There’s an interesting glimpse into recent human evolution in the latest edition of PLoS Genetics. It comes from a team of scientists whose corresponding author is Chad Huff, of the University of Texas MD Anderson Cancer Center, Houston, Texas. The paper is titled “Evolutionary history of Tibetans inferred from whole-genome sequencing”. The team performed whole-genome sequencing of 27 Tibetan individuals and confirmed that present day Tibetans diverged from the ancestral Han Chinese population between 44 and 58 thousand years ago, but with significant admixture until some 9,000 years ago. They confirmed that one positively-selected haplotype EPAS1 arose in the common ancestors of Tibetans and Han through introgression from Denisovans. The haplotype has all but died out in present-day Han, but, because it confers advantages with altitude, has been strongly selected for in Tibetans. Another gene selected for was VDR, which is important in vitamin D metabolism. As they state in the paper: “In a study involving vitamin D status in a cohort of 63 Tibetans, the proportion of nomadic Tibetans with vitamin D deficiency was 100% with 80% of people having severe deficiency; the proportion of non-nomadic Tibetans with vitamin D deficiency ranges from 40% to 83%. Consistently, in another study, 61% of Tibetan children suffer from rickets and 51% have stunted growth. Such a high prevalence of vitamin D deficiency may be explained by the traditional Tibetan diet consisting of barley, yak meat and butter tea which are poor sources of vitamin D, and clothing habits in cold temperatures which allow for minimal skin exposure to the sunlight. Therefore, we hypothesize that VDR gene is positively selected to compensate for the lack of vitamin D”. Other gene variants selected for included the PTGIS gene which promotes vasodilation and angiogenesis, and KCTD12, which is concerned with hypoxia.
It is now well documented that the best way for an infant’s gut (largely sterile at birth) to get populated by the bacterial components of a healthy microbiota is through its mother’s milk. Over 700 species of bacteria have been found in breast milk including the prominent probiotics Lactococcus, Leuconstoc and Bifidobacterium. In “Body by Darwin” I described an extraordinary evolved symbiosis between Bifidobacterium longum and humans whereby human mothers express large quantities of complex long-chain sugars called oligosaccharides in breast milk even though their babies cannot digest them – they completely lack the enzymes to do the job. It turns out that the oligosaccharides are never meant for the baby – but to allow Bifidobacteria a competitive edge in the large intestine. B. longum, for instance, has a suite of 700 unique genes that allow it to digest oligosaccharides such that breast-fed babies become the perfect ecological niche for this bacterium. Now a group of scientists from Japan have added the enzymatic specifics to this story. They have shown that the two main species of Bifidobacterium – longum and bifidum – have evolved different ways to crack open specific oligosaccharides. Bifidobacterium bifidum, they say, possesses a glycoside hydrolase family 20 lacto-N-biosidase for liberating lacto-N-biose I from lacto-N-tetraose, an abundant oligosaccharide unique to human milk, while Bifidobacterium longum subsp. longum has a non-classified enzyme (LnbX), thanks to molecular evolution from the former enzyme, to exploit the same sugar. By determining the crystal structure of the catalytic domain of LnbX they provide evidence for the creation of a novel glycoside hydrolase family, GH136, and show that it is indispensable for B. longum growth on lacto-N-tetraose and is therefore a key genetic factor for persistence in the gut of breast-fed infants. Their results, they say, suggest that human milk oligosaccharides have been the main selective pressure for the evolution of the gene lnbX in B. longum, because a stronger correlation between the gene and bacterial persistence was detected in the stools of breast-fed infants than in those of mixed-fed infants. It seems likely that a whole range of bifidobacterial species and subspecies employ different strategies, involving the evolution of a family of enzymatic complexes, to exploit lacto-N-tetraose, so that this oligosaccharide can be shared among members of the genus and even among strains belonging to the same species/subspecies, but withheld from other bacterial species. it is a wonderful example of the evolution of a complex gut ecosystem of various bifidobacteria which avoids competition for a strategic sugar, to which they all have exclusive access, all of which has been driven by the complexity of mother’s milk.
There are two related and interesting articles on cancer evolution in a recent edition of eLife. The first is a commentary by Devon M Fitzgerald and Susan M Rosenberg, of the Baylor College of Medicine, on a paper in the same issue titled “TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24− cancer cells.” As Fitzgerald and Rosenberg explain, mutations don’t always arise randomly at uniform rates. Many cells and organisms have been shown to increase mutagenesis in response to stress. In the case of cancer this could come about through the insult to cancer cells of anti-cancer medication. The paper by Raffaella Sordella, and her colleagues, of Cold Spring Harbor Laboratory documents a good example of this by showing that TGF-beta signaling can temporarily reduce the fidelity of DNA repair leading to genetic diversity in progeny cells. This can result in the evolution of resistance to chemotherapy.
The CSHL team concentrated on CD44+/CD24− cells which arise in cancer cell lines and behave like stem cells in reaction to the TGF-beta signaling pathway so that they become continuously active. These cells are linked to drug-resistance, metastasis and other poor outcomes for patients, they say. The faulty DNA repair causes copy number changes to genes – a well recognised hall-mark of cancer evolution. They also showed that the gene PMS1 – which is important for so-called mismatch-repair of DNA was also less active in CD44+/CD24− cells. Mismatch repair corrects small errors in DNA replication, and so errors here can allow thousands of small point mutations to pile up in cancer cells.
All this, say Fitzgerald and Rosenberg, points to the importance of looking for “anti-evolvability” drugs rather than drugs which try to deal with the outcomes of cancer evolution. By inhibiting evolution you could, theoretically, decrease the chances of the evolution of resistance.
This is a heads up for a very useful essay, written by Mel Greaves, for The Darwin Cancer Blog – a blog dedicated to commenting on evolutionary approaches to cancer. In this essay, titled “Ways of Escape”, Greaves draws a number of comparisons between chemo-resistance in cancer and antibiotic resistance in bacteria. Both, he points out, frequently come about because the therapy we throw at either bugs or cancer cells selects for pre-existing mutations, rather than inducing de novo mutations (which of course does also occur). Bacteria, he says, that have been discovered in 30,000 year-old permafrost, have mutations that render them resistant to modern antibiotics, for instance. The cancers for which chemotherapy is a success story are very few in number: testicular cancer, acute lymphoblastic leukaemia, and choriocarcinoma – they are the only ones, to date, which retain sensitivity to cancer drugs. In most other cases chemotherapy will have short-lived positive effects but, thanks to selection among cancer clones within the tumor mass, the cancer likely re-occurs with a vengeance.
Cancers are only playing the same evolutionary tricks common throughout the plant and animal kingdom. Escaping from potentially lethal challenge has been a major driving force in evolution, he says, and the majority of species on Earth are parasites and their success depends on immune evasion or disguise. The evolutionary principle could not be simpler – it’s survival of the fittest and the luckiest.
“Given that cells and micro-organisms both divide and mutate, the likelihood of the existence of a mutation endowing resistance is going to be determined by the clone size (number of cells) and the mutation rate. This is why small or ‘early’ tumours are less likely to appear to be resistant. When bacteria are subjected to high levels of stress, they adopt a mutator phenotype which greatly increases the probability of mutations favouring survival. By increasing background mutation rate, the instigation of genetic instability in cancer increases the chance of drug-resistant mutations. The prediction that escape mutations pre-date exposure to cancer drugs and that drug treatment would, essentially, positively select emergent clones with these mutations has now been validated with high depth sequencing of diagnostic samples from patients who later relapsed on targeted drug therapy. It is perhaps one of the ironies of cancer chemotherapy that intensive drug treatment provides strong selective pressure for the emergence of more robust clones.”
Greaves goes on to explain a number of Houdini acts common among cancers before asking what we can do about it. We need to be smarter, he says, which is why we are seeing some success with combinatorial therapy, employing a number of cancer toxins to cut off several escape routes at once. Alternatively, he says, we can make use of appropriate scheduling and dosage of drugs to push cells into a more benign evolutionary trajectory or lower fitness cul-de-sac. This is the “live with cancer, rather than try to eradicate it” approach taken by Bob Gatenby and his colleagues at the Moffitt Cancer Center in Florida.
Aging is associated with a number of chronic diseases – cardiovascular disease, diabetes, Alzheimer’s disease and other dementias, and cancer. They are all part of the process of immunosenescence. The chronic inflammation that is a feature of the declining efficiency of geriatric immune systems has a deleterious effect on normal metabolic and hormonal signaling, is increased by the accumulation of cell debris as we age (for instance in the eye), and is typified by chronically elevated levels of circulating pro-inflammatory cytokines.These processes are well reviewed in a recent paper in the journal Aging Mechanisms and Disease, titled “Macrophages in age-related chronic inflammatory diseases”, by Yumiko Oishi and Ichiro Manabe. These chronic inflammatory processes, say the authors, tend not to be dramatic but are long-term, low-grade smouldering responses to things like tissue repair and insult by pathogens. And changes in the behavior of macrophages in particular, as we age, are central to driving inflammation. Macrophages, they say, not only promote inflammation and tissue dysfunction but also are essential for resolution and healing of inflammation, as well as maintenance of tissue homeostasis. But, as we age, while macrophages turn on the inflammation that underlies healing processes and resistance to infection, they become less good at turning inflammation off when it has done its job. Thus macrophages appear to contribute crucially to the paradoxical activation of basal chronic inflammatory states in the elderly and to the progression of age-associated diseases.