Long-standing genomic mystery about origins of introns explained in new study

One of the oldest fundamental mysteries in biology concerns the poorly understood origins of introns. Introns are non-coding DNA segments that must be removed from the genetic code before being translated in the protein manufacturing process. Introns are an ancient feature present in all eukaryotic life, a wide range of organisms that spans all animals, plants, fungi, and protists, but are absent from prokaryotic genomes such as those of bacteria. There is massive variation in the number of introns found in the genomes of different species, even between closely related species.

Now, a new study by scientists at UC Santa Cruz and published in the journal Proceedings of the National Academy of Sciences (PNAS) points to introns, one of several proposed mechanisms for the creation of introns discovered in 2009, as an explanation for the origin of most introns across species. Researchers believe that introns are the only likely explanation for intron burst events, in which thousands of introns appear in a genome seemingly all at once, and they find evidence of this in species across the tree. of life.

“[This study] provides a plausible explanation for the vast majority of intron origins,” said Russell Corbett-Detig, associate professor of biomolecular engineering and lead author of the study. “There are other mechanisms, but this is the only one I know of. could generate thousands and thousands of introns at a time in the genome. If true, that suggests we’ve discovered a central process driving something really special in eukaryotic genomes – we have these introns, we have genomic complexity. »

Introns are important because they allow alternative splicing, which in turn allows a gene to code for multiple transcripts and therefore perform multiple complex cellular functions. Introns can also affect gene expression, the rate at which genes are turned on to make proteins and other non-coding RNAs. Introns ultimately have a neutral to slightly negative effect on the species in which they exist because when the splicing of introns is not done properly, the gene they live in can be damaged and even die. These cases of missed splicing are the cause of certain cancers.

Corbett-Detig and his colleagues searched the genomes of 3,325 eukaryotic species – all species for which we have access to high-quality reference genomes – to find out how common intron-derived introns are and in which groups of species they are observed most often. They found a total of 27,563 intron-derived introns in the genomes of 175 species, meaning that evidence of introns could be observed in 5.2% of the species studied.

This evidence has been found in species of all types, from animals to single-celled protists, organisms whose last common ancestor lived more than 1.7 billion years ago. The diversity of species in which they are found suggests that introns are both the fundamental and most widespread source of introns in the tree of life.

“It’s diverse — it’s not like there’s a little piece of the tree of life that has what’s going on,” Corbett-Detig said. “You see this across a fairly wide range of species, which suggests it’s a fairly general mechanism.”

This analysis can only detect evidence of inductees dating back a few million years, a relatively short period in evolutionary history. It is likely that intron bursts could have occurred in some species, such as humans, at a time beyond the scope of this analysis, meaning that this study likely greatly underestimates the true significance of the introns derived from introners in all eukaryotes.

Introners as genomic parasites

In the ecosystem of the genome, introners can be considered as parasites whose purpose is to survive and replicate. When an inductor enters a new organism, this new host has never seen this element before and has no means of defending itself, which allows it to proliferate into a new species.

“Everything in evolution is conflict and these elements, [including introners]are selfish bits of DNA,” said Landen Gozashti, the paper’s first author who developed the study’s analytical methods as an undergraduate at UCSC and is now a graduate student. at Harvard University. I don’t want to kill their host, it’s because it kills them.”

By being separated from the DNA sequence before gene-to-protein translation occurs, introners have found a way to have less impact on the fitness of the host gene, allowing them to persist across generations. the evolution of the host species. The researchers found that intron-derived introns seem to splice better than other types of introns, to limit their negative effects on the gene so that both the intron and the host can survive better.

No more inductees in the sea

While all introns were found in all types of species, the results showed that marine organisms were 6.5 times more likely to have introns than terrestrial species.

The researchers believe this is likely due to a phenomenon called horizontal gene transfer, in which genes are transferred from one species to another, as opposed to the typical vertical transfer via mating and passing genes from parent to parent. ‘child. Horizontal gene transfer is already known to occur more frequently in marine environments, particularly between single-celled species with complex ecologies.

Introners can travel this way because they belong to a class of genomic elements called transposable elements, which have the ability to travel beyond the cellular environment in which they live, making them mechanically well-equipped. to travel between species via horizontal gene transfer. As introns transferred from species to species in marine environments, they greatly expanded their presence across the tree of life.

Considering that we know that all species evolved from marine organisms, terrestrial species may have gained introns from intron bursts far back in their evolutionary history.

“If your ancestors were marine organisms, which they all were, chances are a lot of your introns are somehow inherited from a similar organism. [introner burst] event at the time,” Corbett-Detig said. “It could have been very significant in our evolutionary past.”

More introners were also found among fungal species, which are also known to have higher rates of horizontal gene transfer, further supporting the idea that this phenomenon drives introner gain.

In future research, Corbett-Detig plans to look for evidence of horizontal gene transfer in the form of nearly identical introners in two different species. It has data mining pipelines in place so that as the global genomics research community contributes genomes of new species to data repositories, its algorithm searches for the introners of each new genome and compares it to all known inductees to look for similarities.

Understand how complexity evolves

This study presents a challenge to one of the overarching theories of genome evolution as to what drives genomic complexity in eukaryotes. The theory also posits that at some point in evolution, many species had low effective population sizes, meaning that very few organisms of a species produced offspring to create their next generation. This allowed elements known to have mildly negative effects on the population to accumulate in the genome.

According to this theory, itroners, which are neutral to mildly deleterious, would be more frequently observed in populations with lower effective populations, but the researchers found the opposite. For example, they found that Symbiodiniuma protist known to have a much larger effective population size than humans, land plants, and other invertebrates, is the species that appears to gain the most introns among those studied.

But this research points to a complexity resulting not from an adaptation created by the genome itself, but as a response to the conflict caused by the transposable invading element, the introner, as it attempts to proliferate. As inductors and other elements struggle to survive and persist, this conflict drives genome complexity.

Introners and gene expression

Neutral to negative effects of introns are also evidenced by their effect on gene expression. When comparing genes with inserted intronators to those without, those that do have a lower overall level of expression, meaning they are activated less often to perform functions in the body. .

The researchers believe that introners are not necessarily directly responsible for this lower expression, but that genes that are less expressed have a higher tolerance for an element that can affect them negatively because they matter less for the survival of the species. Meanwhile, genes that are highly expressed and can code for key functions in the body probably cannot tolerate the introduction of new introns that could cause them to perform their task less efficiently.

Corbett-Detig’s ongoing research on this topic also involves examining direct evidence for how the appearance of introns in a genome affects individuals within a species. He has identified several species that experience ongoing intron bursts and studies the effect of introns on the cell’s DNA and RNA, and how this affects the evolutionary fitness of the species.