Researchers uncover genetic and hormonal origins behind the evolution of sex organs

X-ray of an adult male skateThe ability of hormones to regulate the genes responsible for external sex organ growth and development evolved nearly 400 million years ago in our aquatic ancestors, University of Florida scientists have found.

Researchers studying cartilaginous fishes called skates found that the genetic pathway leading to the development of sex organs is the same across vertebrates, including humans. The study, released today (April 14) in the online journal Nature Communications, also shows that sex hormones trigger the genetic pathways that lead to external genital formation.

Concern exists that the increasing rate of some genital birth defects, such as malformed genitalia, could be caused by factors disrupting these sex hormones.

 “It is ironic that the genetic innovation responsible for the evolution of external genital organs is the same mechanism that makes these organs so susceptible to malformation when, for example, an individual is exposed to chemicals in the environment that mimic or interfere with sex hormones,” Martin J. Cohn, Ph.D., a Howard Hughes Medical Institute scientist and a professor in the department of molecular genetics and microbiology in the University of Florida College of Medicine, part of UF Health.

Today, one in 200 males are born with hypospadias, a malformation of the penis, and one in 4,500 babies are born with ambiguous genitalia. Comparing biological similarities and genetic pathways across vertebrates can help researchers identify new mechanisms and areas of investigation for disorders of sexual development.

“Our findings show that, deep in our evolutionary past, vertebrates evolved a way for sex hormones to regulate the genes responsible for appendage development, like a fin or a phallus,” said Cohn. “As a result, males could prolong the activity of these genes with testosterone, and this drove the outgrowth of the male copulatory organs.”

In this latest work, cartilaginous fishes called skates, which look like stingrays and are closely related to sharks, were studied for the group’s unique pelvic fin structure. In male skates, these fins form long extensions called claspers, which double as both skeletal fins and a delivery mechanism of sperm to the female. Although these claspers are part of the fin and not technically called a penis, they evolved a similar form and function.

The study found the genetic pathway required to form the external sexual organs, whether clasper or penis, is identical across the vertebrates. One gene, aptly named Sonic hedgehog or Shh, is required to initiate the entire genetic sequence of events to develop external genitalia in mammals and claspers in skates. When the researchers activated the Sonic hedgehog pathway in female skates, they too developed claspers.

Two other genes, Hand2 and Hoxd13, that activate the Shh genetic circuit, also showed prolonged activity in males and pave the way for external sex organs to form. These genes had yet to be identified as a vital step in this process in skates, but were previously known for their roles in vertebrate limb development.

After proving the genetic circuit for clasper formation used the same genes that drive limb and genital development in mice and humans, Cohn and his collaborators, graduate student Katie O’Shaughnessy and Randall Dahn, wondered why these genes remain active only in males. They looked to the hormones responsible for various other sex traits, like androgens.

Androgen not only maintains endocrine functions, but without it, it is now clear male external sex organs do not form. Androgen was found to regulate the Hand2 gene, one of the keys to turning on the Sonic hedgehog genetic circuit. It was the evolution of this androgen-responsive switch that allowed males to keep the circuit going in the fins, when in females it switches off and claspers do not form.

In addition to shedding light on this evolutionary mystery, the study identified a new genetic target of the androgen receptor. “Understanding the pathways that regulate androgen receptor signaling will be important for unraveling these sex-specific differences and may lead to new strategies for fighting diseases,” said Cathy Lee Mendelsohn, PhD, professor of urology, pathology and cell biology, and genetics and development at Columbia University.  

Cohn, a developmental biologist and member of the UF Genetics Institute, has published extensively on the origins and evolution of sexual development in species ranging from birds and lizards to mammals.