Struggle between sex chromosomes underlies evolutionary paradox

DNA-packaging protamine genes evolve rapidly to stay ahead in battle between ‘selfish’ genetic elements and the rest of the genome
stock illustration of X and Y chromosomes as cross-stitch
An arms race between sex chromosomes in fruit flies shapes evolution as each tries to increase its chances of getting passed to the next generation. Stock image courtesy of Getty Images

Forget the battle between the sexes. There’s a tinier battle raging within the sexes — at the genetic level.

In some species’ sperm, X and Y chromosomes wrestle for dominance, each trying to improve its chances of reaching the next generation. New work from scientists at Fred Hutchinson Cancer Center show that certain genes in fruit flies used for DNA packaging have been conscripted into this tussle,  shaping — and accelerating — their evolution. The study, published today in the journal eLife, reveals that these genes, which encode sperm-specific proteins called protamines, help maintain genetic balance by silencing “selfish” bits of DNA on sex chromosomes.

“More than half of these genes are playing a different game than what most people suspected,” said evolutionary biologist Harmit Malik, PhD, who led the study. “It’s a super cool explanation for a very perplexing evolutionary finding.”

Protamine genes with ancient origins play a role in compacting DNA to fit inside sperm, while the more-recently evolved protamine genes act on both sides of what Ching-Ho Chang, PhD, calls the “selfish” DNA war. Chang is a postdoctoral fellow in the Malik Lab who spearheaded the study based on a computational analysis of nearly 80 different Drosophila fruit fly species. He found that younger protamine genes on sex chromosomes act selfishly to help their sex chromosome succeed, while young protamine genes on non-sex chromosomes try to counteract this genetic greed and maintain balance and fertility.

Surprisingly, the findings may offer insights into human health. Protamine genes, which should only be on during sperm development, are sometimes turned on in tumors. Understanding all the roles these genes play could help us better understand how cancers benefit from them — and what to do about it. 

Dr. Ching-Ho Chang in a white lab coat
Dr. Ching-Ho Chang suspected that the rapid evolution of protamine genes could be explained by an evolutionary arms race between sex chromosomes. Photo by Aida de la Cruz / Fred Hutch

Protamines: an evolutionary conundrum

To fit inside a single cell, DNA needs to be carefully bundled with DNA packaging proteins. For sperm cells that must swim, DNA is packaged even more tightly to minimize their load. Sperm depend on protamines, which are smaller than standard DNA packaging proteins, to maximize swimming efficiency by helping condense DNA and shaping the sperm head. Animals from humans to fruit flies have relied on protamines for millions of years.

Generally, genes that encode proteins which perform critical functions, like packaging genomes, are “old and conserved” — meaning they arose a long time ago and their DNA letters haven’t changed much. But in surveys of the genomes of humans and many other species, protamine genes jump out as among the fastest evolving.

It's counterintuitive, said Malik: “You would have thought that given millions of years of evolution, you would have settled on some sort of optimal design so that you don't need to mess with it anymore.”

But many protamine genes are rife with evolutionary tweaking. Rapid genetic change often arises from an evolutionary arms race. The arms race between viruses and host anti-viral proteins, continually changing to outmaneuver each other, is one example.

But genomic DNA has not changed so dramatically since the advent of protamines. What are they trying to outmaneuver?

Some researchers had proposed that rapid protamine gene evolution arose from competition between sperm, each trying to be first to fertilize an egg.

“But it doesn’t explain why you need to constantly address that,” Malik said. In primarily monogamous species, where sperm from one male are less likely to need to outswim sperm from another male, scientists would expect to see a relaxation of sperm competition and slowing of the evolution of the genes involved.

“And you see that in other proteins involved with sperm interactions,” he said.

Chang joined Malik’s lab with the idea of “selfish” DNA and inter-chromosomal competition. Selfish genetic elements work to propagate themselves, even if doing so makes it harder for their host to pass on its genes. Selfish genetic elements called sperm killers arise on a sex chromosome — say, the X — and prevent development of sperm with the other sex chromosome. If more sperm carry the X chromosome (and its selfish genetic element), that ups the X chromosome’s chances of getting passed on. But it’s ultimately bad news for a species’ future if sex ratios get too skewed or one sex’s fertility fails. 

“That basically means that now the rest of the genome needs to suppress this selfish behavior,” Malik said. “It needs to restore the balance, and that’s where this battle arises spontaneously.”

Chang theorized that protamines do much more than package DNA into sperm. He envisioned an additional role, in which they also maintain balance by pushing back against sperm killers. Locked in continual combat with selfish DNA, protamine genes keep evolving to stay one step ahead.

Protamine genes on both sides

To find evidence of this combat, Chang used computational methods to dig into the genomes of 78 Drosophila fruit fly species, discovering that the relationship between protamines and sperm killers was more complex than he or Malik had imagined. Protamines in flies are on both sides of the brawl: quashing selfish DNA or selfishly promoting themselves.

Chang compared protamine genes in both closely and distantly related fly species and discovered that they came in two distinct flavors: old and conserved, or young and rapidly evolving.

Protamines have been packing DNA for millions of years and Chang expected that the conserved protamine genes with ancient origins would be indispensable for sperm function and male fertility.

Instead, it was the opposite. Male Drosophila melanogaster flies procreated just fine when Chang deleted an old, completely conserved protamine gene, but became sterile when he removed a young, fast-evolving gene that is present in only a handful of fruit fly species.

“It’s almost as if [the young genes] actually arose as part of an adaptation of the host,” Malik said. “You’ve got this inverse paradox where gene essentiality is flipped relative to gene age or retention.”

Chang and Malik suspect that because flies have several ancient protamine genes with the DNA-packaging capabilities already baked in, these protamines can cover for each other if one version is lost.

But the war against selfish genetic elements is newer, and variable. The newer versions of protamine genes have evolved to play a unique role — of suppressing selfish genetic elements — that older protamine genes can’t. 

Chang’s computational analyses revealed something else unexpected: Some protamine genes are turncoats.

He saw that while some protamine genes were found on non-sex chromosomes, others had moved to the X or Y chromosome.

“And when they move to the sex chromosomes, they don’t just stay a single gene,” Malik said. “They expand out into 30 to 50 copies — almost as if they’re increasing the dosage.”

Chang discovered that this expansion happened 19 different times among fly lineages, mostly to protamine genes that had jumped onto X or Y chromosomes.

“This made us strongly suspect that those genes are also acting now in their capacity to become selfish themselves because they're part of the sex chromosomes,” Malik said. “The really interesting thing is that the protamine genes that are on the autosomes are quite conserved, whereas the sex chromosome genes are very short lived.”

Chang also discovered that in one fly lineage, D. montium, about half the protamine genes had disappeared or degraded. This solidified his and Malik’s belief that protamines are helping fruit fly X and Y chromosomes duke it out. In this lineage, Chang saw the sex chromosomes had fused: Most Y chromosome DNA had moved to the X chromosome, leaving just a stub of a Y behind.

These two warring sex chromosomes had suddenly become allies. The selfish “weapons” that typically poisoned sperm carrying the other sex chromosome had suddenly become friendly fire — and needed to be jettisoned. This also made the protamine machinery typically required to play peacemaker superfluous, Malik said.

“They became dispensable, which is why they were lost,” he said. “Protamine genes’ evolutionary rate, as well as their evolutionary retention, is really tied to the status of their sex chromosomes.”

A schematic showing how chromosome location changes the role and evolution of protamine genes in fruit flies.
Where protamine (SNBP) genes are located (on sex chromosomes or non-sex chromosomes) changes what role they play in sperm killing. When sex chromosomes fuse, these roles become unnecessary and many protamine genes are lost. Chang CH, et al., eLife 2023

Learning the rules of protamines’ new game

Chang and Malik now believe that protamines play two important roles in sperm: packaging DNA and quelling selfish DNA.

“Protamines generally have gene-suppressive capabilities because they pack DNA tightly,” Chang said.

Chang is currently working to untangle how protamines silence selfish DNA, and how they become selfish themselves.

It appears that protamines genes can become selfish merely by moving to sex chromosomes, but Chang hasn’t ruled out a potential collaboration between protamine genes and other still-unknown selfish genetic elements.

As mammals, humans only have two protamine genes, none of which have jumped to sex chromosomes, so Chang thinks they likely only act to package DNA and suppress selfish genetic elements.

But that doesn’t mean they can’t be turned against us, which is that link to human health. Cancer cells often have the ability to activate genes that should only be turned on at specific times or in specific tissues, such as during embryo development or sperm development. Protamine genes are among the genes that research has shown some cancers coopt.

It remains unclear what cancer cells may be getting from protamines, but knowing protamines’ ability to silence genes could give us a clue. And our cells have plenty of tumor-suppressing genes that cancer cells could benefit from turning off.

DNA-packaging components in sperm and egg cells are important from an evolutionary standpoint, but also serve as an “arsenal” that may be giving cancer cells an edge against healthy cells, Malik said: “In evolutionary battles like these, which are both old and ever-changing, it pays to know your adversary.”

Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at

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