The Evolution and Medicine Review

…bridging the gap.

TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants

A research group drawn from the University of Chicago and University of Nottingham, UK, has just published a paper on Peto’s Paradox with direct reference to the evolution of large body size in elephants. This link takes you to the abstract where there is a download of the entire PDF. Of particular interest is the proposed role of several TP53 retrogenes in making elephant cells more sensitive to DNA damage and apoptosis. Here’s the abstract:

“A major constraint on the evolution of large body sizes in animals is an increased risk of developing cancer. There is no correlation, however, between body size and cancer risk. This lack of correlation is often referred to as ‘Peto’s Paradox’. Here we show that the elephant genome encodes 20 copies of the tumor suppressor gene TP53 and that the increase in TP53 copy number occurred coincident with the evolution of large body sizes, the evolution of extreme sensitivity to genotoxic stress, and a hyperactive TP53 signaling pathway in the elephant (Proboscidean) lineage. Furthermore we show that several of the TP53 retrogenes (TP53RTGs) are transcribed and likely translated. While TP53RTGs do not appear to directly function as transcription factors, they do contribute to the enhanced sensitivity of elephant cells to DNA damage and the induction of apoptosis by regulating activity of the TP53 signaling pathway. These results suggest that an increase in the copy number of TP53 may have played a direct role in the evolution of very large body sizes and the resolution of Peto’s paradox in Proboscideans.”

Newborn gut microbiome predicts later allergy and asthma.

A new paper published last week in Nature Medicine shows that the gut microbes present in some one-month old infants predict a three-fold higher risk of developing allergies by age 2 and asthma by age 4, says a press release issued by the University of California in San Francisco. The study’s senior author, Susan Lynch of UCSF believes that a particular signature of a depleted or dysbiotic microbiome at this very early age could identify neonates at risk and allow physicians in the near future to treat with probiotics or fecal transplants to re-engineer a healthy microbiome in a truly preventative approach.

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Born to be bad?


Barrett’s Oesophagus – mass

Carlo Maley has recently tweeted the arrival of a new paper on measurement of clonal diversity in oesophageal cancer, and the use of such diversity markers in predicting which patients with non-dysplastic Barrett’s Oesophagus will progress to cancer and which will not. Carlo has previously collaborated with two of the great exponents of this “clonal diversity” approach to cancer prognosis – Brian Reid, of the Fred Hutchinson Cancer research Center in Seattle, and Trevor Graham of the Barts Cancer Institute in London. Graham and Maley are among the authors of this paper.

Barrett’s is a pre-cancerous lesion of the lower oesophagus, usually caused by long-term acid reflux from the stomach, and is notorious for the failure of current screening techniques to identify pathological changes in oesophageal cells that can reliably tell you the risk of progression to cancer. As Brian Reid has said, oncologists end up in a position where their screening technique – usually once-in-a-lifetime screening of Barrett’s patients at the age of 50 – selectively detects those dysplasias that are going to remain stable for life – the patient will die with them, not of them – and selectively misses those fast-moving changes that will transition to cancer. The over-diagnosis of benign cases is running at 95% and the under-diagnosis of lethal cancer is also running at 95% – an abysmal track record. And since that over-diagnosis often impels oncologists to wade in with very difficult surgery to remove the entire oesophagus, causing many patients to die on the operating table – or soon after – or consigning them to a very poor quality of life thereafter, it is essential that a more reliable method of distinguishing oesophageal sheep from goats is found as soon as possible. Has this research team found the answer?

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4 more days to register for Oct 6-7 CRG Evolution and Medicine Symposium in Barcelona

Registration is free and open until September 16.

The search for the perfect human embryo is over

Back on May 13th I wrote a post entitled “Evolutionary biology takes a hard look at IVF and human conception”. In it I suggested that aneuploidy – chromosomal abnormality – was in fact normal for human embryos and had evolved as a male strategy for invasiveness in the face of female counter-measures that encapsulated implanting embryos and inspected them for quality and/or compatibility before either accepting or rejecting them. I observed that although fertility failure in human reproduction is very high at about 70%, it is much lower than the amount of chromosomally-abnormal embryos which is in excess of 90%. The obvious conclusion is that some genetically abnormal embryos can go on to make perfectly normal babies.

This sets up the obvious question. How do abnormal embryos “right themselves”? How do they correct these genetic mistakes, or purge them from the developing embryo, once they have neatly side-stepped a mother’s defenses? I suggested that the answer might lie in recent research by Magdalena Zernicka-Goetz of the Gordon Institute in Cambridge, UK, who discovered, thanks to chorionic villus sampling, that 25% of the cells in the placenta of a baby she was incubating at the age of 44 contained aneuploidies. Thankfully her baby was born completely normal. But this motivated Zernicka-Goetz to research the question of why the placenta could be riddled with genetic abnormality but the baby preserved from it. Research with mice embryos made mosaic for aneuploid and normal cells suggested that intense clonal competition among the blastocyst cells that went on to make the baby eradicated all cells that were genetically abnormal, whereas that clonal competition in the fraction of cells that went on to form the placenta was relaxed – allowing clones of aneuploid cells to survive. I suggested to Zernicka-Goetz that this could be an evolved mechanism to retain aneuploidy in the placenta in order to imbue it with the same degree of invasiveness that aneuploidy had already bestowed on the early embryo.

A paper in the journal Reproductive Biology and Endocrinology last week documents five cases of healthy live births of babies formed from aneuploid embryos and questions the necessity for, and effectiveness of, pre-implantation genetic screening, which has been widely adopted by IVF clinics in an attempt to identify aneuploidy in embryos and thus weed out “unviable” embryos. The paper argues that PGS should be abandoned because it may do more harm than good because it produces too many false positives which leads to over-rejection of embryos that could have gone on to make perfectly fine babies. A classic case of iatrogenic medicine that might be adding to the patients’ infertility, not curing it. If so, although these authors do not invoke evolutionary mechanisms explicitly, this story might endure as a prime example of where evolutionary medicine can make a real contribution to medical practice by fundamentally questioning assumptions. The search for the perfect embryo may very well be over.

Evolutionary trade-off keeps deleterious genes in human populations

Deleterious genes for a number of life-threatening diseases which palpably affect human fitness appear to persist in the gene pool at perplexingly high frequencies when you would think they would be eradicated over time by purifying natural selection. Now a group of scientists headed by Tobias Lenz of Harvard Med School and the Max Planck Institute for Evolutionary Biology have come up with the likely answer and it involves an evolutionary trade-off with the process that gives our immune systems the variability they need to counteract the many infectious diseases our environments throw at us. There is an easy-to-read precise of the work by Joseph Caspermeyer, in MBE.

In one part of their study Lenz and his colleagues examined over 160 genes in the MHC – the major histocompatibility complex – which is the area of the human genome that accounts for the cell surface molecules on our adaptive immune cells that recognise the antigens present on germs and guide those cells to attack them. Genes in this area, so-called HLA genes, have high genetic variability. As Lenz puts it, these classical HLA genes are scattered across the MHC region and exhibit exceptional allelic polymorphism and an extreme level of heterozygosity, which is thought to increase pathogen resistance and thus to be maintained by pathogen-mediated balancing selection. In other words it gives our immune systems the flexibility they need to counteract the multiple and constantly evolving threats from infectious microorganisms.

However, the downside to all this is that the MHC is enriched with a number of non-HLA genes that are known to be associated with diseases like autoimmune disease, cancer and schizophrenia. These can also persist at high frequency because they lie at such close proximity to the maintained HLA variants they too are maintained by genetic linkage. Lenz noted that non-HLA genes in very close proximity had a frequency more than two orders of magnitude that of non-HLA genes a little further away. Thus, even if some of these genes have a negative effect on human fitness we cannot get rid of them – they endure because they hang on to the coat-tails of genes that are essential, and have been essential through thousands of years, for human survival.

Old lions die while cougars roar!

Something a little light-hearted for a change. Hui Liu, Linda J. Waite, Shannon Shen and Donna H. Wang have just published a report on the effect of regular and enjoyable sex in later life, in the Journal of Health and Social Behaviour. It appears that, for men, having a good and lusty sex life from your mid-50s onwards carries an increased risk of later heart attacks and other cardiovascular problems. While for older women, good sex seems to be beneficial and can lead to a reduction in hypertension. The risk for sexually-active older men was twice that for men who were sexually inactive. The results of their studies are published in a popular format in Medical Express who quote one of the study’s authors saying that they are not quite sure what causes this elevated risk. It might be the extra and prolonged exertion older men have to apply to the job of reaching orgasm, it might be the medication they take to enable them to perform in the first place, or it may be that elevated testosterone levels in sexually-active older men have a deleterious effect on the health of their hearts!

A virus forms the placenta, causes fetal tolerance, and makes muscular males


Thierry Heidmann (

Nearly 10% of the genome of all mammals is made up of viruses that infected mammalian ancestors eons ago. These retroviruses inserted their DNA into mammalian chromosomes and, while time has reduced many of them to useless genetic rubble, some of them, or fragments from them, became adopted by mammalian DNA and pressed into service by evolution.

As Carl Zimmer documented back in 2012, in a wonderful essay on “The Loom” titled “Mammals Made from Viruses”, we humans could not have been born without them. He was referring to proteins called syncytins that are produced by the ex-viral genes syncytin 1 and 2. When the placenta is developing – thrusting itself deep into the wall of the uterus – the boundary between placenta and uterus, which is essential for the transfer of nutrients from the mother to the fetus, is composed of a layer of fused cells called the syncytiotrophoblast. It is the protein syncytin that causes the cells to fuse together.

According to the French scientist, Thierry Heidmann, who has done most of the work on syncytins, there is a protein that was once part of the envelope of the retrovirus, that has immunosuppressive qualities. This would have allowed the virus to invade mammalian genomes without being destroyed by host immune systems. This immunosuppressive function has been conserved by modern syncytins, says Heidmann, and could well be a part of the crucial system of maternal immune tolerance to the combined unit of fetus and placenta, which would otherwise lead to females rejecting their own fetuses on the basis of the allogeneic effect of the paternal genes they contain.

Now Heidmann has come up with another jaw-dropping role for syncytin. In the same way that it allows cells to fuse together to form the syncytiotrophoblast, he says, syncytin allows muscle cells to form by fusing together the stem cells that give rise to them. Muscle fibers are complex multi-nucleate structures containing large numbers of contractile myotubes that are formed from the fusion of mononuclear myoblasts. In a paper last week in PLosGenetics Heidmann showed that when he knocked out one of the syncytin genes he produced mice with 20% less muscle mass and mean muscle fiber area – but the effect was only seen in males and reduced their muscle mass to the equivalent of the females. He also documented the same male-specificity in the extent to which syncytins help to repair muscles after cardio-toxin-induced injury.

If Heidmann’s research is borne out by further investigation it will mean that not only has this viral gene been turned into a gene that is vital for reproduction throughout the mammals – including us – but has a more wide-ranging pleiotropic effect in that it also contributes towards the sexual dimorphism we see throughout the mammals where males are invariably bigger and bulkier than females. An extraordinary evolutionary story.

PhD job announcement from IEM, Zurich

Just in from Kaspar Staub, the Institute Manager at the Institute of Evolutionary Medicine in Zurich, is this announcement for a placement for a motivated PhD student to study ancient microbiomes. The project is actually titled “”Evolution of the human microbiome: Molecular insights from ancient Egyptian samples”.

Is human obesity related to the composition and richness of our gut microbiota – or not?



There is a sobering paper in the journal of the American Society for Microbiology, mBio, this week, written by Marc Sze and Patrick Schloss from the Department of Microbiology and Immunology at the University of Michigan. As they report, obesity is a growing health concern throughout the western world. 20% of the youth age group in the US from 2 to 19 years is either overweight or obese, they say, and that value exceeds one third in adults aged 20 or over. Since obesity is reliably linked to a host of life-limiting diseases like diabetes, liver disease and heart disease, and since obese individuals and their health problems are increasingly clogging up our healthcare provision systems, we need clear direction on where to place research emphasis to stem this current epidemic. A view that has been gaining in popularity recently is that the richness (in number and species number) of our gut microbes is directly associated with obesity; that obese individuals have an impoverished, dysbiotic, gut microbiota; that they can pass these settings onto their children; and that you can predict obesity from gut microbial species composition. However, Sze and Schloss trained powerful statistical analysis on the pooled data from a number of studies relating the gut microbiota and obesity and concluded that only one of them had sufficient power to detect even a 5% difference in diversity and that “although there was support for a relationship between the microbial communities found in human feces and obesity status, this association was relatively weak and its detection confounded by large interpersonal variation and insufficient sample size”.

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