The book was quite interesting overall, with lots of new information and thankfully no tired metaphors of DNA as being stored in 23 book volumes. Each chapter focused on a type of junk DNA; I particularly liked those on X chromosome inactivation (I find the sex chromosomes fascinating), telomeres, imprinting, miRNAs, and therapeutics, but I generally found the epigenetics sections boring. I think I just don't like epigenetics and so I skimmed some of those parts; I like genetics because of its digital nature, and while I do also like biochemistry, I don't really like the combination of genetics with biochem. That said, there were some interesting aspects of that, like:
Junk DNA that acts as an insulator between repressed and active regions of the genome loses its histone proteins. No histone proteins means no epigenetic histone modifications. No modifications means no spreading of epigenetic activity. This stops repressive modifications creeping into active genes and also prevents the opposite effect....Some tRNA genes can act as insulators. They can stop expression of one gene driving inappropriate expression of a neighbouring gene. This is an additional benefit of having lots of tRNA genes, which demonstrates the economical way with which evolution has made the most of raw material. ... A classical protein-coding gene is coated with epigenetic modifications that promote its expression. The enzyme that binds to this gene and copies it into RNA (which will ultimately be processed to form mature messenger RNA) can be a bit of a runaway train: once it starts copying it tends to keep going. If there is another protein-coding gene nearby, the enzyme could keep going and copy this as well. But if there are two or more tRNA genes in between, this won’t happen. tRNA genes are switched on pretty much all the time, because they are involved in the creation of all proteins. There is an enzyme that copies tRNA genes to create tRNA molecules from the DNA template. But this is different from the enzyme that carries out a similar job to generate messenger RNA molecules from classical protein-coding genes.
I really enjoyed the 'sex chromosomes' section. Here's a bit on how cells can somehow count the number of X chromosomes present:
She then talked about Rett syndrome and described it as something that 'presents in some ways as a really exteme form of autism'. So I guess she's trying to not be offensive to autistic people? Still feels a bit icky but better than nothing I suppose. She then mentions that we never really see boys with Rett syndrome - how did they get so lucky? Oh, because if a boy has it he dies in utero. Oops. I've read about that sort of thing a few times and it's so macabre.One of the oddest things we have come to realise is that our cells can count the number of X chromosomes. Male cells contain an X and a Y chromosome and they never inactivate the single X. But sometimes males are born who have two X chromosomes and one Y. They are still males, because it’s the Y chromosome that drives masculinisation. But their cells inactivate the extra X, just as female cells do. A similar thing happens in females. Sometimes females are born who have three X chromosomes in each cell. When this happens, the cells shut down two X chromosomes instead of one. The flip side of this is when females are born who only have one X chromosome. In this case, the cell doesn’t shut it off at all. Every daughter cell that subsequently develops switches off the same X chromosome as its parental cell
An interesting story about X chromosome inactivation was a woman who had Duchenne muscular dystrophy even though only one parent was a carrier and the woman's identical twin was unaffected; she had just gotten incredibly unlucky with the stochastic process of X inactivation, as by chance all the cells that would go on to give rise to muscle cells had turned off the good X chromosome.
I really liked the part about pseudoautosomal regions. You'd think that a woman with trisomy X (XXX) or Turner syndrome (X0) would be phenotypically identical because in trisomy two Xs will be inactivated and in Turner the single X just won't be inactivated, but you don't see that (though to be fair there aren't huge phenotypic differences, mainly height differences). At the ends of the sex chromosomes are the 'pseudoautosomal regions', where the X and Y chromosomes have alleles and can recombine. These regions escape X inactivation and so an XX woman has four (one on each end of each sex chromosome), as does an XY man, whereas an XXX woman or XXY man would have six, and an X0 woman would have two. These regions make a big contribution to height as they contain the SHOX gene (short stature homeobox), and so we see height differences with these syndromes. Super interesting.
Another interesting sex-related (in the genetic sense) thing was imprinting. For certain genes, their expression patterns depend on whether the gene was inherited paternally or maternally, and it can be related to the evolutionary battle of the sexes, where the male wants his offspring to grow up strong, but the mother has to balance strong offspring with being able to survive to gestate another child later (whereas the father can just go do it with someone else and doesn't care if the mother survives intact). So for example genes from the father might encourage a big placenta to give lots of nutrients to the baby, whereas from the mother it might do the opposite.
Genetic analyses of the abnormal placenta have been very informative. They show that in most cases, hydatidiform moles arise when an egg that for some reason has no nucleus is penetrated by a sperm. The 23 chromosomes in the sperm are copied, to create the normal human chromosome number of 46. In about a fifth of cases the mole is formed when two sperm penetrate one of the unusual nucleus-free eggs simultaneously, again generating the correct number of chromosomes. Just like the mouse experiments, the hydatidiform mole contains the correct number of chromosomes but they derive just from one parent, and this again leads to a severe failure in developmental pathways.
...
During development, the relevant paternal genes often drive expression of a large, efficient placenta, as this is the organ that nourishes the embryos. That’s why in the hydatidiform moles, where all the genetic material is from the father, there is an abnormal and very large placenta
I have to commend the author on her use of caveats rather than just uncritically reporting things, which is a trap popular science can sometimes fall into; she did use plenty of caveats, saying for example about telomeres:
The data are rather preliminary and not always consistent. This is partly because measuring telomeres in a consistent way is challenging, as described earlier, and we usually measure them in cells that we can access easily. These are typically the white blood cells, and they may not always be the most relevant cell type to examine
There was also some discussion about the practice of science, which was interesting. n the subject of the big international ENCODE project, which found that 80% of the genome appears to actually be functional (with caveats that they just found places that look functional but might not be, and used methods that could've just picked up random noise):
ENCODE was an example of Big Science. These are typically huge collaborations costing millions and millions of dollars. The science budget is not infinite and when funds are used for these Big Science initiatives, there is less money to go around for the smaller, more hypothesis-driven research. Funding agencies work hard to get the balance right between the two types of research. In many cases, Big Science is funded if it generates a resource that will stimulate a great deal of other science. The original sequencing of the human genome would be a clear example of this, although we should recognise that even that was not without its critics. But with ENCODE the controversy is not around the raw data that were generated, it’s about how those data are interpreted. That makes it different from a pure infrastructure investment in the eyes of the critics.
.... The rush to create categories and nomenclature has been, and continues to be, a real problem in the whole field of genome analysis because it tends to lock us in to definitions before we really have enough biological understanding to create relevant categories. [on types of non-coding RNAs]
Unfortunately I was pretty bored while reading this book - even though it had lots of interesting information, overall it was quite dry, and very dense in parts. It did have some great quips though:
...The protein is called Sonic Hedgehog, symbol SHH. Researchers went through a phase of giving genes apparently comic names. This is now discouraged as it’s suddenly not so amusing if a genetic counsellor has to pass on a whimsical gene name to the parents of a child with a severe genetic condition.
...They work in complex partnerships and the impact that they have on the final splicing pattern is affected by other things happening in the cell, such as the precise complement of proteins in the spliceosome. The descriptions that are used for these modifying sequences usually include such words as ‘dizzying’ or ‘bewildering’. These are geek speak for ‘unbelievably complicated, way beyond anything we can get our heads around or even design predictive computer algorithms for at the moment.
From an evolutionary perspective, it doesn’t really matter if this means that when we are older we can’t repair our hearts. This is a problem for humans because we like living longer than evolution deems strictly necessary.
...
One of the first Bible stories learnt by children raised in the Judaeo-Christian faiths is the creation tale from Genesis. In this story, God creates the earth and the heavens and all that is in them, and finally he creates Adam and Eve. After that, peopling the earth is down to those two and their descendants, with no further divine intervention apart from the obvious exception in the Christian tradition at the start of the New Testament.
The therapeutics section was really interesting. One idea: many drugs target proteins or enzymes and inhibit them by nestling into a cranny on their surface - but what do you do if the protein is flat and there's nowhere for an inhibitor to lodge? Target the protein while it's still an mRNA, using miRNAs which will target it and cause it to be degraded.This is a sequence of six bases (AAUAAA) within the junk of the untranslated region. It acts as a signal for a messenger RNA-processing enzyme. The enzyme recognises the six-base motif, and cuts the messenger RNA a little distance away, usually ten to 30 bases further downstream. Once the messenger RNA has been cut in this way, another enzyme can add the multiple A bases. This six-base motif often occurs many times in the same untranslated region. It’s not particularly clear how a cell ‘chooses’ which motif to use at any one time. It is probably influenced by other factors in the cell. But because there are multiple motifs that can be used, there may be multiple messenger RNAs that code for exactly the same protein, but which contain different lengths of the untranslated region before the multiple As. These different-length messenger RNAs will have different stabilities and so produce different amounts of protein from each other. This creates additional opportunity for fine-tuning the amount of protein that is produced.
(One gripe: she referred to them as 'smallRNAs' the whole way through the chapter instead of just saying miRNAs and siRNAs. I don't think the more accurate form is that much harder to understand and it was super annoying to see 'smallRNAs' all the time.)
I had never thought of the drugs-go-to-the-liver thing before even during my Metabolism study where I literally cried because the liver does so much work and is underappreciated:
An interesting example of how outside factors can influence drug development:One of the biggest problems that companies have faced in the past when trying to develop drugs around nucleic acids has been the body’s own detoxification abilities. This is also often a problem for traditional drug discovery as well. Essentially, when a new chemical of any type enters the body, there is a very high likelihood that it will go to the liver. One of the main jobs of this vastly energetic organ is to detoxify anything it doesn’t like the look of. For all of our evolutionary history, this has served us well, protecting us from toxins in food. But the problem is that the liver has no means of distinguishing between toxins we want to avoid, and drugs we are trying to use. It will just drag them in, and try to destroy them. To use an old rubric, Alnylam and Mirna are making a virtue from a necessity. Alnylam is targeting expression of a protein that is produced in the liver. Mirna is trying to develop treatments for liver cancer. Their molecules will be taken up by exactly the organ they want them to reach. The companies have adapted the structure or packaging of their molecules to try to ensure that once they are in the liver, they will survive long enough in the cells to do their job. SmallRNA approaches have been put forward for a number of other conditions, and the preliminary cellular and animal experiments often look good. But for a condition such as amyotrophic lateral sclerosis, where the nucleic acids will have to avoid the liver and be taken up by the brain, it’s not clear yet how successful the industry will be in capitalising on this technology
On a more personal note, this from the telomeres section was upsetting to read as someone with anxiety. C'mon guys, now I'm stressed about the effect my stress is having on my health! You're literally killing me! It's worse than smoking and obesity!In 1998 an antisense drug was licensed for use in immunocompromised patients who had developed a viral infection in the retina that threatened their sight. The antisense molecule bound to a viral gene, and prevented the virus from reproducing. It was an effective drug, which raises two questions. Why did this drug work so well? And given that it worked so well, why did the manufacturer stop selling it in 2004? Both answers are quite straightforward. The drug worked well because it was injected straight into the eye. There was never a problem about it being scooped up by the liver, because it didn’t go via the liver. It was also targeting a virus, and only in one selfcontained part of the body, so there wasn’t much risk of widespread interference with human genes. All of which sounds peachy, so why did the manufacturer stop selling it in 2004? This drug was developed for severely immunocompromised patients, of whom the vast majority were people suffering from AIDS. By 2004, there were drugs available that were pretty good at keeping HIV, the causative virus, under control. The patients’ immune systems were in much better shape, and they simply weren’t succumbing to viral infections in the retina anymore.
Chronic psychological stress can be very harmful for an individual, with negative impacts on multiple systems including their cardiovascular health and their immune responses. 34 Individuals who suffer chronic psychological stress tend to die younger than less stressed individuals. A study of women aged between 20 and 50 showed that those in the chronically stressed group had shorter telomeres than the unstressed women. This was calculated to equate to about ten years of life.It was interesting that long non-coding RNAs appear to be involved in maintaining pluripotency in embryonic stem cells; knocking down these lncRNAs induces the ES cells to start differentiating, and inducing them to start differentiating decreases the amount of lncRNAs present. The 'development can be thought of as the opposite of cancer' concept was really interesting.
There were lots of other things, like how the myotonic dystrophy mutation is related to junk DNA (the longer the repeat gets, the more it can sponge up things that should be off regulating other things). I'd recommend it if you like biology, except maybe the epigenetics bits.
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