How to explore the arms race within a single genome

Biological arms races are commonplace in natu.

Although less well known, there are other winning games playing out within the geno.

Although satellite DNA does not encode genes, it facilitates basic biological functions, such as forming the molecular machines that process and maintain chromosom.

Using two closely related fruit flies, the researchers probed this arms race by deliberately introducing a mismatched species, for example, with satellite DNA from one flies conflicting with satellite-binding proteins from anoth.

"We generally think of our genome as a cohesive community of elements that make Or modulate proteins to build a fertile and viable individu.

"But we think some of these factors are actually bad for us," she sa.

The researchers' findings, which may also be relevant in humans, suggest that when satellite DNA occasionally escapes the management of satellite-binding proteins, significant health costs can occur, including affecting molecular pathways required for fertility and possibly even cancer developme.

Cara Brand, a postdoc in Levine's lab and first author of the study, said: "These findings suggest that there is an antagonistic evolution between these elements that can affect these seemingly conserved and necessary molecular pathwa.

evolutionary paradox

It has long been known that the genome is not just made up of gen.

"If genes are words, and you're reading the story of our genome, these other parts are incoherent," she sa.

Satellite DNA is part of what is called "ju.

But recent research has revised this "junk DNA" theory, revealing that "official articles" including satellite repeats play multiple roles, many of which are involved in maintaining genome integrity and nuclear structu.

"This creates a paradox," Levine sa.

In 2001, a group of scientists proposed a theory that co-evolution was occurring with the rapid evolution of satellite proteins and the evolution of satellite-binding protei.

"Often these gene swaps lead to dysfunction, specifically disrupting processes normally mediated by repetitive DNA-rich regions of the genome," Brand sa.

New tool to prove it

These studies provide support for the theory of coevoluti.

In the current study, Levine and Brand found a w.

Another fruit fly, Drosophila simulans, lacks a satellite repeat that spans as many as 11 million nucleotide base pairs in its close relative,.

melanogast.

This satellite is known to occupy the same cellular location as a protein called Maternal Haploid (M.

The researchers also obtained a mutant strain of.

melanogaster lacking 11 million base pair repea.

"It turns out that fruit flies can survive and reproduce well without this duplication," Levine sa.

"So this gives us a unique opportunity to manipulate both sides of the arms ra.

"

To study the satellite-binding protein side first, the researchers used the CRISPR/Cas9 gene editing system to remove the original MH gene from.

melanogaster and re-add the.

simulans version of the ge.

Compared with control female flies, female flies carrying the.

simulans MH gene had significantly reduced fertility and greatly reduced egg producti.

However, flies that completely lacked MH were unable to produce any offspring; these embryos did not survi.

"This is interesting because it shows that these satellite-binding proteins are essential, even though they are rapidly evolving," said Bra.

"Doing thegene exchange showed that we could rescue the ability to make embry.

But the other was related to ovary and egg producti.

" function is impair.

”

When Brand and Levine took a closer look at the ovaries, they found that the obvious cause of reduced egg formation and ovarian atrophy was DNA dama.

This damage normally triggers checkpoint proteins to block developmental pathwa.

When the researchers repeated the experiment in a fly with a broken checkpoint protein, egg production returned to higher leve.

The other side of the co-evolutionary arms race was then ready to be tested to find evidence that the problem with the exchanged MH proteins was due to incompatibility with the 11 million base pair satellites, or that they acted on different genetic elemen.

Here, they relied on strains of Drosophila melanogaster that lacked the repeat sequence and found that the gene exchange now had no effect on these fli.

DNA damage levels, egg production and ovarian size were norm.

By studying a close relative of the human MH protein, a protein called Spartan, the scientists provided clues to the mechanism behind these resul.

It is understood that in humans, spartan-digested proteins can get stuck on DNA, posing obstacles to the various processes and packaging that DNA must go throu.

"After everything we've found so far, we thought, maybe this wrong version of the protein species is chewing something it shouldn't," Levine sa.

One protein that Sparta frequently targets is topoisomerase II (Top2), an enzyme that helps dissolve tangles in tightly wound and tangled D.

To understand whether the negative effects of MH gene mismatch were due to inappropriate degradation of Top2, they overexpressed Top2 and found that fertility was restor.

Lowering Top2 exacerbated the decline in fertili.

"The repair processes that MH is involved in take place in yeast, in fruit flies, in humans, throughout the tree of life," Brand sa.

"However, we see rapid or adaptive evolution of these protei.

This suggests that this seemingly Conservative and necessary pathways require evolutionary innovati.

" In other words, co-evolution must proceed rapidly just to maintain this fundamental pathw.

In future work, Brand and Levine will investigate whether segments of the genome beyond satellites are involved, and will study other organisms, including mammals, to delve deeper into the molecular players in these evolutionary arms rac.

"There's no reason to believe that these arms races are happening only in fruit flies," Levine sa.

"Thesame types of proteins and satellite proteins are evolving rapidly in primates, which tells us that what we're studying is broadly releva.

"

The focal genes involved in this study have important roles in human heal.

Spartan mutations are linked to cancer, and ineffective regulation of satellite DNA may provide clues to infertility and miscarria.

"The number of miscarriages is very high, and of course satellite DNA is an unexplored source of aneuploidy and genomic instability," Levine sa.

Cross-species incompatibility between a DNA satellite and the Drosophila Spartan homolog poisons germline genome integrity