Earl of Desmond, defeated the Lancastrian Butlers of Kilkenny. The Butlers suffered more than 400 casualties. Local folklore claims that the battle was so violent that the local river ran red with blood, hence the names Pill River and Piltown (Baile an Phuill, meaning "Town of the blood"). 

There were Lancastrian revolts in the north of England in 1464. Several Lancastrian nobles, including the third Duke of Somerset, who had apparently been reconciled to Edward, readily led the rebellion. The revolt was put down by Warwick's brother, John Neville. A small Lancastrian army was destroyed at the Battle of Hedgeley Moor on 25 April, but because Neville was escorting Scottish commissioners for a treaty to York, he could not immediately follow up this victory. Then on 15 May, he routed Somerset's army at the Battle of Hexham. Somerset was captured and executed. 

The deposed King Henry was later captured for the third time at Clitheroe in Lancashire in 1465. He was taken to London and held prisoner at the Tower of London, where, for the time being, he was reasonably well treated. About the same time, once England under Edward IV and Scotland had come to terms, Margaret and her son were forced to leave Scotland and sail to France, where they maintained an impoverished court in exile for several years. The last remaining Lancastrian stronghold was Harlech Castle in Wales, which surrendered in 1468 after a seven-year-long siege.

Warwick's rebellion and the death of Henry VI

The powerful Earl of Warwick ("the Kingmaker") had meanwhile become the greatest landowner in England. Already a great magnate through his wife's property, he had also inherited his father's estates and had been granted much forfeited Lancastrian property. He also held many of the offices of state. He was convinced of the need for an alliance with France and had been negotiating a match between Edward and a French bride. However, Edward had married Elizabeth Woodville, the widow of a Lancastrian knight, in secret in 1464. He later announced the news of his marriage as fait accompli, to Warwick's considerable embarrassment. 

This embarrassment turned to bitterness when the Woodvilles came to be favoured over the Nevilles at court. Many of Queen Elizabeth's relatives were married into noble families and others were granted peerages or royal offices. Other factors compounded Warwick's disillusionment: Edward's preference for an alliance with Burgundy rather than France and reluctance to allow his brothers George, Duke of Clarence and Richard, Duke of Gloucester, to marry Warwick's daughters Isabel and Anne. Furthermore, Edward's general popularity was on the wane in this period with higher taxes and persistent disruptions of law and order. 

By 1469, Warwick had formed an alliance with Edward's jealous and treacherous brother George, who married Isabel Neville in defiance of Edward's wishes in Calais. They raised an army that defeated the king's forces at the Battle of Edgecote Moor. Edward was captured at Olney, Buckinghamshire, and imprisoned at Middleham Castle in Yorkshire. (Warwick briefly had two Kings of England in his custody.) Warwick had the queen's father, Richard Woodville, 1st Earl Rivers, and her brother John executed. However, he made no immediate move to have Edward declared illegitimate and place George on the throne. The country was in turmoil, with nobles once again settling scores with private armies (in episodes such as the Battle of Nibley Green), and Lancastrians being encouraged to rebel. Few of the nobles were prepared to support Warwick's seizure of power. Edward was escorted to London by Warwick's brother George Neville, the Archbishop of York, where he and Warwick were reconciled, to outward appearances. 

When further rebellions broke out in Lincolnshire, Edward easily suppressed them at the Battle of Losecoat Field. From the testimony of the captured leaders, he declared that Warwick and George, Duke of Clarence, had instigated them. They were declared traitors and forced to flee to France, where Margaret of Anjou was already in exile. Louis XI of France, who wished to forestall a hostile alliance between Edward and Edward's brother-in-law Charles the Bold, Duke of Burgundy, suggested the idea of an alliance between Warwick and Margaret. Neither of those two formerly mortal enemies entertained the notion at first, but eventually they were brought round to realise the potential benefits. However, both were undoubtedly hoping for different outcomes: Warwick for a puppet king in the form of Henry VI or his young son; Margaret to be able to reclaim her family's realm. In any case, a marriage was arranged between Warwick's daughter Anne and Margaret's son Edward of Westminster, and Warwick invaded England in the autumn of 1470.

Edward IV had already marched north to suppress another uprising in Yorkshire. Warwick, with help from a fleet under his nephew, the Bastard of Fauconberg, landed at Dartmouth and rapidly secured support from the southern counties and ports. He occupied London in October and paraded Henry VI through the streets as the restored king. Warwick's brother John Neville, who had recently received the empty title Marquess of Montagu and who led large armies in the Scottish marches, suddenly defected to Warwick. Edward was unprepared for this event and had to order his army to scatter. He and Richard, Duke of Gloucester, fled from Doncaster to the coast and thence to Holland and exile in Burgundy. They were proclaimed traitors, and many exiled Lancastrians returned to reclaim their estates. 

Warwick's success was short-lived, however. He over-reached himself with his plan to invade Burgundy in alliance with the King of France, tempted by King Louis' promise of territory in the Netherlands as a reward. This led Edward's brother-in-law, Charles of Burgundy, to provide funds and troops to Edward to enable him to launch an invasion of England in 1471. Edward landed with a small force at Ravenspur on the Yorkshire coast. Initially claiming to support Henry and to be seeking only to have his title of Duke of York restored, he soon gained the city of York and rallied several supporters. His brother George turned traitor again, abandoning Warwick. Having outmaneuvered Warwick and Montagu, Edward captured London. His army then met Warwick's at the Battle of Barnet. The battle was fought in thick fog, and some of Warwick's men attacked each other by mistake. It was believed by all that they had been betrayed, and Warwick's army fled. Warwick was cut down trying to reach his horse. Montagu was also killed in the battle. 

Margaret and her son Edward had landed in the West Country only a few days before the Battle of Barnet. Rather than return to France, Margaret sought to join the Lancastrian supporters in Wales and marched to cross the Severn but was thwarted when the city of Gloucester refused her passage across the river. Her army, commanded by the fourth successive Duke of Somerset, was brought to battle and destroyed at the Battle of Tewkesbury. Her son Prince Edward, the Lancastrian heir to the throne, was killed. With no heirs to succeed him, Henry VI was murdered shortly afterwards, on 21 May 1471, to strengthen the Yorkist hold on the throne.

Richard III

The restoration of Edward IV in 1471 is sometimes seen as marking the end of the Wars of the Roses proper. Peace was restored for the remainder of Edward's reign. His youngest brother, Richard, Duke of Gloucester, and Edward's lifelong companion and supporter, William Hastings, were generously rewarded for their loyalty, becoming effectively governors of the north and midlands respectively. George of Clarence became increasingly estranged from Edward, and was executed in 1478 for association with convicted traitors. 

When Edward died suddenly in 1483, political and dynastic turmoil erupted again. Many of the nobles still resented the influence of the queen's Woodville relatives (her brother, Anthony Woodville, 2nd Earl Rivers and her son by her first marriage, Thomas Grey, 1st Marquess of Dorset), and regarded them as power-hungry upstarts ('parvenus'). At the time of Edward's premature death, his heir, Edward V, was only 12 years old and had been brought up under the stewardship of Earl Rivers at Ludlow Castle

On his deathbed, Edward had named his surviving brother Richard of Gloucester as Protector of England. Richard had been in the north when Edward died. Hastings, who also held the office of Lord Chamberlain, sent word to him to bring a strong force to London to counter any force the Woodvilles might muster.[47] The Duke of Buckingham also declared his support for Richard. 

Richard and Buckingham overtook Earl Rivers, who was escorting the young Edward V to London, at Stony Stratford in Buckinghamshire on 29 April. Although they dined with Rivers amicably, they took him prisoner the next day, and declared to Edward that they had done so to forestall a conspiracy by the Woodvilles against his life. Rivers and his nephew Richard Grey were sent to Pontefract Castle in Yorkshire and executed there at the end of June. 

Edward entered London in the custody of Richard on 4 May, and was lodged in the Tower of London. Elizabeth Woodville had already gone hastily into sanctuary at Westminster with her remaining children, although preparations were being made for Edward V to be crowned on 22 June, at which point Richard's authority as Protector would end. On 13 June, Richard held a full meeting of the Council, at which he accused Hastings and others of conspiracy against him. Hastings was executed without trial later in the day. 

Thomas Bourchier, the Archbishop of Canterbury, then persuaded Elizabeth Woodville to allow her younger son, the 9-year-old Richard, Duke of York, to join Edward in the Tower. Having secured the boys, Robert Stillington, Bishop of Bath and Wells then alleged that Edward IV's marriage to Elizabeth Woodville had been illegal and that the two boys were therefore illegitimate. Richard then claimed the crown as King Richard III. The two imprisoned boys, known as the "Princes in the Tower", disappeared and are assumed to have been murdered. There was never a trial or judicial inquest on the matter. Perkin Warbeck claimed he was the younger of the Princes from 1490 and was recognised as such by Richard's sister, the Duchess of Burgundy.
 
Having been crowned in a lavish ceremony on 6 July, Richard then proceeded on a tour of the Midlands and the north of England, dispensing generous bounties and charters and naming his own son as the Prince of Wales.

Buckingham's revolt

Opposition to Richard's rule had already begun in the south when, on 18 October, the Duke of Buckingham (who had been instrumental in placing Richard on the throne and who himself had a distant claim to the crown) led a revolt aimed at installing the Lancastrian Henry Tudor. It has been argued that his supporting Tudor rather than either Edward V or his younger brother, showed Buckingham was aware that both were already dead.

The Lancastrian claim to the throne had descended to Henry Tudor on the death of Henry VI and his son in 1471. Henry's father, Edmund Tudor, 1st Earl of Richmond, had been a half-brother of Henry VI, but Henry's claim to royalty was through his mother, Margaret Beaufort. She was descended from John Beaufort, who was a son of John of Gaunt and thus a grandson of Edward III. John Beaufort had been illegitimate at birth, though later legitimised by the marriage of his parents. It had supposedly been a condition of the legitimation that the Beaufort descendants forfeited their rights to the crown. Henry had spent much of his childhood under siege in Harlech Castle or in exile in Brittany. After 1471, Edward IV had preferred to belittle Henry's pretensions to the crown, and made only sporadic attempts to secure him. However his mother, Margaret Beaufort, had been twice remarried, first to Buckingham's uncle, and then to Thomas, Lord Stanley, one of Edward's principal officers, and continually promoted her son's rights. 

Buckingham's rebellion failed. Some of his supporters in the south rose up prematurely, thus allowing Richard's Lieutenant in the South, the Duke of Norfolk, to prevent many rebels from joining forces. Buckingham himself raised a force at Brecon in mid-Wales. He was prevented from crossing the River Severn to join other rebels in the south of England by storms and floods, which also prevented Henry Tudor landing in the West Country. Buckingham's starving forces deserted and he was betrayed and executed. 

The failure of Buckingham's revolt was clearly not the end of the plots against Richard, who could never again feel secure, and who also suffered the loss of his wife and eleven-year-old son, putting the future of the Yorkist dynasty in doubt.

Henry VII

Many of Buckingham's defeated supporters and other disaffected nobles fled to join Henry Tudor in exile. Richard made an attempt to bribe the Duke of Brittany's chief Minister Pierre Landais to betray Henry, but Henry was warned and escaped to France, where he was again given sanctuary and aid.

Confident that many magnates and even many of Richard's officers would join him, Henry set sail from Harfleur on 1 August 1485, with a force of exiles and French mercenaries. With fair winds, he landed in Pembrokeshire six days later and the officers Richard had appointed in Wales either joined Henry or stood aside. Henry gathered supporters on his march through Wales and the Welsh Marches and defeated Richard at the Battle of Bosworth Field. Richard was slain during the battle, supposedly by the major Welsh landowner Rhys ap Thomas with a blow to the head from his poleaxe. Rhys was knighted three days later by Henry VII.

Henry, having been acclaimed King Henry VII, strengthened his position by marrying Elizabeth of York, daughter of Edward IV and the best surviving Yorkist claimant, reuniting the two royal houses. Henry merged the rival symbols of the red rose of Lancaster and the white rose of York into the new emblem of the red and white Tudor Rose. Henry later shored up his position by executing a number of other claimants, a policy his son Henry VIII continued.

Many historians consider the accession of Henry VII to mark the end of the Wars of the Roses. Others argue that they continued to the end of the fifteenth century, as there were several plots to overthrow Henry and restore Yorkist claimants. Only two years after the Battle of Bosworth, Yorkists rebelled, led by John de la Pole, Earl of Lincoln, who had been named by Richard III as his heir but had been reconciled with Henry after Bosworth. The conspirators produced a pretender, a boy named Lambert Simnel, who resembled the young Edward, Earl of Warwick (son of George of Clarence), the best surviving male claimant of the House of York. The imposture was shaky, because the young earl was still alive and in King Henry's custody and was paraded through London to expose the impersonation. At the Battle of Stoke Field, Henry defeated Lincoln's army. Lincoln died in the battle. Simnel was pardoned for his part in the rebellion and was sent to work in the royal kitchens.

Henry's throne was challenged again in 1491, with the appearance of the pretender Perkin Warbeck, who claimed he was Richard, Duke of York (the younger of the two Princes in the Tower). Warbeck made several attempts to incite revolts, with support at various times from the court of Burgundy and James IV of Scotland. He was captured after the failed Second Cornish uprising of 1497 and killed in 1499, after attempting to escape from prison. Warwick was also executed, rendering the male-line of the House of York (and by extension the whole Plantagenet dynasty) extinct.

During the reign of Henry VII's son Henry VIII, the possibility of a Yorkist challenge to the throne remained until as late as 1525, in the persons of Edward Stafford, 3rd Duke of Buckingham, Edmund de la Pole, 3rd Duke of Suffolk and his brother Richard de la Pole, all of whom had blood ties to the Yorkist dynasty but were excluded by the pro-Woodville Tudor settlement. To an extent, England's break with Rome was prompted by Henry's fears of a disputed succession, should he leave only a female heir to the throne or an infant who would be as vulnerable as Henry VI had been to antagonistic or rapacious regents.

Aftermath

Historians debate the extent of impact the wars had on medieval English life. The classical view is that the many casualties among the nobility continued the changes in feudal English society caused by the effects of the Black Death. These included a weakening of the feudal power of the nobles and an increase in the power of the merchant classes, and the growth of a centralised monarchy under the Tudors. The wars heralded the end of the medieval period in England and the movement towards the Renaissance. After the wars the large standing baronial armies that had helped fuel the conflict were suppressed. Henry VII, wary of any further fighting, kept the barons on a very tight leash, removing their right to raise, arm and supply armies of retainers so that they could not make war on each other or the king. The military power of individual barons declined, and the Tudor court became a place where baronial squabbles were decided with the influence of the monarch. 

Revisionists, such as the Oxford historian K. B. McFarlane, suggest that the effects of the conflicts have been greatly exaggerated and that there were no wars of the roses. Many places were unaffected by the wars, particularly in the eastern part of England, such as East Anglia. It has also been suggested that the traumatic impact of the wars was exaggerated by Henry VII, to magnify his achievement in quelling them and bringing peace. The effect of the wars on the merchant and labouring classes was far less than in the long drawn-out wars of siege and pillage in Europe, which were carried out by mercenaries who profited from long wars. Although there were some lengthy sieges, such as those of Harlech Castle and Bamburgh Castle, these were in comparatively remote and less populous regions. In the populated areas, both factions had much to lose by the ruin of the country and sought quick resolution of the conflict by pitched battle. Philippe de Commines observed in 1470:
The realm of England enjoys one favour above all other realms, that neither the countryside nor the people are destroyed, nor are buildings burnt or demolished. Misfortune falls on soldiers and nobles in particular...
Exceptions to this claimed general rule were the Lancastrian looting of Ludlow after the largely bloodless Yorkist defeat at Ludford Bridge in 1459, and the widespread pillaging carried out by Queen Margaret's unpaid army as it advanced south in early 1461. Both events inspired widespread opposition to the Queen, and support for the Yorkists. 

Many areas did little or nothing to change their city defences, perhaps an indication that they were left untouched by the wars. City walls were either left in their ruinous state or only partially rebuilt. In the case of London, the city was able to avoid being devastated by convincing the York and Lancaster armies to stay out after the inability to recreate the defensive city walls.

Few noble houses were extinguished during the wars; in the period from 1425 to 1449, before the outbreak of the wars, there were as many extinctions of noble lines from natural causes (25) as occurred during the fighting (24) from 1450 to 1474. The most ambitious nobles died and by the later period of the wars, fewer nobles were prepared to risk their lives and titles in an uncertain struggle.

The kings of France and Scotland and the dukes of Burgundy played the two factions off against each other, pledging military and financial aid and offering asylum to defeated nobles and pretenders, to prevent a strong and unified England from making war on them. 

Armies and warfare

Following defeat in the Hundred Years' War, English landowners complained vociferously about the financial losses resulting from the loss of their continental holdings; this is often considered a contributory cause of the Wars of the Roses. The wars were fought largely by the landed aristocracy and armies of feudal retainers, with some mercenaries. 

At the end of the Hundred Years' War large numbers of unemployed soldiery returned to England seeking employment in the growing armies of local nobility. England drifted toward misrule and violence under the weak governance as local noble families like the Nevilles and Percies increasingly relied on their feudal retainers to settle disputes. It became common practice for landowners to bind their mesnie knights to their service with annual payments.

Half of an indenture contract, the randomly cut (or indented) edge proves a match to the counterpart document
 
Edward III had developed the contract system where the monarch entered into formal written contracts called indenture with experienced captains who were contractually obliged to provide an agreed upon number of men, at established rates for a given period. Frequently the landed nobility acted the principal or main contractor. Knights, men at arms and archers were often sub-contracted. A lord could find men amongst his tenantry who included landless men and others who would crave the security of maintenance and livery. Skilled archers could command as high a wage as knights. As baronial armies grew in size, the rule of law was weakened. 

Support for each house largely depended upon dynastic factors, such as blood relationships, marriages within the nobility and the grants or confiscations of feudal titles and lands. Given the conflicting loyalties of blood, marriage and ambition, it was not uncommon for nobles to switch sides; several battles (such as Northampton and Bosworth) were decided by treachery. The armies consisted of nobles' contingents of men-at-arms, with companies of archers and foot-soldiers (such as billmen). There were sometimes contingents of foreign mercenaries, armed with cannon or handguns. The horsemen were generally restricted to "prickers" and "scourers"; i.e. scouting and foraging parties. 

Much like their campaigns in France, it was customary for the English gentry to fight entirely on foot. In several cases, noblemen dismounted and fought amongst the common foot-soldiers to both inspire them and due to the fact that, as proven by the experiences of battles on the continent, heavy cavalry is of limited tactical value when both sides possess large numbers of skilled Longbowmen. 

It was often claimed that the nobles faced greater risks than the ordinary soldiers as there was little incentive for anyone to take prisoner any high-ranking noble during or immediately after a battle. During the Hundred Years' War against France, a captured noble would be able to ransom himself for a large sum but in the Wars of the Roses, a captured noble who belonged to a defeated faction had a high chance of being executed as a traitor. Forty-two captured knights were executed after the Battle of Towton. The Burgundian observer Philippe de Commines, who met Edward IV in 1470, reported,
King Edward told me in all the battles which he had won, as soon as he had gained victory, he mounted his horse and shouted to his men that they must spare the common soldiers and kill the lords, of whom none or few escaped.
Even those who escaped execution might be declared attainted therefore possess no property and be of no value to a captor.

Political psychology

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