Technology that can map
out the genes at work in a snake or lizard's mouth has, in many cases, changed
the way scientists define an animal as venomous. If oral glands show expression
of some of the 20 gene families associated with "venom toxins," that
species gets the venomous label.
But, a new study from
The University of Texas at Arlington challenges that practice, while
also developing a new model for how snake venoms came to be. The work, which is
being published in the journal Molecular Biology and Evolution
based on a painstaking analysis comparing groups of related genes or "gene
families" in tissue from different parts of the Burmese python, or Python
A team led by assistant
professor of biology Todd Castoe and including researchers from Colorado and
the United Kingdom found similar levels of these so-called toxic gene families
in python oral glands and in tissue from the python brain, liver, stomach and
several other organs. Scientists say those findings demonstrate much about the
functions of venom genes before they evolved into venoms. It also shows that
just the expression of genes related to venom toxins in oral glands of snakes
and lizards isn't enough information to close the book on whether something is
"Research on venom
is widespread because of its obvious importance to treating and understanding
snakebite, as well as the potential of venoms to be used as drugs, but, up
until now, everything was focused in the venom gland, where venom is produced
before it is injected," Castoe said. "There was no examination of
what's happening in other parts of the snake's body. This is the first study to
have used the genome to look at the rest of that picture."
Learning more about
venom evolution could help scientists develop better anti-venoms and contribute
to knowledge about gene evolution in humans
Castoe said that with
an uptick in genetic analysis capabilities, scientists are finding more
evidence for a long-held theory. That theory says highly toxic venom proteins
were evolutionarily "born" from non-toxic genes, which have other
ordinary jobs around the body, such as regulation of cellular functions or digestion
demonstrate that genes or transcripts which were previously interpreted as
'toxin genes' are instead most likely housekeeping genes, involved in the more
mundane maintenance of normal metabolism of many tissues," said Stephen
Mackessy, a co-author on the study and biology professor at the University of
Northern Colorado. "Our results also suggest that instead of a single
ancient origin, venom and venom-delivery systems most likely evolved
independently in several distinct lineages of reptiles."
Castoe was lead author
on a 2013 study that mapped the genome of the Burmese python. Pythons are not
considered venomous even though they have some of the same genes that have
evolved into very toxic venoms in other species. The difference is, in highly venomous
snakes, such as rattlesnakes or cobras, the venom gene families have expanded
to make many copies of those shared genes, and some of these copies have
evolved into genes that produce highly toxic venom proteins.
python diverged from the snake evolutionary tree prior to this massive
expansion and re-working of venom gene families. Therefore, the python
represents a window into what a snake looked like before venom evolved,"
Castoe said. "Studying it helps to paint a picture of how these
gene families present in many vertebrates, including humans, evolved into
deadly toxin encoding genes."
Jacobo Reyes-Velasco, a
graduate student from Castoe's lab, is lead author on the new paper. In
addition to Castoe and Mackessy, other co-authors are: Daren Card, Audra
Andrew, Kyle Shaney, Richard Adams and Drew Schield, all from the UT Arlington
Department of Biology; and Nicholas Casewell, of the Liverpool School of
The paper is titled
"Expression of Venom Gene Homologs in Diverse Python Tissues Suggests a
New Model for the Evolution of Snake Venom." The abstract is available online at:
The research team
looked at 24 gene families that are shared by pythons, cobras, rattlesnakes and
Gila monsters, and associated with venom. The traditional view of venom
evolution has been that a core venom system developed at one point in the
evolution of snakes and lizards, referred to as the Toxicofera, and that the
evolution of highly venomous snakes, known as caenophidian snakes, came
afterward. But little explanation has been given for why evolution picked just
24 genes to make into highly toxic venom-encoding genes, from the 25,000 or so
"We believe that
this work will provide an important baseline for future studies by venom
researchers to better understand the processes that resulted in the mixture of
toxic molecules that we observe in venom, and to define which molecules are of
greatest importance for killing prey and causing pathology in human snakebite
victims," Casewell said.
When they looked at the
python, the team found several common characteristics among the venom-related
gene families that differed from other genes. Compared with other python gene
families, venom gene families are "expressed at lower levels overall,
expressed at moderate-high levels in fewer tissues and show among the highest
variation in expression level across tissues," Castoe said.
"Evolution seems to
have chosen what genes to evolve into venoms based on where they were expressed
(or turned on), and at what levels they were expressed," Castoe said.
Based on their data,
the new paper presents a model with three steps for venom evolution. First,
these potentially venomous genes end up in the oral gland by default, because
they are expressed in low but consistent ways throughout the body. Then,
because of natural selection on this expression in the oral gland being
beneficial, tissues in the mouth begin expressing those genes in higher levels
than in other parts of the body. Finally, as the venom evolves to become more
toxic, the expression of those genes in other organs is decreased to limit
potentially harmful effects of secreting such toxins in other body tissues.
The team calls its new
model the Stepwise Intermediate Nearly Neutral Evolutionary Recruitment, or
SINNER, model. They say differing venom levels in snakes and other animals
could be traced to the variability of where different species, or different
genes within a species, are along the continuum between the beginning and end
of the SINNER model.
Castoe said the next step
in the research would be to examine the genome of highly venomous snakes
to see if the SINNER model bears out. For now, he and the rest of the team hope
that their findings about the presence of venom-related genes in other parts of
the python change some thinking on what species are labeled as venomous.
"What is a venom
and what species are venomous will take a lot more evidence to convince people
now," Castoe said. "It provides a brand new perspective on what we
should think of when we look at those oral glands."
Card DC, Andrew AL, Shaney KJ, Adams, RH, Schield, DR, Casewell NR, Mackessy SP,
Castoe, TA. (2014). Expression of venom gene homologs in diverse python tissues
suggests a new model for the evolution of snake venom. Molecular biology and evolution, msu294.