The University of Alabama

Sequencing the Python Genome

The Burmese python’s ability to ramp up its metabolism and enlarge its organs to swallow and digest prey whole can be traced to unusually rapid evolution and specialized adaptations of its genes and the way they work, a team of international biologists, including one from The University of Alabama, said in a new research paper.

Dr. Stephen Secor, associate professor of biological sciences at UA, and 38 co-authors from four countries sequenced and analyzed the genome of the Burmese python, or Python molurus bivittatus. Their work published recently in the Proceedings of the National Academy of Sciences along with a companion paper on the sequencing and analysis of the king cobra, or Ophiophagus hannah.

The papers represent the first complete and annotated snake genomes.

Because snakes contain many of the same genes as other vertebrates, studying how these genes have evolved to produce such extreme and unique characteristics in snakes can eventually help explain how these genes function, including how they enable extreme feats of organ remodeling. Such knowledge may eventually be used to treat human diseases.

Dr. Stephen Secor

Dr. Stephen Secor

“The Burmese python has an amazing physiology,” said Secor. “With its genome in hand, we can now explore the many untapped molecular mechanisms it uses to dramatically increase metabolic rate, to shut down acid production, to improve intestinal function, and to rapidly increase the size of its heart, intestine, pancreas, liver and kidneys. The benefits of these discoveries transcends to the treatment of metabolic diseases, ulcers, intestinal malabsorption, Crohn’s disease, cardiac hypertrophy and the loss of organ performance.”

“One of the fundamental questions of evolutionary biology is how vertebrates with all the same genes display such vastly different characteristics,” said Dr. Todd Castoe, the paper’s lead author and an assistant professor of biology at The University of Texas at Arlington College of Science. “The Burmese python is a great way to study that because it is so extreme,” said Castoe, who began working on the python project as a postdoctoral fellow at the University of Colorado School of Medicine in the laboratory of Dr. David D. Pollock, an associate professor.

“We’d like to know how the snake uses genes we all have to do things that no other vertebrates can do,” Castoe said.

The new python study calls into question previous theories that major obvious physical differences among species are caused primarily by changes in gene expression. Instead, it contends that protein adaptation, gene expression and changes in the structure of the organization of the genome itself are all at work together in determining the unusual characteristics that define snakes, and possibly other vertebrates.

Pollock said the python and king cobra studies represent a significant addition to the field of  “comparative systems genomics – the evolutionary analysis of multiple vertebrate genomes to understand how entire systems of interacting genes can evolve from the molecules on up.”

“I believe that such studies are going to be fundamental to our ability to understand what the genes in the human genome do, their functional mechanisms, and how and why they came to be structured the way they are,” Pollock said.

The Burmese python’s phenotype, or physical characteristics, represents one of the most extreme examples of evolutionary adaptation, the authors said. Like all snakes, its evolutionary origin included reduction in function of one lung and the elongation of its mid-section, skeleton and organs. It also has an extraordinary ability for what researchers call “physiological remodeling.”

Physiological remodeling refers to the process by which pythons are able to digest meals much larger than their size, such as chickens or piglets, by ramping up their metabolism and increasing the mass of their heart, liver, small intestine and kidneys 35 percent to 150 percent in only 24 to 48 hours. As the digestion is completed, the organs return to their original size within a matter of days. The authors suggest that understanding how snakes accomplish these tremendous feats could hold vital clues for the development of treatments for many different types of human diseases.

To complete their work, the research team aligned 7,442 genes from the python and cobra with genes sequences available in the Ensembl Genome Browser from

other amphibians, reptiles, birds and mammals. They used a statistical method called “branch site codon modeling” to look for genes that had been positively selected (or evolutionarily changed due to natural selection) in the python, the cobra and early in snake evolution in the common ancestor of these two snakes. They found changes in hundreds of genes. They believe the results demonstrate that natural selection-driven changes in many genes that encode proteins contributed substantially to the unique characteristics of snakes.

Analyses showed a remarkable correspondence between the function of the selected genes, and the many functionally unique aspects of snake biology – such as their unique metabolism, spine and skull shape and cell cycle regulation, Castoe said. Many of the altered genes the team observed also have prominent medical significance. For example, the python genome showed some changes to the gene GAB1, which other research suggests plays a role in breast cancer, melanomas and childhood leukemia.

In addition to changes to individual genes and their expression, researchers also found that the extreme characteristics in snakes could also be linked to duplications or losses in multigene families. Some of those include ancient loss and more recent re-evolution of high resolution vision, and their ability to detect chemical cues from the environment. Researchers also observed that, while most assume that reptile genes and genomes change at a very slow rate, snake genomes evolve at one of the fastest rates of any vertebrate.

The work reported in the two papers was supported by grant funding from the National Science Foundation and the National Institutes of Health as well as funding from the University of Colorado School of Medicine, UT Arlington and 454 Life Sciences.