Posts Tagged ‘Natural selection’

Tumor Progression

Larry H. Bernstein, MD, FCAP, Curator



GEN News Highlights Nov 10, 2015   Darwinian Selection Does Not Influence Tumor Progression


New answers may have just emerged in a long-standing debate in the field of oncology and molecular evolution. The neutral theory of molecular evolution states that changes occurring at the molecular level are not caused by natural selection, but rather by the random genetic drift of mutant alleles. In contrast, Darwinian selection adheres to the idea that a molecular mutation holds some selective advantage over the wild-type, allowing it to thrive.

When viewing these two theories through the lens of carcinogenesis, it is not difficult to envision the applicability of either theory. However now, new evidence from scientists at the University of Chicago and the Beijing Institute of Genomics may tip the scales in favor of neutral theory. This collaborative scientific effort assembled data from one of the most rigorous genetic sequencing ever carried out on a single tumor—revealing a much greater level of genetic diversity than expected.

The investigators excised a tumor roughly 3.5 centimeters in diameter (slightly smaller than a ping-pong ball), from a hepatocellular carcinoma tumor of the liver. The research team estimated that the tumor contained more than 100 million distinct mutations within genetic coding regions, which is thousands of times more than they anticipated. The impact of this finding is that even microscopic tumors are likely to contain extremely high genetic diversity and with so much variation there are likely many cells contained within able to resist standard post-surgical cancer treatment such as chemotherapy and radiation.

“With 100 million mutations, each capable of altering a protein in some way, there is a high probability that a significant minority of tumor cells will survive, even after aggressive treatment,” explained study director Chung-I Wu, Ph.D., professor of ecology and evolution at the University of Chicago. “In a setting with so much diversity, those cells could multiply to form new tumors, which would be resistant to standard treatments.”

The findings from this study were published recently in PNAS through an article entitled “Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution.”


Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Shaoping Linga,1Zheng Hua,1Zuyu Yanga,1Fang Yanga,1Yawei LiaPei LinbKe ChenaLili DongaLihua CaoaYong Taoa , et al.
PNAS Nov 11, 2015,    


A tumor comprising many cells can be compared to a natural population with many individuals. The amount of genetic diversity reflects how it has evolved and can influence its future evolution. We evaluated a single tumor by sequencing or genotyping nearly 300 regions from the tumor. When the data were analyzed by modern population genetic theory, we estimated more than 100 million coding region mutations in this unexceptional tumor. The extreme genetic diversity implies evolution under the non-Darwinian mode. In contrast, under the prevailing view of Darwinian selection, the genetic diversity would be orders of magnitude lower. Because genetic diversity accrues rapidly, a high probability of drug resistance should be heeded, even in the treatment of microscopic tumors.


The prevailing view that the evolution of cells in a tumor is driven by Darwinian selection has never been rigorously tested. Because selection greatly affects the level of intratumor genetic diversity, it is important to assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution. To provide the statistical power, many regions in a single tumor need to be sampled and analyzed much more extensively than has been attempted in previous intratumor studies. Here, from a hepatocellular carcinoma (HCC) tumor, we evaluated multiregional samples from the tumor, using either whole-exome sequencing (WES) (n = 23 samples) or genotyping (n = 286) under both the infinite-site and infinite-allele models of population genetics. In addition to the many single-nucleotide variations (SNVs) present in all samples, there were 35 “polymorphic” SNVs among samples. High genetic diversity was evident as the 23 WES samples defined 20 unique cell clones. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Under the non-Darwinian model,MALL (the number of coding region mutations in the entire tumor) was estimated to be greater than 100 million in this tumor. DNA sequences reveal local diversities in small patches of cells and validate the estimation. In contrast, the genetic diversity under a Darwinian model would generally be orders of magnitude smaller. Because the level of genetic diversity will have implications on therapeutic resistance, non-Darwinian evolution should be heeded in cancer treatments even for microscopic tumors.

intratumor heterogeneity  genetic diversity  neutral evolution  cancer evolution  natural selection

This article contains supporting information online at


Scientists at the Beijing Institute of Genomics sampled nearly 300 regions from one slice of the hepatocellular tumor and sequenced or genotyped each one searching for genetic changes. Once they analyzed their data and applied a modern population genetic theory, their results lead them to the 100 million coding-region mutation estimate for the whole tumor.

This extensive level of heterogeneity within a single tumor, which is way beyond what a Darwinian process would permit, makes the selectionism vs. neutralism debate of the 1980s “suddenly medically relevant,” Dr. Wu remarked. Since previous to the current study, no one had ever genetically dissected a tumor as thoroughly, the commonly held theory was that tumors had from a few hundred up to 20,000 genetic alterations that were not present in the patient’s healthy cells.

“Our study is the non-Darwinian process writ small, down to the cellular level,” Dr. Wu noted. “In the Darwinian struggle, there are—from the tumor’s point of view—few beneficial mutations, meaning changes that give tumor cells a growth advantage. When there are no such limits on genetic variation, however, mutations can emerge and apparently thrive.”

“This could potentially change how we think about tumor growth and spread, but the direct clinical implications of this study may not be obvious on the surface,” added co-author Daniel Catenacci, M.D., assistant professor and medical oncologist at the University of Chicago.

While the bulk of the mutations were at very low frequencies, drug intervention could provide some of the genetic mutations with a progression path forward.

“The presence of so many random mutations could present a problem to specifically targeted therapies,” Dr. Catenacci stated. “It almost guarantees that some cells will be resistant. But it also suggests that aggressive treatment could push tumor cells into a more Darwinian mode.”

Since the current study only focused on a single tumor type, it remains to be seen how comparable this data will be for other types of cancerous tumors. However, regardless of narrow focus, the results from this analysis raises important question about tumor evolution and heterogeneity.




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Reporter: Aviva Lev-Ari, PhD, RN

UPDATED 9/16/2013

Enzymes That Are Not Proteins: The Discovery of Ribozymes
Listen to past HHMI President Dr. Thomas Cech discussing his Nobel Prize-winning discovery of RNA’s catalytic properties.

Stanford Report, March 15, 2013

Long-term evolution is ‘surprisingly predictable,’ Stanford experiment shows

A protein-folding simulation shows that the debated theory of long-term evolution is not only possible, but that the outcomes are predictable. The Stanford experiment provides a framework for testing evolutionary outcomes in living organisms.


L.A. CiceroVisiting scholar Mike Palmer left, and Professor Marcus FeldmanDr. Michael Palmer, left, and Professor Marcus Feldman, with co-author Arnav Moudgil (not pictured), found that the long-term evolutionary dynamics were surprisingly predictable in a model of protein folding and binding.

Two birds are vying for food. One bird’s beak is shaped, by virtue of a random mutation, such that it’s slightly more adept at cracking seeds. This sets the bird on the road toward acquiring more food, a better chance of scoring a mate and, most important, passing on its genetic endowment.

This individual’s success is an example of short-term evolution, the widely accepted Darwinian process of natural selection by which individual organisms that have better adapted to their surroundings prevail.

In recent years, however, some scientists have argued that natural selection occurs not just at the individual organism level, but also between lineages over the course of many generations. In a new study, Stanford biologists have demonstrated that not only is this long-term evolution possible, but that long-term evolutionary outcomes can be surprisingly predictable.

The group set up a computer simulation in which 128 lineages of proteins continuously folded into new shapes, competing to bind with other molecules, called ligands, in each new configuration. The better each protein could attach itself to the ligands, the more ligands it would scoop up, and the higher its fitness – that is, its average number of “offspring” – would be. The simulation was run for 10,000 generations.

Although the chaos of 128 lineages – a total of more than 16,000 individual proteins – mutating over thousands of generations might seem unpredictable, and that it would be nearly impossible for the same thing to happen twice, it’s actually the opposite.

“Even though things look complicated, the possible evolutionary trajectories are quite constrained,” said lead author Michael Palmer, a computational biologist at Stanford. “There are only a few viable mutations at any point, which makes the dynamics predictable and repeatable, even over the long term.”

The study, co-authored by Marcus Feldman, a biology professor at Stanford, and Stanford research biologist Arnav Moudgil, was recently published in the Journal of the Royal Society Interface.

In some experiments, the lineages that consistently came out on top in the long term were not initially the best adapted at binding to ligands. “The immediate fitness is not the only important thing,” Palmer said. “Yes, a lineage does have to survive in the short term. But just as important is how it is able to adapt to new and potentially variable environments over the longer term.”

A good example of this scenario is Darwin’s famous finches. It’s thought that individuals – perhaps just a single pair of birds – from a South American species ended up on the Galápagos Islands about 1 million years ago. Today their descendants have diversified into about 15 modern species. Some eat seeds, some eat insects, or flowers. Some eat ticks, or even drink the blood of other birds.

“If there was some catastrophe that removed one of those food sources, it might wipe out one or more of the 15 species, but the rest of the lineage – the descendants of that initial pair of birds – would persist,” Palmer said. “Now say there was a competing lineage that was great at cracking seeds, but unable to evolve to other diets due to some prior genetic constraint. The same catastrophe could wipe it out.”

The finding, and others like it, could represent a significant shift in viewpoint for biologists. For one thing, it means that in certain situations, scientists should look beyond the details at the level of the individual organism, as the evolutionary dynamics can be accurately understood as lineage selection.

It also has implications on a species’ genomic architecture, or how a genome is organized on the lineage level. While a lineage’s genome might primarily select for a particular set of traits in order for individuals to survive in the short term, in order to out-compete other lineages, it must also be able to adapt to new conditions over the long term.

“An individual can have a lucky mutation that produces an immediate adaptation,” said Palmer. “Or a lineage can have a lucky mutation that happens to position it to adapt to the range of environments it will experience over the next thousand generations. A single mutation can have a distinct short-term and long-term fitness.”

The authors believe that the work can be replicated in microorganisms, and are now hoping that microbiologists will apply the new metrics of selection in vitro.

“There is already some evidence in vitro that there is a lot of constraint on evolutionary trajectories,” Palmer said, “and we think we’ve come up with a good framework to quantify evolutionary predictability and long-term fitness.”

Media Contact

Michael Palmer, Biology: (415) 867-3653,

Bjorn Carey, Stanford News Service: (650) 725-1944,


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