Platypus Genome Reveals Evolutionary Path That Gave Mammals Reproductive Edge, Stanford Scientist Says

Business Wire,  May 7, 2008  

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STANFORD, Calif. -- The odd-looking platypus is often cited as proof that God has a sense of humor. Now researchers at the Stanford University School of Medicine have turned to the strange animal to understand the genesis of an evolutionary tour de force that led to a reproductive advantage possessed by nearly all of today's mammals.

Biologists have debated the origins of the Australian animal for more than 200 years. The newly sequenced platypus genome, to be published concurrently with the Stanford research, provides a wealth of data about the unique egg-laying mammal.

The information enabled the Stanford researchers to trace the evolution of two genes involved in moving the testicles away from the warm core of the body during the development of most mammals. Moving the testicles' heat-sensitive cargo, the sperm, to an outer pouch called the scrotum allows it to be stored in a cooler environment. Understanding the molecular mechanisms behind this adaptive process may help physicians understand why the testes of about 30 percent of premature boys fail to descend to the scrotum properly.

"Testicular descent is a very specialized process that required the evolution of specific genes," said Sheau Yu Teddy Hsu, PhD, assistant professor of obstetrics and gynecology and senior author of the study. "The platypus serves as a 'bridge' animal between nonmammals like birds and reptiles, which maintain their testicles in their body cavity, and placental and marsupial mammals, which hold their testes in an external scrotum."

Hsu's research will be published online May 8 by Genome Research along with several other papers devoted to findings made possible by the sequencing of the platypus genome. Also on May 8, Nature will publish a paper on the sequencing of the platypus genome.

In appearance, the platypus is a beaverlike animal with webbed feet and a rubbery beak similar to a duck's. Although, like reptiles, the platypus keeps its testes near its kidneys throughout life, its genome bears the imprint of changes that eventually allowed most other male mammals, including humans, to store their reproductive organs in cooler temperatures outside the body. Evolutionary biologists believe that the adaptation allowed these mammals to have the higher core temperatures necessary for quick reflexes and fast movement.

The platypus belongs to a very small group of mammals called the monotremes. The word, which means "one opening," refers to the fact that the animal defecates, urinates and lays eggs through a single canal, called the cloaca. Although the platypus resembles reptiles in that it lays eggs, it resembles mammals because it secretes milk through the skin for its young and maintains a warmer body temperature.

Hsu wasn't always interested in platypuses. He and his colleagues study a family of genes called relaxins that are involved in a variety of mammal-specific biological processes including nipple development and cervical softening, as well as testicular descent. When the platypus genome became available for study, Hsu was eager to compare the sequence of their relaxin genes with that of relaxin family members from fish, birds, marsupials and placental mammals.

"We really wanted to understand how these processes evolved," said Hsu, "but we couldn't turn to fossil records for clues because soft tissues, like the testes and nipples, rapidly decompose."

Hsu's group found that two relaxin family members, RLN3 and INSL3, arose from a common ancestor. INSL3 interacts with a receptor called LGR8 and has been shown to be critical to testicular descent, while RLN3 interacts with a related receptor called LGR7, which has been implicated in mammary gland and nipple development. The ancestor gene, however, showed no such bias. In fact, it was equally able to activate either receptor.

"You can imagine that it would be difficult to evolve highly complex physiological processes with relatively nonspecific interactions between proteins," said Hsu.

The real tipping point, Hsu discovered, occurred when the ancestor gene was duplicated in a way that was likely a genetic fluke. This type of random event is thought to be important in evolutionary leaps, such as the development of a placenta, that are difficult to explain by the ongoing gradual accumulation and selection for minute changes, such as beak shape or coat color.

In the case of the INSL3 ancestor, the duplication fluke occurred sometime before the monotremes, marsupials and placental mammals split, but after fish and frogs became separate groups. The presence of two identical copies of the ancestor gene freed one copy from the selective pressure that had likely restrained its evolution and allowed it to mutate and attain new functions while losing others.

Hsu found that fish, which became a separate group before the duplication, maintained ancestorlike genes that activate both receptors. But marsupials and placental mammals evolved two proteins, one for each receptor. Fish keep their reproductive organs in their bodies, while marsupials and placental mammals have scrotums. But the information, though useful, was like a time-lapse photograph with a critical frame--the one showing how the change occurred--missing.