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Females and males exhibit unique physical traits beyond what defines each sex. Notably, some health conditions distinctively affect the sexes. A catalog for how males and females uniquely use human hereditary information could help us figure out why the sexes are differently affected by diseases.

Now, researchers have shown that human and mammalian sexes don’t use their genomes—a lifeform’s entire set of hereditary information—in the same way. This phenomenon of sex bias in genome use is seen in both humans and mammals across body parts and tissues. However, most instances of sex-biased genome use are not shared between humans and mammals. This work is the basis for treating human health conditions that affect the sexes differently.

Battle of the sexes

Across the tree of life, you will find sexual dimorphism—dissimilarities in a trait between the sexes beyond the sexual organs. For example, there’s the bulbous schnozz of the male elephant seal, the manes of male African lions, and the male peacock’s flamboyant and iridescent “train” of tail feathers. On the other hand, females are larger in many species of insects, fish, reptiles, owls, birds of prey, and certain mammals, like the spotted hyena and the blue whale.

Then there’s the extreme case of the anglerfish. The females are much larger than the males—female anglerfish may be more than 60 times longer and half a million times heavier than males. But that’s just the beginning. The minuscule anglerfish male looks like a totally different species, missing the female’s huge jaws and characteristic lure. But that’s just the beginning. These tiny males, with the biggest nostrils in proportion to its head of any animal on Earth, spend their lives searching for the females. When they do, the males latch and fuse onto the females as a parasite, leeching blood transported nutrients.

Men are from XY and women are from XX

So, what drives sexual dimorphism? Most of what we know about sexual dimorphism focuses on sex chromosomes—threadlike strands of hereditary information that determine an individual’s sex. Sex may be determined either by the presence of a sex chromosome or by how many the organism has.

Humans are born with 46 chromosomes in 23 pairs, one of which are the two sex chromosomes. X and Y chromosomes determine a person’s sex. The Y chromosome carries hereditary unites—genes—responsible for activating male development. On the level of molecules, sex is determined solely by the presence or absence of a Y chromosome. In this way, female and male humans—and many other animals, insects, and, even, plants—are generally XX and XY, respectively.

However, sex chromosomes probably don’t account for all the physical and behavioral instances of sexual dimorphism. There must be other parts of the genome in the remaining 22 pairs of chromosomes that are sources for sexual dimorphism. Along these lines, we don’t know how being XX or XY influences the rest of the genome to create the diversity of sex-biased physical and behavioral traits.

Let’s talk about sex

There are many traits unique to each human sex. Males have a greater laryngeal prominence—Adam’s apple—making the pitch of their voices deeper. Females generally have finer body and facial hair. The human sexes differ biologically in many ways including the use of energy, the size and shape of the brain, and how the immune system and heart function.

Traits can impact health status as sexual dimorphism extends to a lot of diseases. Many autoimmune diseases are more common in females than in males. Autism and other neurodevelopmental disorders are more common in males as well as cardiovascular disease. Sex differences are also evident in the incidence, prevalence, and mortality across diseases. What causes this is still not known.

Sexual dimorphism is also common in mammals, many used as models for human sex-biased traits and diseases. Likely, sexual dimorphism is linked to sex-biases in genome use. Notably, in basic pharmaceuticals, non-human mammals are often used to model the diseases that are sex-biased in humans. But we don’t really know the sex differences between species at the molecular level. Understanding this has important implications for using mammalian models of human disease.

Human dna research technology symbols. Spiral molecule medical bio tech vector icons. Research chemistry and medicine, helix genetic genome illustrationHuman dna research technology symbols. Spiral molecule medical bio tech vector icons. Research chemistry and medicine, helix genetic genome illustration
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Pulling down mammalian genes

A team of researchers sought out to address these questions surrounding mammalian sexual dimorphism—namely, how the rest of the genome contributes to sexual dimorphism in humans and how similar this is amongst mammals.

To do so, they examined genome use in male and female humans and four non-human mammals: mice, rats, dogs, and macaques. They collected male and female samples from 12 different non-reproductive tissues and in the four non-human mammals and looked at the sex bias of genome use.

We knew that bias exists within multiple species and multiple tissues. Previous work, however, had only focused on one species or only one tissue, like the liver. As a result, it wasn’t really known how conserved or similar gene expression was across species,” said lead author Dr. Sahin Navqi.

In every tissue examined, they saw differences in genome use between the sexes. Some of these genes were conserved across species. However, most of the observed sex biases in gene expression were not conserved.

A tall order

“In terms of genetic studies that contribute to human attributes, height is incredibly well studied,” says Dr. Navqi.  “We essentially know all the genes that contribute to height. It is also a very conserved sexual dimorphism. Just look at most species—the males are just larger in most species.”

So, could sex-biased gene expression contribute to the sex difference in height and body size seen in humans and other mammals? Since there is a lot of data on male and female height and size as well as the genes that contribute to these processes are well classified, Dr. Navqi and his fellow researchers could address just that.

“In genetics studies, you take thousands of people and look for links between genetic changes and changes in the trait. This is incredibly easy to do for height—you just measure how tall people are. We used these sex biases in gene expression to show how they might contribute to sex differences in human height. Then, we looked at genes known to contribute to human height. We saw that sex biases in gene expression explained about 12% of the sex difference in human height.”

Sex-specific treatment

“This work has major consequences for designing treatment programs optimized for males or females,” predicts Dr. Navqi. “To do this, we need to first have a basic understanding of the differences between males and females. I think that’s where our study comes in, showing how one can understand that respect to height.”

Dr. Navqi also says that sex differences manifest themselves across the course of development from the moment of conception. Puberty and the onset of hormones are also major developmental milestones. He thinks that it would be interesting to look at how sex differences change throughout the course of a being’s life.

Going forward, there are many cases of sexual dimorphism that I think would be really interesting to look at,” says Dr. Navqi. “In diseases that affect specific cells and cell types within the bodies, I think it would be most relevant to study sex differences in those cells affected. In future studies, for example, you could look at sex differences in specific immune cells in autoimmune disease in a similar way to we’ve done for height.”