Slow Motion Waves of Jumping Genes in the Human Genome
Action movies often employ slow motion to give audiences an unobstructed view of a dramatic fight scene or blowout, while geneticists also employ this technique when studying “jumping genes”, which move independently across genomes or complete sets of instructions.
Alu elements (LINE-1 and its relatives) are present throughout our genomes as relics from viruses that infected ancient primate ancestors and provide raw materials that become complex gene regulatory switches.
1. Transposons
DNA transposons possess an impressive power: they can cut themselves away from their host genome, hop around to new spots and repeat this action repeatedly, making the human genome more flexible so cells can juggle multiple genetic tasks at the same time.
As most TE sequences are dormant, some actively move through the genome and can cause disease. Researchers face an ongoing challenge identifying these sequences from other genetic debris; to do this successfully they need to look out for those that assemble near genes that are most active under specific conditions – for instance those more likely to occur in nutrient-limited environments – and identify which TEs possess 5′ truncations that renders them inactive.
As researchers continue to gather more and more data about the human genome, it has become clear that jumping genes affect every cell in our bodies and play an essential role in diseases like cancer, autoimmunity and neurodegeneration – although the exact mechanisms remain elusive.
Erwin and colleagues discovered an intriguing hint from their study of brain cells: Erwin and his team found that the common DNA transposon LINE-1 tends to hop around frequently in regions critical for memory and decision making such as the hippocampus and frontal cortex – regions essential for memory retention and decision-making respectively. Their studies reported this fact last year in Nature Neuroscience. This phenomenon affected between 44-63% of cells present there.
Models using statistical physics predict that LINE-1 and its relatives Alu and SINE will ‘hop’, much like ecosystems or predator-prey interactions do. These models account for how LINE and SINE populations change over time, projecting that their oscillations mirror those of tides. Furthermore, oscillations could be further affected by features present within DNA itself that govern how these genes copy themselves and oscillations might also depend on features associated with how well LINE and SINE copies itself.
2. Coordinator elements
Many mobile bits of DNA that float around are remnants of former viruses. Sometimes they do nothing; sometimes their effects can be profound – disrupting how genes are arranged may lead to diseases like cancer and blood-clotting disorders, while some even can influence whether a gene becomes active, or “expresses itself”, within a cell.
Scientists understand that millions of noncoding letter sequences serve essential regulatory functions in different cells, like turning genes on or off, but their effects remain elusive – nor is there any indication as to how they may work together.
T2T (funded by the National Institutes of Health) made strides toward understanding this silent majority in July 2020 by publishing their feat: sequencing an entire human X chromosome without gaps or errors and using this as a “reference sequence” against which to compare DNA from other people.
Scientists using this approach can pinpoint all of the genetic sequences present in an individual’s genome and analyze how they interact. Furthermore, it enables them to pinpoint genetic contributions to common diseases like cancer, osteoporosis, Alzheimer’s and schizophrenia which involve multiple genes rather than just one.
However, to gain a fuller picture of how our genomes as a whole are affected by jumping genes requires much more high-quality data. As part of their effort to do just this, UC San Francisco researchers and several other institutions have come together in ENCODE — an initiative where they’ll sequence hundreds of genomes end-to-end using automated methods; results should be available sometime around 2022.
3. Alu elements
DNA transposons, commonly referred to as jumping genes, can have profound impacts on human DNA through insertion and exclusion. When they’re present in a genome, transposable elements usually replicate themselves causing mutations and copy number variation (SV). They also cause chromosomal rearrangements due to interelement recombination which contribute to most of the variation within our genomes. Because they’re so widespread they account for most of this diversity.
Researchers recently used techniques from modern statistical physics to simulate interactions among common types of LINEs and SINEs (L1 and Alu) found in human genomes, using computer simulations. Their models showed that the movement of these elements is governed by chance interactions among individual elements – accounting for differences in transposable element substitution rates; some elements move faster than others.
TEs also alter human genome by interacting with RNA binding proteins (RBPs), such as HuR, to alter gene expression. Alu elements contain antisense sequences which can be recognized by HuR and used to recruit the cellular machinery needed to splice out an exon from protein-coding mRNAs; this has resulted in hundreds of new protein coding sequences being added into our genomes.
Recent analysis of genomic sequencing data have also demonstrated that certain TEs, specifically Alu and L1 families, have differentially amplified between humans and other mammals. This indicates that these high copy number families have played an essential role in primate genomic evolution. When these elements appear orthologously in two species’ genomes it’s almost certain that their insertion occurred before divergence took place as the likelihood of exactly the same element appearing at exactly the same spot is very unlikely.
4. RNAs
The discovery that genes can move around within genomes has fundamentally transformed how scientists view evolution of organisms and their genes. Now it is possible to study how gene movers alter genomic landscapes over time, and observe any shifts like how predators and prey patterns change in natural environments.
One way movers influence the genome is through turning off or silencing genes close by them through DNA methylation – this molecular tape prevents certain genes from producing their intended protein or performing their intended functions as intended.
Movers also influence genome by driving regulatory innovation. This may take the form of providing new genetic regulatory circuits or altering how existing ones are controlled.
Alu elements, or transposable elements (TEs), play an essential part in this phenomenon. Alu elements are leftover pieces from viruses that have since integrated themselves into human DNA; each person contains over one million instances where either full or partial copies have landed; collectively these Alu elements represent approximately 11 percent of our genomes.
Researchers in Illinois’s group have taken an innovative approach to studying these genes by simulating an ecosystem with two competing types of moving DNA called long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), representing species fighting over resources within each other’s habitats.
5. Proteins
Researchers studying the human genome have long suspected that some sequences contained within are “junk DNA,” sequences with no discernible function and neither harmful nor helpful effects on its use or other parts of the genome. Now, researchers may be closer to understanding this kind of dross — and its effect on other aspects of it — as well as any implications it might have for medical disorders like cancer.
Scientists have recently discovered that transposable elements have taken to using control switches originally meant for their own transposition to keep other DNA in check. Many of the newly utilized control switches are small RNAs repurposed as switches; two in particular cut DNA at gene ends when jumping genes end, according to Di Chen of the Intercollege Graduate Program in Genetics. Some RNAs even end up recycled back into protein components that aid cell health.
SiRNAs may be key to understanding how jumping genes impact other parts of the genome, according to one team’s investigation. By employing advanced sequencing technology, they discovered that siRNAs could block transcription thereby preventing new DNA sequences from being added and allowing transposable elements to stay put within cells.
These findings indicate that certain brain cells contain large concentrations of these repurposed transposable elements, possibly providing a source for unique neuronal plasticity that could assist learning, memory and other cognitive processes.
However, it must be remembered that ENCODE’s claim that 80% of the genome has functional roles is based on an operational definition of function which does not use historical selection as its criterion. As such, this definition encourages attributing functions to effects that have not been selected for and may include many noncoding RNAs and intron transcripts which account for over three-quarters of those said to have functions.
