Information Wellness Blog

While Goble argues that slow motion was technically possible from the first days of Hollywood cinema, until recently it was used only rarely. Even as the “blockbuster” culture dominated the 1970s and ’80s, slo-mo was a “trivial and often pretty tasteless technique.” Why did it suddenly explode? He suggests that the answer is political.

DNA Transposons

DNA transposons, also known as transposable elements (TEs) and jumping genes, are sequences of genetic information that can move locations within genomes. They are widespread in prokaryotic and eukaryotic cells, often making up significant portions of an organism’s genetic material. TEs have played fundamental roles in genetic evolution, gene regulation and cell biology, and have had a profound impact on human health and agricultural advancements.

First discovered by Barbara McClintock in maize, DNA transposons are present throughout the tree of life – in humans, they make up half of our genomes. They are a vital part of the dynamic architecture of our chromosomes and a key to understanding how we evolved.

DNA transposon insertions can be either “intentional” or “accidental.” Intentional insertions occur when the transposase protein of an element inserts itself into a genomic site at random. Intentional insertions can lead to mutations or new genetic functions. On the other hand, accidental insertions often occur when the DNA polymerase gene makes mistakes while inserting DNA into chromosomes. Such accidental insertions can create large gaps in chromosomes, which can then be filled in with DNA from other sources, such as retrotransposons or other TEs.

The genomes of most eukaryotic organisms contain many DNA transposons, especially the short Alu family. In humans, Alu is the most prevalent of all active TEs, making up an estimated 15%-17% of our genome. The remaining active TEs include long terminal repeat retrotransposons and non-LTR DNA transposons such as L1 and piggyBac.

Unlike LTR retrotransposons, which have long terminal repeats, non-LTR DNA transposons do not require the presence of an RNA intermediate to move. This makes them more likely to cause DNA double-strand breaks, which can lead to mutations. To avoid this, host organisms have developed several mechanisms to regulate TE activity. These include DNA methylation, which reduces TE activity by blocking gene expression, and various RNA interference-based mechanisms that target TEs for degradation or inactivation.

Not all insertions caused by transposons are harmful, however. Sometimes, a TE excises perfectly, and can take along with it other fragments of genomic DNA. This phenomenon is called exon shuffling, and it can alter gene regulatory regions and phenotypes. For example, a DNA transposon in medaka fish called Tol2 is linked to the pigmentation pattern of their skin. Exon shuffling with this gene has led to a range of phenotypes in different inbred lines of this fish, including some that are albino.

Retrotransposons

The class of DNA transposons known as retrotransposons resemble retroviruses in that they are a DNA-based copy and paste mechanism. However, unlike viral genomes which can be encoded in a single gene, most of these elements are characterized by several genes. These genes code for a protein with a specific function. These proteins are typically involved in the cellular response to stress or environmental cues and also in cell differentiation, neurogenesis and aging.

In mammals, most retrotransposons are no longer active but some remain in an epigenetically silent state. Despite this, a significant portion of the human genome consists of these dormant genetic elements.

Transposon insertions can disrupt a host genome by mutating neighboring sequences or introducing new regulatory regions. As a consequence, many TEs are associated with disease and the aging process.

Using genomic approaches based on RNA sequencing, we can track the fate of these inserted sequences. For example, RNA-seq data revealed that L1 ORF2p and HERV RT generate cDNA with a potential quadruplex structure in their 3’ untranslated region (3′ UTR). This cDNA is recognized by a protein complex (LoxP) and can trigger innate immune responses. These data suggest that the epigenetic silencing of these TEs is a dynamic process that may be influenced by stress and environmental cues.

While much genomic scale work focuses on the number of TEs present in a genome and their flanking sequences, other aspects of their impact have been overlooked. These mainly include the effects of a particular TE on its neighbouring genes which can result in changes like alternative splicing, premature termination or long-range interactions. In addition, some TEs can be directly incorporated into cellular processes and functions through a process called domestication or exaptation [99].

It has been estimated that approximately 40% of the human genome consists of retrotransposons. Although these elements are a major force in genome evolution, their insertion rates have varied significantly over the course of 35 million years. These variations are due to differences in the number of functionally important DNA regions that are available for insertion into a host gene. Through various approaches, it has been demonstrated that a large fraction of these evolutionary conserved regulatory regions such as promoters, enhancers and some TF binding sites are derived from TEs.

Control Switch Transposons

Control switch transposons are the most abundant of all DNA transposable elements, and their insertion patterns have been associated with complex human diseases such as cancer. In general, Class II transposons move by cutting themselves out of one place in the genome and “pasting” themselves into a new location using a transposase that is coded by the transposon itself. This process causes a lot of mutations and disrupts the gene expression of the cells that they invade.

In order to understand how these mutations occur, researchers have recently developed a computational model that simulates the insertion of Class II transposons in chromatin. The simulation allows them to test the hypothesis that placement adjacency is largely determined by local changes in chromatin stiffness.

Chromatin stiffness is determined by a combination of factors, such as the type and density of methylated nucleotides, the number of H3K9me3 and H3K27me3 methylation domains, and the amount of histone modifications such as acetylation and methylation of Lysine residues. The results of the simulations suggest that these factors all influence the placement of a given transposon within a specific genomic region.

Specifically, they found that regions of chromatin with low stiffness are more likely to be invaded by Class II transposons. Conversely, areas of chromatin with high stiffness are less likely to be invaded by these DNA transposable elements. This suggests that the presence of these insulators, which can block DNA transposable element activity, is necessary for maintaining genome stability and regulating gene expression.

They also found that there is a strong correlation between the insertion efficiency of a transposon and its sequence similarity to the host genome. For example, transposons with more homologous DNA to the host genome tend to have lower insertion efficiencies than those with fewer homologous chromosomes.

This suggests that, by establishing a large pool of genetically related elements in a particular genomic region, the genomic environment can facilitate the formation of insulator domains that prevent the activity of DNA transposable elements. This mechanism may help explain how the genome manages to keep transposable elements under control, even during periods of intense DNA methylation change.

Jumping Gene Remnants

Before molecular genetics, scientists believed genes occupied fixed positions on chromosomes. Barbara McClintock, who won the Nobel Prize for her research on the colours of maize kernels, challenged this view in the early twentieth century with her discovery of mobile DNA sequences. These are known as transposable elements, and they can move within a chromosome or even between genomes (in bacteria). Some have become so abundant that their presence is now the dominant feature of some species’s genomes.

Over time, some broken transposon bits have reverted to their original function as gene-regulating switches. In fact, it’s thought that many of the key switches in the human genome, including some that control the activity of telomerase, are repurposed bits of former transposons. This suggests that jumping genes aren’t just genetic garbage, but a source of evolutionary innovation.

But some live transposons can also cause problems as they move around the genome, and can disrupt genes by hitting them randomly. That’s why our cells try to keep them at bay by tinkering with their structure. A common way is to add a sticky chemical called silencing tag to the DNA around them. This binds to another protein, which then cuts the transposon into pieces and leaves it where it isn’t wanted.

The problem with this silencing approach is that it can also affect genes that are supposed to be active at the same time. The cellular machinery that normally transcribes the genome into RNA can be accidentally inhibited, and this is thought to have helped give rise to cancer. So researchers have been looking for new ways to stifle these mobile genes.

Molecular geneticist Joanna Wysocka and colleagues have found that fragments of the old endogenous retroviruses can help block the movement of transposons. These fragments, which she and her team call Coordinator, can be added to chromosomes to make them more resistant to jumping genes. She and her team have also looked at enhancers, which are regions of the genome that can alter the activity of certain genes. They found that LINE-1 and Alu fragments often sit at enhancers that show variable activity between humans and chimps. This is because chimps evolved Coordinator mutations that are good at turning on their genes, while humans have Coordinator mutations that don’t work as well for them.