Horizontal Gene Transfer – Meaning, Methods, Detection and Outcomes

Both prokaryotic and eukaryotic organisms have developed genetic mechanisms by which they can evolve to adapt to and meet the challenges thrown at them by a changing environment. One process by which they do this is known as horizontal gene transfer (HGT), also referred to as lateral gene transfer (LGT).

In this article, we will discuss what HGT is, how it is used in research, how to detect it and the threat it poses to humanity.

What is horizontal gene transfer (HGT)?

HGT is the movement of genetic material from one organism to another and allows the transfer of genes between unrelated species. The process was first described in a prokaryotic species, Streptococcus pneumoniae, by Frederick Griffith in 1928 in the form of transformation,¹ followed in 1946 by Joshua Lederberg and Edward Tatum’s discovery of conjugation² and finally the first description of transduction by Norton Zinder and Joshua Lederberg in the early 1950s.³ In 1971, Fritz Went first speculated that HGT might be important in the evolution of eukaryotes.⁴ It was initially believed that for a transferred gene to survive in a new host, it needed to provide some form of selective advantage, and this is still the case for many transferred genes. However, it is now understood that many genes transferred in both prokaryotes and eukaryotes have a neutral or nearly neutral effect.^5,6

Horizontal gene transfer in bacteria and other prokaryotes vs eukaryotes

While HGT is known to occur in eukaryotes by processes including phagocytosis and endocytosis, viral mediated and pathogen/parasite interactions with the host,⁷ it is far more common and the mechanisms have been studied in more detail in prokaryotes. HGT allows bacteria to acquire advantageous traits, including virulence factors, antibiotic resistance, heavy metal resistance or metabolic capabilities, boosting their adaptability to environmental pressures. These traits can be carried on mobile genetic elements, including conjugative and non-conjugative plasmids, integrative conjugative elements (ICEs), transposons, insertion sequences and bacteriophage that can facilitate rapid evolution.⁸

Lateral gene transfer vs vertical gene transfer

LGT and vertical gene transfer (VGT) are both mechanisms by which genetic information is passed between organisms. They are similar in that they both contribute to evolution and adaptation to changing environments. They also both use molecular systems like replication, repair and recombination to maintain the acquired genetic traits. However, they are also different in several aspects, as summarized in Table 1.

Table 1: Differences between LGT and VGT.

Horizontal gene transfer methods – Conjugation, transformation and transduction

The three mechanisms of HGT in bacteria are (Figure 1):

• Transduction: The process of genetic exchange in which a virus transfers genetic material from one organism to another.
• Conjugation: The process of genetic exchange in which genetic material is transferred from one host to another by direct physical contact.
• Transformation: The process of genetic exchange in which a cell takes up free DNA from its environment and incorporates it into its genetic makeup.

Figure 1: A diagram showing the processes of transduction, conjugation and transformation. Credit: Technology Networks.

The interplay of horizontal gene transfer and genetic recombination in bacteria

While HGT allows bacteria to acquire novel advantageous traits rapidly, it can lead to an associated fitness cost to the new host by potentially interfering with existing genetic networks and imposing an increased genetic load. Homologous recombination (HR) systems work synergistically with HGT to mitigate these costs and drive advantageous evolutionary events. The HR mechanisms can remove deleterious mutations and non-beneficial regions of incoming DNA and merge and optimize genes into existing regulatory networks so that they are not disrupted and functional efficiency is maintained.⁹

In addition to the benefit to the individual cell of core genome homogenization, HR also benefits the entire structure of microbial populations.¹⁰ Together, HGT and HR create a dynamic and diverse genetic pool that allows bacterial communities to adapt more efficiently to the environmental challenges they face daily.

Reproduction in bacteria – the role of HGT in evolution

Bacteria primarily divide by asexual reproduction in a rapid process known as binary fission. Briefly, the cell duplicates its chromosome, elongates and then forms a septum to separate the two identical (unless a mutation occurs) daughter cells containing a single chromosome.

In the strictest sense of the word, bacteria do not perform sexual reproduction in the same way that animals and plants do, i.e., they do not produce gametes or zygotes. However, they do utilize unidirectional processes, which mimic some aspects of sexual reproduction, i.e., transduction, transformation and conjugation. These processes allow bacteria to evolve rapidly and adapt to changing environments, e.g., acquisition of antimicrobial resistance (AMR) genes.

Mutation vs HGT in microbial genetics

Both mutation and HGT are crucial in the evolution of microorganisms but there are some key differences between the processes, summarized in Table 2.

Table 2: A comparison between mutation and HGT.

What promotes horizontal gene transfer?

A wide array of factors, from biological to chemical and environmental, is known to promote HGT in bacteria. These include, but are certainly not limited to, those mentioned below.

1. The development of biofilms increases rates of HGT compared to planktonic states due to the close cell-to-cell contact found within them.¹¹
2. The development of competence systems within certain species of bacteria has enhanced HGT by the process of transformation.
3. Hot spots like the human microbiome may increase the frequency of HGT.¹²
4. Environmental chemical contaminants like non-antibiotic drugs,¹³ chlorine¹⁴ and sweetners¹⁵ have all been shown to increase rates of HGT.
5. Heavy metals, e.g., copper, have been shown to increase HGT.¹⁶ There is also increasing evidence that heavy metal contamination is a co-selective pressure contributor to the persistence and dissemination of AMR genes.¹⁷
6. There is evidence that antibiotics can induce HGT,¹⁸ and misuse has been shown to alter gut homeostasis, promoting the transfer of resistance genes.¹⁹ Additionally, sub-lethal levels of antibiotics can also increase the rate of HGT.²⁰

HGT can be promoted by several factors, understanding these is vital to preventing the spread of AMR genes and improving our ability to manage microbial environments effectively.

How can horizontal gene transfer be detected?

There are various methods employed by scientists to detect HGT events in bacteria, including both computational and experimental approaches. Some methods are listed below:

1. Sequence similarity: Using programs like BLAST to compare genes and identify similarities to genes already known.
2. Functional analysis: Demonstrating the functional role of an acquired trait by experimental means, like gene knockout.²¹
3. Detection of known HGT-associated elements: Looking for elements like plasmids, ICEs, transposons and phage.
4. Comparative genomics: Comparing closely related genomes and identifying regions present in some species but not others.
5. Phylogenetic approaches: Identifying incongruences within phylogenetic trees that may infer HGT events.
6. Genomic context: Detecting genes that do not fit with the general makeup of the genome that is being studied, e.g., variation in the guanine/cytosine (GC) content.

There are a large number of computer programs that have been and are continually being developed by bioinformaticians that enable scientists to identify HGT events, including PhyloGenie,²² Gubbins, IslandViewer, HGTector and Alien Hunter.

Exploiting horizontal gene transfer in the lab

Scientists have employed HGT in a vast array of applications, including genetic engineering, vaccine development, bioremediation, biotechnology, drug development and basic research. The impact of its use in science is enormous, and without these HGT-based techniques, many of the advances we see today would not have been possible. Specific examples can be found in the related articles that focus on transformation, transduction and conjugation.

HGT and public health

HGT is one of the primary methods by which bacteria acquire AMR genes and, therefore, resistance to one or multiple antibiotics used to treat bacterial infections. Research published in The Lancet in 2022 by a global group of collaborators showed that the burden of deaths attributed to resistance is truly staggering, with an estimated 1 million plus deaths per year since 1990 and a predicted estimate of more than 39 million lives in the years up to 2050. In 2021, they estimated that 4.71 million deaths were associated with AMR, and of those, 1.14 million were directly attributable.²³

According to the World Health Organization (WHO), the pipeline for new antibiotics is almost gone, but there are programs in place to prioritize the research required to combat the ever-growing threat of AMR. This includes research into developing new antibiotics, vaccines, epidemiology tools and diagnostics, and lab-based HGT methodologies will undoubtedly be used to help drive these aims.

In summary, HGT is crucially important to the evolution of bacteria and has been pivotal to the understanding of biological systems and developing tools to combat some of the biggest threats to health we have ever seen.