Canine Transmissible Tumors: Seeking Immortality By Becoming a Parasite

Cancers are composed of cells that have forgotten who they are supposed to be.  They become independent brats in the body, hogging resources and dividing uncontrollably.  From the cancers perspective the problem is that being a spoiled brat may bring short-term rewards, like lots of offspring and freedom from having to do the job they were supposed to do, but in the long-term—or very short time unfortunately for many—they kill their host from which they have rebelled and thus cause themselves to go extinct.

How might a cancer cell achieve continued existence over many generations rather than being limited to the host’s lifetime?  What if cancer could escape the host that gave birth to it and move to another host?  These aren’t theoretical questions. Biologists have identified three  examples in nature of cancers that have broken free of their initial hosts  and escaped to live another day. In fact they have done much more than live another day but have gone on to infect hundreds of thousands of other hosts jumping from one to another in a continuing quest for immortality.

One of these cancers, if that is what we can still call them, I have written about previously. It is a transmissible cancer that infects Tasmanian Devils (see: What is a Species: Tasmanian Devil Transmissible Tumors). The second is a common tumor of domesticated dogs recognized since the late 1800s.   Initially it was though to be a cancer that arose independently in each victim just as all other known cancers were at the time.  In 2006 researchers proved that one form of cancer which has been found in hundreds of millions of domestic dogs has a single origin.

The tumor is called canine transmissible venereal tumor (CTVT) and is passed from dog to dog through sexual contact and licking.  The cancer is thought to have originated as a unique mutation in a dog thousands of years ago and then passed from that dog to millions of domesticated and feral dogs since its origin.   It has even been shown to be transferable to other canine species such as wolves, coyotes and foxes.

To better understand the origins and evolution of this independent lineages of tumors in dogs, two tumors from dogs from different continents (Australia and South America) have had their complete genomes sequenced (An 11,000 year old dog tumor) allowing comparisons of their DNA sequences with dog breeds and each other.  These sequence have allowed scientists to determine the characteristics of the original dog population from which the cancer originated and to estimate how long ago that cancer formed and spread to other dogs.

I want to share some of the research findings with you and ask a few questions such as:  is this tumor really a dog or should it be considered a new organism and how are these tumors a challenge to the young earth creationist’s views of the origins of biological diversity?

A tale of two tumor genomes

Two CTVTs (dog tumors) were sequenced. One was from an old lineage of domestic dogs from Australia while the other was from a modern breed of dog from South America.  when compared to each other these two tumor genomes shared 1.9 million single nucleotide (individual ATCG changes) differences from all other dog genomes sequenced to that point.  This number of differences is strong evidence that these tumors have their origins from a common ancestor domestic dog (or possibly wolf or coyote) a long time ago.

In addition, each tumor had just over 100,000 unique mutations or about 200,000 total differences between them.  What this tells us is that from the origin of the tumor in some ancient canine to the time when the common ancestor of these two tumors existed there were around 1.9 million mutations.  Since then more than 200,000 more mutation have occurred with just over 100,000 occurring in each line of cells leading to the tumors alive in these two dogs at the time they were collected.

That sounds like a lot of mutations but how does that compare to mutations in human tumors.  Human cancers are known to have extraordinary high mutation rates such that human cancer tissue that has been grown in the lab will show between 1000 and 5000 mutations compared to the cells of the person from which the cancer was derived.  As a bit of an aside, some recent work (see references) in which parents and their children had their DNA codes completely read out it was found that there were fewer than 100 new mutations in the kids compared to their parents DNA.  It should be apparent that  mutation rates of cancer cells are far greater than in normal tissues which possess an excellent checking and repair systems when they copy their DNA.  Even so, these dog tumor have several hundred times as many mutations as any other known cancer compared to its host origin tissue.  It would take thousands of years for any human tumor to come close to having the number of mutations that these dog tumors exhibit compared to normal dog DNA.  This genetic divergence from its origins with the direct observation that this transmissible cancer was already widespread in the 1800s is compelling evidence that these tumors are an ancient long-lived cancer cell line.

The mutations mentioned above are only the ones that cause one base to be replaced with another in the DNA code.  In addition to these single-site mutations the two tumors shared more than 2100 structural variants compared to dogs and wolves.  These structural variants could be missing or additional pieces of DNA in the genome or positions where the genome has been rearranged (e.g. a large piece of DNA turned around so it faced the wrong direction or moved to another chromosome).  Like the 1.9 million single site mutations, these variants would represent all the changes that occurred since the origin of the cancer to the time when the two tumors had a common ancestor.  Eve since diverging from their common ancestor these two tumors have each accumulate another 200 structural variants that are unique to each tumor.

What effect has this had on the genome of this cancer?  Well 646 genes of the 22,000 genes found in a dog genome are either defective (don’t work) or have been completely lost (their code has been removed) from the genome.  In some cases genes have been copied or have been moved to new locations in the genome.  Six hundred and forty-six genes may sound like a lot of genetic material but remember that a tumor cell isn’t ever going to make a fully functional dog and so there will be many genes that will not be needed anymore.  As a result, any mutation that occurs in those genes will not be  removed by natural selection but remain in the genome.  Over time those mutations will build up and knock out the function of the genes that were not being used anyway.

At the same time that many genes will be lost through disuse in the cells, there are many genes that undoubtedly experienced mutations that provided the cells with a greater capacity to survive in their new lifestyle as a parasite.  The cancer cell lineage must be able to get around the host immune system and make themselves easily accessible and transferable in order to continue their existence.  This has necessitated modifications to the genome to give it new properties that the original host-dog genome did not have.

In addition to genes that are absent or defective the tumor genomes reveal that there are over 10,000 genes, almost half of the entire set of genes!, that had at least one mutation that changed an amino acid and thus changed the structure of the protein product of the gene and so potentially could change its function or efficiency.  This is an enormous amount of change in proteins.  For comparison, 29% of genes that humans and chimpanzees share have no amino acid differences and most genes only have a single mutation that changes an amino acid.

When did these two tumors share a common ancestor? 

The authors provide an estimate of the age of the common ancestor of these tumors.  They use errors rates from known tumors to get a rough estimate of how long it would have taken for these tumors to accumulate the mutations found in each of them. They estimate that the common ancestor (ie. the last time that the cells were in the same animals and thus had identical genomes) of this tumor from a dog from Australia and one from South America was around 500 years ago.  Since that time pieces of that tumor have spread from dog to dog accumulating additional changes (the 100,000 single-site mutations and 200 structural mutations) along the way until they came to be in the present day dogs from which they were collected.   This seemed like a reasonable estimate to the authors as this would have placed the ancestor of the today’s tumors around 500 years ago which corresponds to when people began really moving around the world a lot more along with their dogs.

But what about the ultimate origin of the tumor?  This would have happened much earlier than 500 years ago.  Remember that the two sequenced tumors have accumulated bout 100,000 mutations since they diverged from one another but before that this cancer had accumulated 1.9 MILLION mutations since it first became a cancer cell in some unfortunate ancient dog.  The authors estimate that this ultimate origin of the cancer probably occurred between 10,500 to 12,500 years ago depending on the mutation rates used in their calculations.  In addition, the genome sequence enabled them to definitively place the tumors origin in an ancient domesticated dog and not from a wolf or coyote.

So what is it!?

What has happened here?  I don’t think it would too radical to say that this transmissible tumor has evolved into a parasitic organism.  Is this a new species?  If so is is a mammal? Is this just definitions?  Are parasitic worms living things? Many nematodes and other parasitic organisms have lost the ability to live independently and must use a host to survive and reproduce.  Here we have a lineage of cells that started as a single mutant cell in a single dog. That cell has propagated itself for some 11,000 years and infected millions of new hosts.   This cancer has learned how to get from host to host and is now genetically distinct from its first host.  Clearly the tumor is no longer a dog and yet it retains genes that are most similar to dogs indicative of sharing a common ancestor with dogs.

A new species? A new life form? A new class of organism? I would say the tumor is not a member of the dog species (Canis lupus var. familiaris).  It probably deserves its own species name as a self-sustaining replicating lineage of cells though I don’t know how it could be classified into a group.  Although it is multi-cellular it is similar to an asexually reproducing cell line like a bacteria.

Ancient dog tumors in the context of young-earth creationism

What do transmissible canine tumors have to do with young-earth creationism (YEC)?  Any topic which touches on the origins of biological diversity has the potential to identify differences between the young-earth hypotheses on origins and other theistic or secular theories.  You won’t be surprised to learn that I think the studies of these tumors are another example of how modern genetic analysis presents serious obstacles to young earth creationist’s views of biological diversity.

How so?  Quite simply, most modern young-earth creationists believe that Noah preserved a single pair of representatives of a “kind” or “baramin”  on the Ark less than 4500 years ago.  With respect to the origin of domestic dogs, YECs such as Ken Ham have been telling us that there were no foxes, wolves or coyotes or domestic dogs on the Ark but rather a single pair of animals that was the common ancestor of all of these species.  After those ancestors departed the ark and spread across the earth they adapted to the new environments and “evolved” into all the species we have today.

How does this tumor fit into this picture or species origins?  The genetic evidence strongly suggests that the tumor evolved from an ancient domestic dog rather than a wolf.  Therefore, wolves, coyotes and domestic dogs must have already evolved into their respective species before this tumor came into existence.  Creationists can’t propose the tumor originated before the Flood. It could not have been in the ancestral pair of canines on the Ark otherwise its DNA would look as similar to a fox, wolf, coyote as it would a domestic dog.

This tumor must have come into existence after dogs were domesticated from one lineage of ancestral.  After its origins that tumor then had to experience all 1.9 million mutations and 2100 other structural rearrangements between 4000? and 500 years ago.  At best, creationists must compress all that genomic change into a maximum of 3500 years if not far less.   These are very high rates of mutations and no model—creationists or otherwise—of genetics has demonstrated support such rates of change.

Adaptation through mutation and natural selection

Life finds a way to adapt. This tumor is a striking example of cells that have found a way to escape from what would appear to be a very temporary existence.  They have done so through modification of the genome both at the fine scale (individual base-pair changes and large scale (losses of genes, duplications, rearrangements within chromosomes and recombination of genomes).  Despite a radically modified genome these cells continue to live and even thrive as the result of natural natural selection acting on those genomic mutations allowing adaptation into a form of parasitic organism.

No one is sure what will happen to this rogue tumor.  Since it survives by clonal reproduction, new strains of the tumor will continue to independently evolve just as the two tumor sequences already differ at over 200,000 locations.  As the do so they may take on distinguishable morphologies (they likely already express themselves differently but enough genetic work hasn’t’ been done to identify different morpho-strains) over time in the same way that a population of animals may split into two species over time via mutations and natural selection.  Only time will tell and we are watching as it happens.

References:

Transmissable Dog Cancer Genome Reveals the Origin and History of an Ancient Cell Lineage.  Elizabeth P. Murchison, David C. Wedge, Ludmil B. Alexandrov, Beiyuan Fu, Inigo Martincorena, Zemin Ning, Jose M. C. Tubio, Emma I. Werner, Jan Allen, Andrigo Barboza De Nardi, Edward M. Donelan, Gabriele Marino, Ariberto Fassati, Peter J. Campbell, Fengtang Yang, Austin Burt, Robin A. Weiss, Michael R. Stratton.  Science 24 January 2014:   vol. 343 no. 6169 pp. 437-440 DOI: 10.1126/science.1247167

An 11,000 year old contagious dog tumor.  http://www.the-scientist.com/?articles.view/articleNo/38975/title/Contagious-Dog-Cancer-Sequenced/

Wang, Xuan, Bo-Wen Zhou, Ting-Ting Yin, Fang-Liang Chen, Ali Esmailizadeh, Melissa M. Turner, Andrei D. Poyarkov et al. “Canine transmissible venereal tumor genome reveals ancient introgression from coyotes to arctic sled dogs.” bioRxiv (2018): 350512.

Jones, E. A., Y. Cheng, and K. Belov. “The origin, dynamics, and molecular evolution of transmissible cancers.” Advances in Genomics and Genetics 2015, no. 1 (2015): 317-326.

Decker, Brennan, Brian W. Davis, Maud Rimbault, Adrienne H. Long, Eric Karlins, Heidi G. Parker, Vidhya Jagannathan et al. “Comparison against 186 canid whole genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor.” Genome research (2015): gr-190314.

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This article is an updated version of one first published January of 2014.