molecular evolution

Predicting neuroblastoma outcomes with molecular evolution

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A research team led by the German Cancer Research Center in Heidelberg, Germany, has discovered that the genetic sequence of a tumor can be read like a molecular clock, traced back to its most recent common ancestor cell. Extracting the duration of tumor evolution can give an accurate predictor of neuroblastoma outcomes.

In a paper published in Nature Genetics titled “Neuroblastoma arises in early fetal development and its evolutionary duration predicts outcome,” the team details the steps they took in identifying a genomic clock tested against a whole genome sequenced population combined with analysis and mathematical modeling, to identify evolution markers, traceability and a likely origin point of infant neuroblastomas.

Cancer cells start out life as heroic healthy tissues, with the sort of all for one, one for all, throw yourself on a grenade to save your mates–type attitude that is taking place throughout the body every day. At some point, something goes wrong, and a good cell goes bad.

It begins with miscommunication in dividing or an injury to a cell’s DNA, which happens with great regularity throughout the body. Typically this is handled before trouble can start by a repair mechanism. If the repair cannot be made, it is time to engage in apoptosis or cell death.

A healthy cell response to a call for apoptosis is to throw itself on the “grenade” to keep all of the surrounding cells and cell tissues safe. If a cell is not able to hear the call for apoptosis, as can happen with chromosomal damage, it takes no action. Without the conforming behavior to grow or stop growing, a cell becomes a threat to its surroundings, a rogue cell, a cancer cell and—if it proliferates unchecked—a tumor.

A cell on its own, no longer able to communicate with its neighbors because the communication network between cells has been lost, still tries to survive. Within a cell is most of what it needs to continue the mission of life—to grow, to reproduce, and to thrive. But from the outside the perspective is very different. From outside the isolated and injured cell, cancer is growing. Depending on where the cancer is, and how it is constructed, the outcomes can be very different.

In the case of neuroblastoma, the most frequent solid tumor in infants, a wide spectrum of clinical outcomes is possible, ranging from low-risk cases requiring light or no treatment to a high-risk situation that is fatal for about 50% of patients.

In the current study, cohorts of primary and relapsed neuroblastoma tumors were retrospectively analyzed. Whole genome sequencing was applied to 100 neuroblastomas and validated in an independent group of 86. Neutral single-nucleotide variants were selected and tracked as a molecular clock to time key events.

By comparing tumor clone sequences to the molecular clock, researchers found that the density of somatic single-nucleotide variants (SSNVs) in cloned cells was similar for the different copy numbers, essentially a continuation of the molecular clock in the clone, and as a result, traceable back to a most recent common ancestor cell. Compare this to standard tumor sampling that can tell if different tumor cells are related but lacks the time-dependent evolutionary connection, and the importance of this method becomes strikingly clear.

Researchers further discovered that the duration of evolution was found to be an accurate predictor of outcome. Cells that quickly became tumors did so without the ability to sustain growth, while others that more slowly transitioned into tumors built an infrastructure for more prolonged and aggressive tactics for survival. Knowing this, researchers could then identify neuroblastomas with favorable clinical outcomes.

Origin story

Researchers were able to wind back the molecular clock of their model and pinpoint a likely origin of neuroblastomas by combining whole-genome sequencing, molecular clock analysis and population-genetic modeling in a comprehensive cohort covering all subtypes. Tumors across the entire clinical spectrum likely begin to develop via aberrant mitoses as early as the first trimester of pregnancy. This is when the adrenal medulla forms from sympathetic neuroblasts, and the modeling suggests that the initial oncogenic event is limited to this time window. The transcriptomes of neuroblastomas most resemble those of sympathetic neuroblasts that are highly proliferative in the first trimester, which may make them vulnerable to aneuploidy (chromosomal abnormalities).

A tremendous effort is underway now to compile a gene atlas, a document of every cell in the human body, their functions and interconnected communications. Everything that science has revealed, from basic anatomy to the discovery of DNA and the human genome project. From unraveling the ways that DNA is transcribed, spliced, translated, and modified to how epigenetics and gene variants affect health. All of it leads to a platform from which we can understand molecular cellular evolution in predictive enough ways to take proactive, preventative and procedural steps to ensure sustained longevity of human life.

The current study is a window into that future, with a predictive and time-dependent understanding of the molecular evolution of a single tumor cell type. The age of modern miracle medical science is not the age we are living in, but it is the age we are now building.

Study tracks pace of molecular evolution.

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A new study compares the relative rate of molecular evolution between humans and chimps with that of their lice. The researchers wanted to know whether evolution marches on at a steady pace in all creatures or if subtle changes in genes – substitutions of individual letters of the genetic code – occur more rapidly in some groups than in others.

A report of the study appears in the Proceedings of the Royal Society Biology.

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The team chose its study subjects because humans, chimps and their lice share a common historical fate: When the ancestors of humans and chimps went their separate ways, evolutionarily speaking, so did their lice.

“Humans are chimps’ closest relatives and chimps are humans’ closest relatives – and their lice are each others’ closest relatives,” said study leader Kevin Johnson, an ornithologist with the Illinois Natural History Survey at the University of Illinois. “Once the hosts were no longer in contact with each other, the parasites were not in contact with each other because they spend their entire life cycle on their hosts.”

This fact, a mutual divergence that began at the same point in time (roughly 5 million to 6 million years ago) allowed Johnson and his colleagues to determine whether occurs faster in primates or in their parasites.

Previous studies had looked at the rate of molecular changes between parasites and their hosts, but most focused on single in the mitochondria, tiny energy-generating structures outside the nucleus of the cell that are easier to study. The new analysis is the first to look at the pace of molecular change across the genomes of different groups. It compared a total of 1,534 genes shared by the primates and their parasites. To do this, the team had to first assemble a rough sequence of the chimp louse (Pan troglodytes schweinfurthii) genome, the only one of the four organisms for which a full genome sequence was unavailable.

The team also tracked whether changes in gene sequence altered the structure of the proteins for which the genes coded (they looked only at protein-coding genes). For every gene they analyzed, they determined whether sequence changes resulted in a different amino acid being added to a protein at a given location.

They found that – at the scale of random changes to gene sequence – the lice are winning the molecular evolutionary race. This confirmed what previous, more limited studies had hinted at.

“For every single gene we looked at, the lice had more differences (between them) than (were found) between humans and chimps. On average, the parasites had almost 15 times more changes,” Johnson said. “Often in parasites you see these faster rates,” he said. There have been several hypotheses as to why, he said.

Humans and chimps had a greater percentage of sequence changes that led to changes in protein structure, the researchers found. That means that even though the louse genes are changing at a faster rate, most of those changes are “silent,” having no effect on the proteins for which they code. Since these changes make no difference to the life of the organism, they are tolerated, Johnson said. Those sequence changes that actually do change the structure of proteins in lice are likely to be harmful and are being eliminated by natural selection, he said.

In humans and , the higher proportion of amino acid changes suggests that some of those genes are under the influence of “positive selection,” meaning that the altered proteins give the primates some evolutionary advantage, Johnson said. Most of the genes that changed more quickly or slowly in primates followed the same pattern in their , Johnson said.

“The most likely explanation for this is that certain genes are more important for the function of the cell and can’t tolerate change as much,” Johnson said.

The new study begins to answer fundamental questions about changes at the molecular level that eventually shape the destinies of all organisms, Johnson said.

“Any difference that we see between species at the morphological level almost certainly has a genetic basis, so understanding how different genes are different from each other helps us understand why different species are different from each other,” he said. “Fundamentally, we want to know which genetic differences matter, which don’t, and why certain genes might change faster than others, leading to those differences.”