Tag Archives: genetics

Infectious tumors steal host mitochondria in canines

What’s scarier than cancer? Infectious cancer? Dogs have been living with it for the last 10,000 years. In fact, canine transmissible venereal tumor, or CTVT, appears to have originated at roughly the same time that early canine domestication began. CTVT is considered a highly adapted cancer composed of asexually reproducing cells that are now believed to be genetically distinct from the host. These “cancer cells” essentially act as unicellular pathogens, invading a new host during copulation and reproducing to form nasty, though thankfully somewhat treatable, tumors.

Through extensive sequencing of the canine mitochondrial genome, evolutionary biologists have successfully constructed a high-resolution phylogeny of domestic dogs, tracing all extant clades back to the most recent common ancestor. To determine whether or not the CTVT disease was in fact genetically separate from its hosts,  15 host mitochondria were sequenced in conjunction with their tumor genome. In all cases, CTVT mitochondrial genes proved to be genetically unrelated to their host.

The twist in this study came when the researchers realized that CTVT mitochondrial genes are not only unrelated to their host, but differ dramatically from their own nuclear genes. How could a single cell contain a nucleus and mitochondria with seemingly unrelated genes?

It turns out that the unique biology of CTVT provides an opportunity for geneticists and evolutionary biologists to study an event that occurs quite rarely in nature- the transfer of genes between a complex multicellular eukaryote and a single celled organism. Horizontal gene transfer from pathogen to host is a relatively common phenomenom, but rarely does it operate the other direction, and examples of horizontal gene transfer from a complex eukaryote are particularly scarce. However, in the case of CTVT this phenomenom provides the best explanation for a number of puzzling aspects of the pathogen’s genome. The occasional transfer of canine mitochondria into CTVT cells explains the unusually high level of genetic variability within CTVT mitochondria, as well as the stark unrelatedness of mitochondrial and nuclear DNA.

This unusual transfer event, rather than being a randomly occuring, stochastic process, may in fact be keeping the CTVT cell line alive. CTVT cells have abnormally high metabolic rates, necessitating the production of lots of mitochondria. A high rate of mitochondrial division also means an increased number of deleterious mutations in the mitochondrial genome. When enough “bad mutations” accumulate, mitochondria lose the ability to function properly. Researchers are now suggesting that host mitochondria may be more “evolutionarily fit” than their pathogens’, and that occasional transfer events may in fact resuce CTVT mitochondrial function. The horizontal transfer of mitochondrial genes has been experimentally achieved in mammalian tissue cultures. This unique mechanism of replacing a broken genome with a perfectly functioning one from host cells is not outside the realm of possibility.

The only other known transmissible tumor, Devil facial tumor disease, occurs in Tasmanian devils.

Rebbeck et al. 2011.  Mitochondrial Capture by a Transmissible Cancer. Science. In press.

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GeoChip: linking genetics with environmental processes

Over the past decade, environmental scientists have been casting a wider net in their attempts to understand complex environmental processes on a molecular scale. Once fascinating new line of research involves co-opting techniques developed by geneticists, largely for the biomedical industry, in order to understand how genes are important regulators of earth-scale processes as carbon and nitrogen cycling.

The GeoChip is a clear example of this search for new methods to answer old questions. Microbiologists  are working on remote Antarctic islands to understand some of the simplest nutrient cycling pathways in the world. The ecosystems they study are often composed of only a handful of fungal and microbial species. These simple food chains allow resarchers to contruct basic models of how energy and nutrients (such as carbon and nitrogen) are transferred.

This is where GeoChip comes in. GeoChip is a gene microarray chip designed to identify “functional genes” involved in important nutrient cycles. It allows the identification of genes in an environmental sample that regulate carbon fixation, decomposition, and atmospheric nitrogen fixation, to name a few.  Understanding what functional genes are available in a system allows scientists to both understand the potential of that system for cycling nutrients and better predict how that system will respond to environmental change.

Imagine a glass floor divided into hundreds of indentical squares. Each of these squares contains a different fragment of DNA, reconstructed by geneticists from known DNA sequences. When scientists want to probe an environmental sample for specific DNA sequences, they “wash” their sample over the floor. Fragments of DNA will stick to their complementary sequence on the floor, causing a square to light up. Scientists can “read” a GeoChip by identifying fluroescently lit spots where environmental DNA has attached. They use this information to develop a picture of the functional genes present in that system.

In Antarctica, GeoChip is already been used to answer important ecological questions. For example, scientists are finding that genes for nitrogen fixation, the crucial ecosystem process that produces plant-useable nitrogen in the soil, occur in lichen-rich areas. Lichens are believed to be among the earliest land colonizers, and the ability of lichen-dominated systems to add nitrogen to the soil may be an important finding in reconstructing the early colonization of terrestrial systems. Other findings include carbon-fixation genes in plots that lack vegetation, indicating microbial communities that are able to perform some sort of photosythesis in the absence of plants.

Citation:

Yergeau et al. 2007. Functional microarray analysis of nitrogen and carbon cycling genes across an Antarctic latitudinal transect. The ISME Journal 1: 163–179

microbiologists watch evolution in action

rapid advances in molecular genetics are now allowing scientists to watch, and even manipulate, evolution. this may seem hard to reconcile with the idea that evolution is a very gradual, long-term process, whose effects are seen only on timescales of thousands or millions of years. the misconception here is that time governs the rate of evolution. time in the abstract is relentless and constant, moving forward endlessly. this conception of time does not take the broad range of life strategies that evolution has produced into account.

in fact it is generation time that governs rates of evolution. human beings, who tend to have several children over the course of a multi-decadal life, have relatively slow generation times. it can take millions of years for noticeable evolutionary shifts to occur in a population that grows and reproduces slowly, simply because the genetic mutations that lead to evolution are very rare, and advantageous mutations take a long time to become established in a population.

it has long been known that microbial evolution occurs rapidly- noticeable genetic shifts can be observed in a manner of days or weeks. the evolution of pathogen resistance to pesticides or medicine occurs through natural selection for a rare genetic mutation that allows survival. because microbial populations often grow exponentially and generation time can be as short as twenty minutes, rare genetic mutations can sweep through a population and become ubiquitous rapidly. this is evolution in action!

historically, experiments in microbial genetics have focused on determining the function of an existing gene. this is generally accomplished by creating a strain with a defective, mutant version of the gene of interest, and observing how its function differs from the normal gene. studying defective mutants, however, does not provide insight into how gene pools can be improved.

now scientists are growing microbial cultures whose entire genetic makeup is known, and performing experiments that test evolutionary theory. any number of questions are being asked- how do the bugs evolve in response to an environmental change? a new food source? the introduction of a genetically different strain? for example, if a microbial population that requires oxygen to breathe is suddenly placed in a low oxygen environment, will genetic shifts occur that allow the microbes to use oxygen more efficiently? this certainly seems to be the case with humans- human populations that have existed for centuries at high altitudes, where oxygen is scarce, exhibit slight alterations in genes that encode hemoglobin, the protein that binds oxygen and transports it throughout the body. controlled evolution experiments allow replication, which means that scientists can now ask how frequently a positive evolutionary outcome, such as increased oxygen efficiency, occurs.

though such experiments may only provide a simplistic illustration of evolution, the mechanisms leading to genetic changes in microbial populations are remarkably similar to the basic mechanisms governing genetic change in higher organisms, including humans. insights developed from these experiments may be a first step towards unraveling the complex chain of events that has created the extraordinary diversity of adaptive traits across all types of life.

the meaning of life

when most people hear the word “virus”, the first image that comes to mind is generally something along the lines of a sick person, an epidemic, trips to the doctors office, vaccinations, or, for those with some biology background, a crystalline, nightmarish spider-alien injecting DNA into a defenseless cell. viruses are generally perceived as perpetrators of malaise, a scourge to society that modern science can and will eventually eradicate. only in the past decade, since the advent of fast and relatively cheap genetic sequencing technology, have scientists begun to recognize the staggering diversity of viruses in the world, many of which are entirely benign and have no known ecological function. the dawning realization that really are just about everywhere- they are ten times more abundant than bacteria in the ocean- indicates an incredibly effective strategy for self-propagation. this strategy in turn represents  a form of existence so simple that scientists have been debating for decades whether or not viruses can be classified as life.

despite their apparent simplicity, understanding viruses has been one of biology’s greatest challenges since the beginnings of the molecular revolution. the traits that we have discovered to be ubiquitous among viruses are relatively straightforward. generally, a virus consists of a single piece of naked DNA, encapsulated in some sort of protein-based coat. viruses cannot be considered cells because they contain none of the internal machinery necessary for growth or self-replication. instead, many viruses replicate by inserting their DNA into the cells of a host. this invading DNA is able to co-opt the host cell’s own replication proteins, and turn the host into a small factory for new viruses.

many but not all of the viruses that cause human disease use this strategy, and they often do so with alarming efficiency. another common viral replication strategy is to insert DNA into a host, and integrate that DNA into the hosts own DNA. viruses that employ this strategy are effectively choosing symbiosis inside a host, and replicate themselves in step with the host cell’s own cycle.

it may seem strange that some viruses act aggressively- invading, replicating and moving on once they have plundered all the resources available, while others choose a life of harmless symbiosis within their host. how can we come up with a general definition for all viruses if this is the case? shouldn’t we classify these critters as two unique types – neither truly alive perhaps, but fundamentally different in their non-living existence?

to answer this question, one must think carefully not about what viruses are doing but why. in both cases, a fragment of DNA is simply trying to replicate itself in the most effective way possible. for some, this means integrating itself into an organism, and reproducing in concert with the organisms own generations. for others, it means rape, kill, pillage and burn. viruses  are the ultimate narcissists- no ambitions for complex structure or function,, simply a raw, unabashed need for self-propagation.

if existence driven entirely by the need to replicate and produce more of oneself what it means to be a virus, i don’t think it’s a far stretch of the imagination to draw parallels with organisms that we officially classify as “alive”. with simple single-celled life, the similarity is easy to see. unicellular bacteria are essentially DNA vessels, but with extra compartments for the tools and machinery required to replicate. some single-celled bacteria do reproduce sexually and, in exchanging DNA, produce offspring that are not genetic clones. nevertheless, the idea is essentially still simple propagation of genes, but given one more level of complexity in that the replication process is self-sufficient.

but how much similarity can there possibly be between a complex, multi-cellular organism, and a single replicating strand of DNA? try thinking of a complex organism, like a cat, horse, or even human, as a nation of cells. each cell is an individual citizen, and each citizen has a specialized job that he must perform as an effective member of the community. if too many citizens dissent, or get lazy, and choose not to perform their allocated jobs, the community falls apart. and what do these citizens, many of whom look and act very different, and would certainly never be caught getting coffee or drinks together, all have in common? dependency on each other for replication.

a human being is orders of magnitude more complex than a virus, and I am not trying to diminish that complexity, or even to claim that it can be reduced to aggregate of cells driven by a simple process. but the common purpose of genes, in everything from their rawest form that do not even consider living, to the most complex organism evolution has produced, speaks to the ancestry we all share.