The prokaryotes and eukaryotes is the most crucial

The genome of any
organism is referred to as the total genetic content possessed by that
organism. The movement of genetic material is defined as the process of Gene
Transfer. Gene Transfer can be done in two directions: vertical gene transfer
(transfer of genetic material from parent to offspring) and horizontal gene
transfer or lateral gene transfer (transfer of genetic material from donor
organism to recipient organism). The process of gene transfer is a type of
DNA-sharing process in which direct movement of DNA is observed between two
organisms and not parent to offspring. The first occurrence of Horizontal Gene
Transfer (HGT), also known as Lateral Gene Transfer (LGT) was seen in
micro-organisms in the late 1940s. For the transferred gene to survive in the
host for long period of time, it either needs to provide selective advantage to
itself (selfish genetic element) or it needs to provide selective advantage to
the host or recipient 2.

HGT mostly occurs between
various prokaryotes (mainly bacteria) and eukaryotes where it plays a major
role in the evolution of eukaryotic organisms. HGT is also witnessed between
other group of organisms such as plants, fungi, animals, algae and insects and
between organelles of the eukaryotes which contain DNA i.e. nucleus,
mitochondria and chloroplast. HGT is also identified between hosts and viruses
which is a major factor responsible for host-virus-co-evolution 5. However,
the transmission of DNA between prokaryotes and eukaryotes is the most crucial
and well-studied as it is one great factor responsible for evolution of
eukaryotes. The best-known example of HGT from bacteria to eukaryotes is HGT of
Agrobacterium tumefaciens to plants.
The bacteria A. tumefaciens uses a
type IV secretion system which is a syringe-like protein to inject the
bacterial proteins and its tumor-inducing plasmid, known as Ti plasmid, into plant
cells. 1,6

HGT has the ability to
transfer the novel genotypes between different species thereby helping in
evolution of various species which forms the fundamental rule of endo-symbiotic
theory. Besides their role in evolution of eukaryotes, HGT genes are also
identified for their roles in metabolizing sugar, hemicellulose for feeding on
plants and also in degrading complex structures 5. For successful HGT to
occur, the two organisms must be in close physical proximity to one another and
there should be compositional similarity between donor and recipient genomes.
This compositional similarity promotes homologous recombination that leads to
exchange of genetic material 6. HGT is often associated with microbial
antibiotic resistance and pathogenicity. However, the most outstanding role of
HGT in the evolution of eukaryotes by exchange of genetic material is of
importance 2.

Examples of HGT



“Endosymbiosis” means “to
cooperate inside” and it is a type of symbiosis in which one of the organism
lives within another organism. Endosymbiosis is the process by which
prokaryotes have given rise to eukaryotic cells and this process is carried out
by endosymbionts. Endosymbionts are the organisms which live within the body or
cells of another organism. All eukaryotes have endosymbionts. This theory
proves the evolution of mitochondria and chloroplast from a-proteobacteria
and cyanobacteria respectively. The Endosymbiotic theory was first published
by Lynn Margulis in
the late 1960s.


There are roughly four
factors that affect the frequency of gene transfer such as the ability of an
organism to take up exogeneous foreign DNA, how accessible its germ line is
(specifically, whether it is sequestered away from somatic tissue), its
recombino­genic tendencies and the frequency of the donor DNA in the
environment. The HGT follow a very simple rule for their integration – “first
do no harm”. The chances of HGT are significantly increased if there is
presence of stably associated germline of endosymbionts. After the transfer of
foreign exogenous DNA, the foreign DNA must be selected either by transcribing
itself into RNA or delivering a function to the genome. If the transfer DNA is
not selected by either of the two processes, the newly transferred DNA will
likely be deleted from the host or it might get mutated 2,3.

The three most well-known
mechanisms of HGT in prokaryotic organisms are conjugation, transformation and
transduction. Conjugation requires proximity, particularly, physical con­tact
between a donor organism and a recipient organism. This contact is mostly via a
conjuga­tion pilus, through which genetic material is transferred. Conjugation
is restricted to bacterial cells with Agrobacterium
spp. being an exception as it uses conjugation machinery for HGT into plant
cells. Transformation is defined as the uptake of exogenous DNA from the
external environment through cell membrane and has been seen in both archaea
and bacteria. Transduction is the process of delivery of genetic material
through a phage which results in the integration of exogenous host genetic
material into a phage genome, and this phenomenon has been observed in both
bacteria and archaea. In essence, Transduction is a type of gene transfer
carried out by viruses such as bacteriophage. Two types of transduction are
known: generalized transduction, wherein a ran­dom piece of the host DNA is
incorporated during cell lysis; and specialized transduction, wherein a
prophage indistinctly excises itself from genome of the host and incorporates
some of the flanking host DNAs.

Gene Transfer can also
occur through various other mechanisms, such as gene transfer agents (GTAs) and
cell fusion. GTAs are gene delivery sys­tems that use capsids for the delivery.
They carry small random pieces of DNA in the gene-delivery systems, i.e.
capsids for its integrated into a host chromosome. GTAs are found in both
bacteria and archaea. The GTA-encoding genes do not provide an obvious benefit
to the host or to the GTA-encoding genes. It’s still not known how these genes
remain under selection for function. One study discovered that GTAs from Rhodobacter capsulatus were able to
transfer antibiotic resistance to bacteria from different phyla; however, other
studies have found that not all bacteria, including bacteria that have the
GTA-encoding genes, are able to receive genes via GTAs. Prophages that have
lost the ability to target their own genetic material for packaging are
transformed into GTAs. Unlike transduction, GTAs cannot transfer all the genes
to a new host. Cell fusion has been studied on solid media where one organism
forms aggregates and the cells physically join each other by several bridges of
fused cell membrane. Cell fusion has been observed in both Euryarchaeota (Haloferax spp.) and Crenarchaeota (Sulfolobus spp.). This method has very
high degree of bidirectional gene transfer which means that it is more similar
to sexual reproduction in eukaryotes than it is to conjugation in prokaryotes

Non-homologous end
joining (NHEJ) is another major mechanism by which the foreign DNA is
incorporated into the eukaryotic genome. NHEJ functions in all the types of
cells, from bacteria to man, and it carries out various functions such as
repair of double stranded DNA breaks, telomere maintenance, and the insertion
into the genome of HIV-1 and repetitive sequences. NHEJ seems to function
in three main steps: 1) DNA end-binding and bridging, 2) terminal end
processing, 3) and ligation of the two strands ( Another
mechanism by which genes can be exchanged between related species is through –
Introregression – that is, flow of genetic material as a result of interspecies
hybridization followed by repeated backcrosses to any one of the parents. It is
a major type of gene transfer mechanism in transgenic crops that are grown in
proximity to non-domesticated relatives. However, it is not just restricted to
plants. Introgression was believed to have intro­duced an allele which is
required in functional brain development from archaea to humans 2.

The DNA that is being
transferred seems to play an important role in HGT and whether the transferred
sequence will become functional or not. HGT events which incorporate large DNA
sequences are more likely to result into junk DNA as compared to smaller DNA
sequences. The reason for this is that large sequences undergo rapid
non-functionalization through pseudogene formation and DNA deletion and hence
show low levels of transcription. For example, in the pillbug Armadillidium vulgare, incorporation of
an ~1.5Mb fragment of Wolbachia spp. DNA
is involved in creation of a new sex chromosome 3.

Mobile genetic elements (MGEs):
MGEs or jumping genes are gene sequences which can exchange places between
chromosomes between same species or even different species. Plasmids,
bacteriophages and transposons are some examples of MGEs. They are also called as
selfish genetic elements because they perform no other function other
replicating themselves. MGE are involved in promoting HGT and they also carry
out rearrangements of the genome 2. 


Fig 1: Various mechanisms
of Horizontal Gene Transfer (HGT)

The HGT events are
classified into two broad types: 1) innovative transfer – that provide a new
function to the recipient organism, 2) maintenance transfer – that replace or
repair or maintain a functional loss in the recipient organism. The functions
of innovative transfers include to enable recipient organisms to feed on nutri­tionally
poor or toxic diets, parasitize other eukaryotes, survive in cold, hot, acidic,
anaerobic or toxic environ­ments or protect themselves from other organisms.
The function of maintenance transfers is normal host function and to maintain
the function initially encoded in an organelle genome 3. It has been found
that there are more than 130 traces of possible HGT events in the human genome—
for example the presence of fungal hyaluronan synthases, a fat mass and obesity
associated gene (FTO), and the

gene responsible
for blood types (ABO) 12.


For a nonhuman
gene to appear in the genomes of many people, HGT needs to occur in the germ
cells so that it can be passed on to future generations; and, it must confer
some selective benefit to the host. Such humans may not witness such strong
selection for new functions in our genome, and because our germ cells are
protected from other organisms and their DNA, such HGTs may be rare. However, HGT might be possible
in the somatic human genome; such insertional mutations would be very difficult
to detect, though, without sequencing large numbers of human cells 12.







Plastids are believed to be evolved
from cyanobacterium with the help of HGT in eukaryotic host. This development
of cyanobacterial endosymbionts or plastids has led to the origin of Plantae:
red algae, glaucophytes and green algae. It was also found that cyanobacterial
and chlamydial endosymbionts was existed in early eukaryotes host cell 2.



variety of organisms require a complex network of sym­bionts for different functions
ranging from defense and immu­nity to metabolism. The holobiont is a collective
term for the host and its associ­ated microbiota. The diet and ecology of human
host, competition between members of microbiota all affect the composition of
human gut microbiota. For example, Japanese people can break down
polysaccharides from cell walls of seaweeds in the Japanese diet because the
bacteria in the gut of Japanese people carry out this degradation with the help
of certain enzymes and genes encoding these enzymes were transformed from
parasites of marine algae to the bacteria of the gut. Thus, as a result of HGT Japanese
people can use carbohydrates from algal cell walls as nutrient source but other
population cannot 2.








Viruses and hosts undergo
a continuous co-evolutionary process, which incorporates both host defense and
viral evasion mechanisms. There are a variety of strategies which viruses have
devised to circumvent the host immune system. For example, Herpesviruses, a
group of large DNA viruses encode proteins that mimic cellular cytokines and
cytokine receptors which modulate cytokine mediated signals during invasion of
pathogens. Host immune system is developed to protect itself from invading
pathogens. The gene flow between viruses and humans happens only after
integration of viral genetic DNA into host genome.


HGT is reported
between 51 human encoding genes and 27 viral encoding genes. Studies were
carried out and it was proved that these 27 viral HGT related genes are encoded
by 14 virus species such as herpesviridae
(human herpesvirus type 5, 6, 8, equine
herpesvirus 2, Saimiriine herpesvirus 2), poxviridae (deerpox virus, molluscum contagiosum virus, vaccinia virus,
fowlpox virus, yaba monkey tumor virus), retroviridae (rous sarcoma virus,
baboon endogenous virus, simian retrovirus) with the remaining one from bornaviridae (bornavirus). All these viruses showed the common characteristics they
shared which is that should have the capability to induce latent infection, signifying
that they are capable of modifying and evading the immune

system of host.


It was also found
that there was structural similarity existed between viral encoding G-protein
coupled receptor E1 and human encoding chemokine receptors (CCR3). In 13 out of
the 27-human immune related HGT proteins, structural identity of 33.5-55.8% was
observed and comparison analysis of protein sequence, transmembrane domains and
3d structure between E1 and CCR3 was performed to prove this. Studies revealed
high rate of similarities in all these parameters 5.







After the transfer
of the foreign DNA into human somatic genome, there are very high chances that
HGT insertions can cause severe diseases such as cancer and autoimmune disease.

example, human
papillomavirus (HPV) is the cause of 80-100 percent of cervical cancers. The
virus is integrated into the DNA of cervical cells, and if the integration is not
completed, certain HPV proteins are unregulated, which leads to disruption of apoptosis,
cell proliferation, and ultimately causing cancer. Similarly, hepatitis B virus
(HBV) causes hepatocellular cancer and has been found to insert its DNA into
infected hepatocytes. HBV repeatedly integrates its viral DNA and its core gene
into cancer-related genes, which causes increased cell proliferation and
survival, the two symbols of cancer. One such integration is integration into
human telomerase reverse transcriptase gene which causes altered gene
expression and results in carcinogenesis.


In 2013, it was
found that sequences from Acinetobacter
species were identified in acute myeloid leukemia (AML) samples, Helicobacter pylori in stomach cancer
samples m and Pseudomonas species was
identified in stomach adenocarcinoma (STAD) samples.  In AML, it was found that bacterial DNA
integration was found more frequently in human mitochondrial genome than human
somatic genome. In both the AML and STAD cancer samples, only bacterial 16S and
23S rRNA fragments integrating into the human genome were identified. These
rRNA genes contain secondary structures that have the ability to form various
stem-loops or hairpin loops. Integration of DNA occurs in the 5′-untranslated
regions (5′-UTR) of the cancer-related genes, i.e. they are transcribed but not
translated. The stem-loops in the inserted rRNA gene could alter the secondary
structures of the transcripts, hence disrupting the process of transcription
and/or translation. It was also found that putative STAD integrations were
present in G-rich regions of the cancer-related genes 1,6.




A bacterial DNA integration that occurs in a human cell

and leads to the expression of a bacterial compound
recognized by the human immune system has the

potential to trigger autoimmune disease, for example