Vital genes evolve in the back of the genome

Even vital genes can lose out in an evolutionary arms race that can cause them to change and even replace those genes.

Inside the cell nucleus, most of the active genes are located in a region of DNA called euchromatin (indicated in pink).  The more concentrated heterochromatin DNA (in black) is genetically mostly inert, but researchers are studying how new genes can develop there.
Inside the cell nucleus, most of the active genes are located in a region of DNA called euchromatin (indicated in pink). The more concentrated heterochromatin DNA (in black) is genetically mostly inert, but researchers are studying how new genes can develop there.

It is often believed that vital genes are “frozen” in evolutionary time – they develop very slowly, if at all, since the change or death of such a gene will lead to the death of the organism. Between insects and mammals – hundreds of millions of years of evolution, but, as experiments show, genes Hox, regulating the formation of body complexion in fruit flies Drosophila can easily be replaced with similar genes found in mice – they are so similar. This remarkable evolutionary conservation is a fundamental concept in genomic research.

But the new study is turning that rationale for genetic conservation on its head. Staff at the Fred Hutchinson Cancer Research Center in Seattle reported in a magazine eLifethat a large class of genes in fruit flies are both critical to survival and rapidly evolving. In fact, the analysis carried out by scientists shows that the ability of these genes to constantly change is the key to their nature. “This not only casts doubt on the dogma, but also shatters it,” says Harmit Malik, a researcher at the Howard Hughes Medical Institute who was the study’s supervisor.

“This work is so beautiful,” said Manuyan Long, an evolutionary geneticist at the University of Chicago. “Researchers have found that rapidly changing heterochromatin accelerates the evolution of new vital genes. Simply breathtaking!

The Unexpected Importance of Novelty

In the 1970s and 1980s, evolution and developmental biology were dominated by the idea that genes that code for vital functions have highly conserved sequences—and vice versa. It was believed that new genes rarely, if ever, arise. But by the early 2000s, several researchers had shown that young, rapidly evolving genes are not uncommon in nature. Although the evolution and functioning of these young genes are fraught with big questions, it was assumed that they were, in essence, tinsel, and such genes provide only small and insignificant advantages, not at all important for survival.

That’s why, in 2010, Long was so surprised by what happened when he and his students knocked out 200 young, new genes in Drosophila using a technique called RNA interference.

It turned out that almost 30% of these young genes are vital; Without them, the flies would die. But even more surprisingly, the percentage of vital old genes turned out to be about the same – only about 25% -35%. Young genes can code for vital functions with about the same probability as old ones.

“I was really shocked and really encouraged,” said Long, “we felt that the old ideas shared in our discipline were wrong, incorrect.” Since their discovery seemed heretical, Long said they decided to carefully collect data and conduct additional tests using new technologies, in particular, CRISPR. The team updated their 2010 study by releasing fresh preprint, which addressed some of the methodological difficulties of the first study, with an extended analysis covering an additional 702 new Drosophila genes. Overall, the new paper draws the same general conclusions, but poses new questions: what exactly do these young genes do, and how did they become so important?

Comparing old and new

To answer these questions, Malik and his graduate student Bhavatharini Kasinathan focused on genes. ZAD-ZNF, the largest family of transcription factors in insects. Some of these genes were labeled new and vital in Long’s earlier study, but their function was not well understood. It turned out that about 70 of these genes ZAD-ZNF present in all species Drosophila, but 20 are not: they were acquired and lost several times during the evolution of various species Drosophilastretching for 40 million years.

To the researchers’ surprise, 20 genes specific to Drosophila melanogaster could encode vital functions with the same probability as those 70 that “strictly” persisted for more than 40 million years. These results provided independent support for Long’s genome-wide observations. Drosophila; it is this result that Long calls “beautiful”.

But there was another oddity: Malik and Kasinathan observed that among these 20 genes specific for D. melanogaster, it was precisely those that most likely coded vital functions that developed most rapidly; others developed more slowly.

At this stage of the research, according to Malik, “you start to really question all your ideas about biology, because it’s like asking yourself: “Wait a minute. And what is it?””

Race for importance

To dig deeper into these puzzling results, Kasinathan looked for clues in functions. Nicknack and Oddjob, two vital genes ZAD-ZNFwhich have developed rapidly. When she checked exactly where they are active in the cells Drosophila, another surprise awaited her: these transcription factors were not localized at all in euchromatin, the part of the genome where most of the genes are located.

Instead, they were located in heterochromatin, densely packed stretches of DNA that remain predominantly dormant because they contain mostly non-coding DNA and other so-called “genetic junk.” Molecular biology has so far largely ignored heterochromatin, preferring to focus on gene-rich euchromatin, which is where most of the interesting stuff happens. But even though heterochromatin is considered the boring dumping ground of the genome, it does contain some sequences that are important for the ongoing maintenance of the cell. For example, centromeres are ribosomal RNA involved in protein assembly, as well as some regulatory regions of RNA that control gene expression throughout the genome. Because these genes develop so rapidly, the heterochromatin regions in different genes are responsible for basically the same vital functions, but the underlying DNA sequences are completely different.

According to Malik, this is precisely what explains such a rapid development Odd job and Nicknack: they have to adjust the rapidly changing DNA environment of heterochromatin to keep it functional. In some respects, they resemble the genes of the immune system, rapidly changing in response to the rapid evolution of pathogens and participating in a kind of arms race. But in this case, says Malik, “you could say there is an arms race in the genome itself, just to preserve its essential functions.”

To explore the functions of these two genes in more detail, the researchers swapped instances Nicknack between two closely related species of flies, D. melanogaster and D. simulationsto see if the two versions of the gene can functionally replace each other. Curiously, it turned out that the gene Nicknack from melanogaster can only save the life of females simulationsbut not to males. The fact is that males have a huge Y-chromosome full of heterochromatin. Malik explains: Nicknack from melanogaster can sufficiently restore the work of the genome to ensure the survival of females simulations, but in males simulations his work is drowned out by rapidly developing heterochromatin.

“We think that during development, the really important genes … are preserved exceptionally well,” says Kasinathan, “but there is an example of a family of genes that is very important for development, and it is enough to change the transcription factors in these genes for the genes to stop working. It’s amazing and cool in its own way.”

How to be irreplaceable

There is a paradox in this: if new genes are vital, then how did organisms previously manage without them? Malik sees two possibilities. First, the ancestral gene may have given up its function to the new gene. Second, the new gene may perform a function that older organisms did not need. Today, species are facing problems that their ancestors never had to deal with, and these new problems require new solutions. But what if “it was the evolution of these heterochromatin sequences that became the factor that required the emergence of a new vital function?” asks Malik.

“The vital function itself may not be conserved, and this is a heretical concept,” he continues, “we are not just saying that vital genes are not conserved. We say that perhaps vital functions are not preserved, because here everything depends on the context.

Now Kasinathan and Malik are eyeing other transcription factors ZAD-ZNF, many of which are also localized in heterochromatin. “This region of the genome, which we previously largely ignored because it is so gene-poor… it is, at least as far as ZAD-ZNF, holds the key to the paradox of why young genes become vital,” Malik said.

This discovery could be important in identifying genes that cause many diseases and explain many biological mysteries. “If you’re interested in how centromeres work and you’re just looking at genes that are completely preserved in humans, yeast and flies, then you may be missing out on some other important genes that could be targeted by therapy,” Malik says. “Our intuition and dogma seems to confuse us, leading us to a point of view from which we do not see many important biological aspects.

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