Advertisements
Feeds:
Posts
Comments

Posts Tagged ‘Genetic diversity’


Tumor Progression

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

GEN News Highlights Nov 10, 2015   Darwinian Selection Does Not Influence Tumor Progression
http://www.genengnews.com/gen-news-highlights/darwinian-selection-does-not-influence-tumor-progression/81251958/

http://www.genengnews.com/Media/images/GENHighlight/85273_large1068523712.jpg

 

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,              http://dx.doi.org:/10.1073/pnas.1519556112

Significance

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 www.pnas.org/lookup/suppl/doi:10.1073/pnas.1519556112/-/DCSupplemental.

 

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.

 

 

Advertisements

Read Full Post »


Variability of Gene Expression and Drug Resistance

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

New Data Suggest Extreme Genetic Diversity of Tumors May Impart Drug Resistance

NEW YORK (GenomeWeb) – Researchers from the University of Chicago and the Beijing Institute of Genomics have undertaken one of the most extensive analyses of the genome of a single tumor and found far greater genetic diversity than anticipated. Such variation, they said, may enable even small tumors to resist treatment.

“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,” Chung-I Wu, a University of Chicago researcher and senior author of the study, said in a statement. “In a setting with so much diversity, those cells could multiply to form new tumors, which would be resistant to standard treatments.”

 

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 TaoaLingtong HaoaQingjian ChenbQiang Gonga, et al.

Shaoping Ling,  PNAS   http://dx.doi.org:/10.1073/pnas.1519556112      http://www.pnas.org/content/early/2015/11/11/1519556112

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.

Semantically Related Articles

 

 

 

The findings, which appeared in the Proceedings of the National Academy of Sciences this week, also call into question the widely held view that evolution at the cellular level is driven by Darwinian selection, revealing a level of rapid and extensive genetic diversity beyond what would be expected under this model.

In the study, the researchers focused on a single hepatocellular carcinoma tumor, roughly the size of a ping pong ball. They sampled 286 regions from a single slice of the tumor, studying each one with either whole-exome sequencing or genotyping under both the infinite-site and infinite-allele models of population genetics.

Based on their analyses, the team estimated more than 100 million coding region mutations in what they called an “unexceptional” tumor — more mutations than would ordinarily be expected by orders of magnitude, according to Wu.

This extreme genetic diversity, the study’s authors wrote, implies evolution under the non-Darwinian mode, which is driven by random mutations largely unaffected by natural selection. It also raises the question of why there is so little apparent Darwinian selection in the tumor.

The scientists speculated that in solid tumors, cells remain together and do not migrate, “so that when an advantageous mutation indeed emerges, cells carrying it are competing mostly with themselves. These mutations may confer advantages in fighting for space or extracting nutrients, but they are stifled by their own advantages,” they wrote.

Beneficial mutations may emerge on occasion, but in solid tumors the cell populations are “so structured that selection may often be blunted,” they stated. “The physiological effect has to be very strong to overcome those constraints.” Cancer drugs could remove those constraints, loosening up a cell population and allowing competition to occur, the investigators added.

Wu and his colleagues see the presence of so many mutations in a tumor as creating problems when it comes to treatment. “It almost guarantees that some cells will be resistant,” study co-author and University of Chicago oncologist Daniel Catenacci said in the statement. “But it also suggests that aggressive treatment could push tumor cells into a more Darwinian mode.”

Overall, the findings highlight the need to consider non-Darwinian evolution and the vast genetic diversity it can confer as factors when developing treatment strategies, even for small tumors, the researchers concluded.

Read Full Post »


Reporter: Aviva Lev-Ari, PhD, RN

 

 

photo

Researchers from Germany, Denmark, and the US sequenced a hyper-variable portion of the koala’s mitochondrial genome sequence using DNA from more than a dozen museum samples. The samples, obtained from museums in Australia and beyond, represented koalas that had been collected in different parts of Australia from the late 1800s to the 1980s.

The team found surprisingly similar mitochondrial profiles in the historical koala samples and samples from modern day koalas. And all four of the mitochondrial haplotypes identified in the older museum samples persist in modern koala populations, the researchers said. That hints that relatively low genetic diversity has been present in koalas for at least 120 years — prior to dramatic population declines at the end of the 19th century, which have been attributed to factors such as hunting, habitat loss, and disease.

“The event which reduced the genetic diversity of koalas must have happened a long time ago, perhaps during the late Pleistocene when the larger species of koala, P. stirtoni, became extinct,” Leibniz-Institute for Zoo and Wildlife Research’s Alex Greenwood, the study’s corresponding author, said in a statement.

SOURCE:

Historically low mitochondrial DNA diversity in koalas (Phascolarctos cinereus)

Kyriakos TsangarasMaria C Avila-ArcosYasuko IshidaKristofer M HelgenAlfred L Roca and Alex D Greenwood

BMC Genetics 2012, 13:92   doi:10.1186/1471-2156-13-92

Published: 24 October 2012

Abstract

Background

The koala (Phascolarctos cinereus) is an arboreal marsupial that was historically widespread across eastern Australia until the end of the 19th century when it suffered a steep population decline. Hunting for the fur trade, habitat conversion, and disease contributed to a precipitous reduction in koala population size during the late 1800s and early 1900s. To examine the effects of these reductions in population size on koala genetic diversity, we sequenced part of the hypervariable region of mitochondrial DNA (mtDNA) in koala museum specimens collected in the 19th and 20th centuries, hypothesizing that the historical samples would exhibit greater genetic diversity.

Results

The mtDNA haplotypes present in historical museum samples were identical to haplotypes found in modern koala populations, and no novel haplotypes were detected. Rarefaction analyses suggested that the mtDNA genetic diversity present in the museum samples was similar to that of modern koalas.

Conclusions

Low mtDNA diversity may have been present in koala populations prior to recent population declines. When considering management strategies, low genetic diversity of the mtDNA hypervariable region may not indicate recent inbreeding or founder events but may reflect an older historical pattern for koalas.

SOURCE:http://www.biomedcentral.com/1471-2156/13/92/abstract

http://www.biomedcentral.com/content/pdf/1471-2156-13-92.pdf

Cutest Koala

This cute baby koala was shot in Currumbin Wildlife Sanctuary, QLD, Australia.
_____________________

Learn about Koalas:
The Koala (Phascolarctos cinereus) is a thickset arboreal marsupial herbivore native to Australia, and the only extant representative of the family Phascolarctidae.

The Koala is found in coastal regions of eastern and southern Australia, from near Adelaide to the southern part of Cape York Peninsula. Populations also extend for considerable distances inland in regions with enough moisture to support suitable woodlands. The Koalas of South Australia were largely exterminated during the early part of the 20th century, but the state has since been repopulated with Victorian stock. The Koala is not found in Tasmania or Western Australia.

Koala on Wikipedia

Contrary to (un)popular belief: A koala is NOT a bear!

The US Government have declared the koala a threatened species, however the Australian Government has not. A review of the species national conservation status concluded that the koala are not threatened at a national scale, with a population that numbers in the hundreds of thousands

As with most native Australian animals, the Koala cannot legally be kept as a pet in Australia without a permit.
_____________________

About this photo

This was my first photo in Flickr Explore! Check this photo’s Explore history.
Highest recorded Explore: 16 on Saturday, March 29, 2008!

It is currently the number one hit if you search for “koala” on Flickr, and the number one google-hit for “cutest koala”. I get a LOT of views for this one, so thanks goes out to each and ever one of you for having a look at it!

It is currently used as one of several illustrative photos on the Wikipedia article on Koalas.

-Added to the Cream of the Crop pool as most interesting.

You can purchase prints of this photo here! Available framed or on canvas.
_____________________

View Large On Black

If you like this photo please consider adding it to your favourites. Also check out my photostream, or just my other animal photos. If you want to licence this photo for commercial use, please contact me by e-mail (erik at erikveland com) or flickr-mail. Cheers mates!

 

Read Full Post »


Reporter: Aviva Lev-Ari, PhD, RN

 

Economics and genetics meet in uneasy union

Use of population-genetic data to predict economic success sparks war of words.

10 October 2012 Corrected: 

  1. 12 October 2012
The United States has the right amount of genetic diversity to buoy its economy, claim economists.

picture: D. ACKER/BLOOMBERG VIA GETTY

“The invalid assumption that correlation implies cause is probably among the two or three most serious and common errors of human reasoning.” Evolutionary biologist Stephen Jay Gould was referring to purported links between genetics and an individual’s intelligence when he made this familiar complaint in his 1981 book The Mismeasure of Man

Fast-forward three decades, and leading geneticists and anthropologists are levelling a similar charge at economics researchers who claim that a country’s genetic diversity can predict the success of its economy. To critics, the economists’ paper seems to suggest that a country’s poverty could be the result of its citizens’ genetic make-up, and the paper is attracting charges of genetic determinism, and even racism. But the economists say that they have been misunderstood, and are merely using genetics as a proxy for other factors that can drive an economy, such as history and culture. The debate holds cautionary lessons for a nascent field that blends genetics with economics, sometimes called genoeconomics. The work could have real-world pay-offs, such as helping policy-makers to “reduce barriers to the flows of ideas and innovations across populations”, says Enrico Spolaore, an economist at Tufts University near Boston, Massachusetts, who has also used global genetic-diversity data in his research.

But the economists at the forefront of this field clearly need to be prepared for harsh scrutiny of their techniques and conclusions. At the centre of the storm is a 107-page paper by Oded Galor of Brown University in Providence, Rhode Island, and Quamrul Ashraf of Williams College in Williamstown, Massachusetts1. It has been peer-reviewed by economists and biologists, and will soon appear in American Economic Review, one of the most prestigious economics journals.

The paper argues that there are strong links between estimates of genetic diversity for 145 countries and per-capita incomes, even after accounting for myriad factors such as economic-based migration. High genetic diversity in a country’s population is linked with greater innovation, the paper says, because diverse populations have a greater range of cognitive abilities and styles. By contrast, low genetic diversity tends to produce societies with greater interpersonal trust, because there are fewer differences between populations. Countries with intermediate levels of diversity, such as the United States, balance these factors and have the most productive economies as a result, the economists conclude.

The manuscript had been circulating on the Internet for more than two years, garnering little attention outside economics — until last month, when Science published a summary of the paper in its section on new research in other journals. This sparked a sharp response from a long list of prominent scientists, including geneticist David Reich of Harvard Medical School in Boston, Massachusetts, and Harvard University palaeoanthropologist Daniel Lieberman in Cambridge.

In an open letter, the group said that it is worried about the political implications of the economists’ work: “the suggestion that an ideal level of genetic variation could foster economic growth and could even be engineered has the potential to be misused with frightening consequences to justify indefensible practices such as ethnic cleansing or genocide,” it said.

“Our study is not about a nature or nurture debate.”

The critics add that the economists made blunders such as treating the genetic diversity of different countries as independent data, when they are intrinsically linked by human migration and shared history. “It’s a misuse of data,” says Reich, which undermines the paper’s main conclusions. The populations of East Asian countries share a common genetic history, and cultural practices — but the former is not necessarily responsible for the latter. “Such haphazard methods and erroneous assumptions of statistical independence could equally find a genetic cause for the use of chopsticks,” the critics wrote.

They have missed the point, responds Galor, a prominent economist whose work examines the ancient origins of contemporary economic factors. “The entire criticism is based on a gross misinterpretation of our work and, in some respects, a superficial understanding of the empirical techniques employed,” he says. Galor and Ashraf told Nature that, far from claiming that genetic diversity directly influences economic development, they are using it as a proxy for immeasurable cultural, historical and biological factors that influence economies. “Our study is not about a nature or nurture debate,” says Ashraf. 

“It seems like the devil is in the interpretation more than the actual application of the statistics,” says Sohini Ramachandran, a population geneticist at Brown University who provided the genetic data for the study. She adds that Galor and Ashraf used estimates of genetic diversity that she and her colleagues specifically developed to overcome many of the confounding factors caused by the overlapping genetic and cultural histories of neighbouring countries.

Galor and Ashraf are not the first economists to use genetic-diversity data. Spolaore has also found that the differences in genetic diversity between countries can predict discrepancies in their level of economic development2. But he is clear that this is not necessarily a causal relationship:  “In my view it’s not genetic diversity itself that is responsible for this correlation,” he says. “A lot of this could be culture.”

Some say that the field needs a dose of rigour. Many studies linking genetic variation to economic traits make basic methodological errors, says Daniel Benjamin, a behavioural economist at Cornell University in Ithaca, New York. He is part of the Social Science Genetics Association Consortium, a group that brings together social scientists, epidemiologists and geneticists to improve such studies. Problems that medical geneticists have known about for years — such as those stemming from small sample sizes — crop up all too often when economists start to work with the data, he says.

For instance, while searching for genetic associations with factors such as happiness and income in a study of 2,349 Icelanders, Benjamin and his colleagues found a statistically significant association between educational attainment and a variant in a gene involved in breaking down a neurotransmitter molecule3. But the researchers could not replicate this association in three other population samples — a test for false positives that is standard practice in medical genetics — and the team now has reservations about the association. If the field is to develop fruitfully, “I think it’s essential for us to have geneticists involved”, says Benjamin. “We couldn’t do it without their help and insight.”

Nature 490, 154–155 (11 October 2012) doi:10.1038/490154a

Corrected:

In the original text, we wrongly attributed to Enrico Spolaore the opinion that using genetic data in economics could help policy-makers to set immigration levels. He actually suggested that the work could reduce barriers to the flows of ideas and innovations across populations. The text has been amended to reflect that.

References

  1. Ashraf, Q. & Galor, O. Am. Econ. Rev. (in the press).

    Show context

  2. Spolaore, E. & Wacziarg, W. Q. J. Econ. 124, 469–529 (2009).

    Show context

  3. Benjamin, D. J. et al. Annu. Rev. Econ. 4, 627–662 (2012).

Read Full Post »