Archive for the ‘epigenetics’ Category
epigenetics at the very beginning of life – my explorations
So let me see if I can understand epigenetics through other sources, and through what I’ve read so far. First, it’s essential for the very first cell divisions in human – or shall we say mammalian – life, at least for placental mammals. Their lives begin with a fertilised egg, a sperm cell and an egg cell (both known as gametes), each with its complement of DNA (but the egg cell contains much more, and there’s a difference between an ovum and an oocyte, which I won’t go into, as if I could). This cell, also known as a zygote, is the ultimate totipotent stem cell, potentially able to form every type of somatic (diploid) cell. So what causes this cell to divide and multiply, and become, in a few days, a blastocyst?
A blastocyst is already quite a complex collection of cells, with an outer layer, the trophectoderm, an inner cell mass, and a blastocoel, which is a fluid-filled cavity. So, already quite a jump from a zygote, so I need to know how that happens. But even before that, I need to know how a zygote comes into being. Wikipedia puts it this way:
The formation of a totipotent zygote with the potential to produce a whole organism depends on epigenetic reprogramming. DNA demethylation of the paternal genome in the zygote appears to be an important part of epigenetic reprogramming.
That doesn’t help too much, but I’m guessing that this ‘epigenetic reprogramming’ thing is what creates cell diversity – but this description tells us that the formation of the zygote is itself an epigenetic product. Here’s another description of the first steps:
The four stages of embryonic development include fertilization (zygote formation), cleavage (rapid cell division), blastocyst formation, and finally, implantation into the uterine lining.
Cleavage? The website I filched this from (ferty9.com, listed below) fails to elaborate, and looking up the word an sich just takes me to female breasts, which is pleasant but distracting. AI (never lies) gives more detail, claiming four cleavage stages, 1. the zygote stage, 2. the 2 to 8 cell stage, 3. the morula stage, and 4. blastocyst formation. And presumably epigenetics plays a role in the move from one stage to the next?
So, I’ve tracked down a most sciencey article, from ScienceDirect, entitled ‘Epigenetic regulation of early human embryo development’, which I hope to make sense of. Its opening paragraph is a bit daunting though:
Epigenomes undergo profound change during the first few days of embryonic development. The resetting and establishment of epigenomes are coordinated within and contribute to the wider processes of embryogenesis. As a consequence, faithful epigenetic regulation is required to safeguard development and to establish long-lived epigenetic states that have effects on genome function throughout the life course.
So now we have epigenomes, and here’s a definition:
Epigenome: The epigenome consists of all the chemical modifications of DNA and histones of a cell/organism that contribute to regulate gene expression independently of DNA sequence.
Histone modification involves the post-translational modification of specific amino acids that influence the overall structure of histone proteins. Changes in histone structure may then influence their function, resulting in incomplete DNA unwinding that may also effect transcription activity. Major histone modifications include acetylation, methylation, phosphorylation, ubiquitylation, and, less frequently, ribosylation, sumoylation, and citrullination
References
https://pmc.ncbi.nlm.nih.gov/articles/PMC4783933/
https://www.sciencedirect.com/science/article/pii/S153458072101042
https://embryology.med.unsw.edu.au/embryology/index.php/Blastocyst_Development#Introduction
https://www.sciencedirect.com/science/article/pii/S1934590923003314
could I ever manage to get my head around epigenetics?
Nessa Carey’s book, The epigenetics revolution, was published in 2011, and discusses, and introduces, to many of us, gene methylation, histones, a number of different types of RNA, the names of specific genes, karyotypes, selective serotonin re-uptake inhibitors (SSRIs), phosphorylation, the Waddington epigenetic landscape and much else besides. Wikipedia’s account of epigenetics is no doubt more up-to-date, and is just about book-length (how long does a book have to be?), with over 200 references to scientific papers and such. Although the term was coined in the 1940s, the study of epigenetics is very much a 21st century thing, Our current knowledge of the area, like our knowledge of neurophysiology, has been one of the great developments in modern science. To read about it is exasperating, because there’s just too much to learn, to explore, to get your head around, and yet it’s vital to an understanding of who and what we are. When I think of SETI, for example, the Search for Extra-Terrestrial Intelligence, I wonder – how could such ineffable super-complexity have developed more than once in the universe, even given its incalculably massive extent?
I wish I was young and gifted with the opportunity to work in such a field, one which explains us, or tries to. How we manage to replenish all the cells in our bodies throughout our lives – not perfectly, for then we could live forever – but for a period extended enough for us to learn our own history, to fall in love, to learn from our many mistakes, to experience, delight in and suffer through all the stages of life, to observe all its amazing variety – the birds and the bees as they say, and the flowers and the trees, all of which have their genetic blueprints.
To think we had virtually no idea of this only a century ago, and we are 300,000 years old as a species, and DNA-driven creatures have existed for millions, maybe billions of years on this planet. We only worked out the structure of this molecule in the 1950s, and now we know for example that a spruce tree contains about six times more DNA than a human, and that it’s likely that our world was preceded by an RNA world, which still enlivens the viruses that plague us with influenza, hepatitis, polio, COVID-19 and so much else.
And all this epigenetic stuff – which is mainly about DNA methylation and histone modification – has been going on beneath our awareness, and certainly without our permission, since our life began as an embryo. That’s how our cells differentiate into some 200 different types. It has much to do with whether we’re tall or short, sickly or healthy, extroverted or introverted – even before we’ve ever met another soul. All of these goings-on in our growing bodies, as well as the inter-connections, disconnections and reconnections in our growing brains, in the time spent connected to a placenta and the subsequent years being buffeted by parents, relatives, strangers and frenemies, are what shape us for a lifetime.
So where am I going with all this? Those who know me might guess, and be much annoyed, or much heartened.
To return to Carey’s book, which explores, inter alia, how laboratory creatures like rats and mice show specific patterns of behaviour for a lifetime after early deprivation, stress and other conditions, I was struck by this passage:
The human brain possesses sufficient flexibility to generate adult outcomes in response to similar childhood experiences. Our brains contain one hundred billion nerve cells (neurons). Each neuron makes links with ten thousand others to form an incredible three dimensional grid. This grid therefore contains a thousand trillion connections – that’s 1,000,000,000,000,000 (a quadrillion). It’s hard to imagine this, so let’s visualise each connection as a disk that’s 1mm thick. Stack up the quadrillion disks on top of each other and they will reach to the sun (which is 93 million miles from the earth) and back, three times over.
That’s a lot of connections, so it’s perfectly possible to imagine that our brains have a lot of flexibility. But the connections are not random. There are networks of cells within the giant grid which are more likely to link to each other than to anywhere else. It’s this combination of huge flexibility, but constrained within certain groupings, that is compatible with a system that is mechanistic but not entirely deterministic.
Nessa Carey, The epigenetics revolution, pp 235-6
This is, I believe, the only passage in Carey’s 300-page book that refers to determinism, and of course it struck me enough to write one word in the margin.
‘Really?’
I don’t often write in the margins of my books these days. Decades ago I had a girlfriend who expressed shock and great disapproval at finding margin notes in some of my books. She apparently found this behaviour to be sacrilegious in some way. Texts were sacred even if they were reproduced in their thousands. So, though I respectfully disagreed, I’ve reduced my sacrilegious behaviour, maybe to honour her memory. But this time I couldn’t resist.
– ‘mechanistic but not entirely deterministic’? What is the difference between these two terms? Aren’t these mechanisms determined by other mechanistic processes? Isn’t this what the book is all about? Isn’t this how we know about epigenetic processes, because they produce certain changes under certain specific conditions? Aren’t the determining factors precisely what we’re looking for, and what knowledge is all about. And yet there is, I find, a kind of fear or distrust of the word, even amongst those researchers who rely on mapping out the causal chain, often a complex and elusive one, to make good their discoveries. Whether we’re looking at the causes of cancer, or how one or two bees become queens while thousands more become workers, to mention just two topics explored in Carey’s book, we’re always trying to uncover and explain the determining conditions. It’s the sine qua non of all science.
Maybe I’m mis-representing Carey here. Maybe she meant, when she described the ‘huge flexibility’ of our neuronal system, the impossibility of trying to pin things down, cause-and-effect-wise, with absolute certainty. But then, that’s not what she wrote. She wrote ‘not entirely deterministic’, and that was a red flag to me. So what was the part that escaped determinism? It doesn’t actually make sense.
The idea, it seems to me, and the argument that most people try to use against determinism, is that complexity trumps it (sorry to use the word ‘trump’ here). If complexity was infinite, that might be so, but complexity isn’t infinite, it’s just complex.
So, that’s enough for now. Again, I wish I was fifty years younger, and a more disciplined person than I was in my youth, because I’d love to be working in the field of organic chemistry, or molecular biology, or neurophysiology, rather than peering at it over a vast stretch of ignorance, as I am today. But never mind…
References
Nessa Carey, The epigenetics revolution, 2011
on epigenetics and the free will debate, and such…
The free will thing has come to the fore of my head again recently because of an offhand ‘no free will’ remark I made, which of course caused some friendly argy-bargy. When the topic comes up I like to throw ‘the lot’ at it, our early neurological wiring, unwiring and rewiring, our hormonal activity, our genetics, our epigenetics, our position in the womb, our early interactions with parents, siblings and others, our culture, our gender, our first language, the time and place of our birth and so on.
Of all these variables, epigenetics is one that’s likely to catch people off guard. If they ask, I’ll say it’s all about gene expression, hoping that will silence them, and even impress them. But if they inquire further, I’d only be able to say something like ‘environmental factors affect how genes are expressed’ – and that would be the limit of my knowledge, even though, some years ago, I read Nessa Carey’s The epigenetics revolution, published in 2011.
So now I’m reading it again, and it seems for the first time. I’m finding it really hard to understand, and I’m sure it isn’t Carey’s fault. I suspect it’s the kind of topic in which you need to be active in the field to fully understand it, and even then….
But, I’ll have a go. Rett syndrome is a rare but devastating neurological disease which occurs almost exclusively in girls. Apparently, if a male child contracts it, it’s more or less immediately fatal. As AI (never lies) puts it:
Infants typically develop normally for 6 to 18 months before experiencing a severe regression in motor skills, speech, and hand use. While there is no cure, symptoms can be managed with targeted therapies and specific medications.
The development of this syndrome happened to coincide with infants receiving the MMR vaccine, which, as we know, caused much controversy some time ago, but the mechanism was worked out in 1999. It mostly has to do with mutations in a gene called MECP2, which severely affects the production of a functional MECP2 protein. Dysfunction/mutation in other genes have caused the syndrome, or something like it, in a minority of cases. The cells are able to methylate their DNA correctly, which is what much of what epigenetics is all about, but they’re unable to read that section of the epigenetic code properly. So Rett syndrome isn’t a mental/psychological disorder at all, it’s purely genetic, and because the dysfunction is on the X chromosome, and because females have two X chromosomes while males have XY, the male karyotype is more vulnerable to the condition.
I choose this extreme condition (suffered by one in 8500 females) as one among many examples of how our genetics can fail us, and there are many others, much more subtle and hard to pin down, both in terms of our genes themselves and how they are expressed. We – I mean the scientists and researchers among us, and those going along for the ride – have learned especially in recent decades just how complex and beyond our control our brains and bodies are, not just in terms of physical make-up, but genetic and cultural inheritance. A regular awareness of this – a mindfulness, if you like – helps me to cope with the people who damage our world – the war-mongers, the bullies, the intolerant and over-confident – as well as to sympathise with the overwhelmed (like myself).
So, again to epigenetics – I’ll keep trying to comprehend at least some of it, as it’s intrinsically interesting when it’s not completely baffling. Meanwhile, I’ve had a book recommended to me, by two humanists and no-free-will proponents, called Being: why it’s harder to be human than a hamster or a herring, by a daughter and father duo, Rachel and Ross Menzies. Sounds like an antidote to all that epiphenomena…
References
Nessa Carey, The Epigenetics Revolution: How modern biology is rewriting our understanding of genetics, disease and inheritance, 2011.
Pinker on free will, and more about myself
I’m still feeling anger, after all these years, at the free will proponents who, I feel, have benefitted from a cushy upbringing and have no idea what it’s like to have had nothing like the opportunities they’ve had. Of course, it’s always a worry that we can just attribute our relative failure to that lack of opportunity, but facts are facts, and it’s simply a fact that our macro world is determined.
And so to Steven Pinker, who, in his 2002 book The blank slate, ventured a few remarks on free will. I’ve written about Pinker before, and I consider it amusing to compare my life with his. We were both born in the mid 1950s’ – he’s a bit older – but that’s just about where the similarities come to an end (though I, too, have quite a big personal library – just saying). On the free will issue, I’d be inclined to make the small point, and I think Sapolsky makes it too, that successful career people would be more inclined to believe in free will than more or less abject failures – which of course isn’t saying anything about me.
Chapter 10 of The blank slate is titled ‘The fear of determinism’, and in it he starts looking at determinism from what I would call the wrong end – what he calls ‘molecules in motion’. My own thinking on this always starts from ‘thrown-ness into the world’, at an unchosen time and place, and as an unchosen living specimen. From there we get to our own parentage, our genes and our pre-natal and antenatal development, and their epigenetic effects.
Pinker also jumps quickly into the confusion I always find when I speak to people about this topic – that between determinism and predeterminism/fatalism:
‘All our brooding and agonising over the right thing to do is pointless, it would seem, because everything has already been preordained by the state of our brains’.
Pinker highlights the fear of determinism for a reason, claiming that ‘it is the existential fear of determinism that is the real waste of time’, though it seems to me that few people suffer such fear – and this appears to be borne out by experimental evidence. When we’re primed by tricky lab-coated types to reflect on ‘victims of circumstance’, there is an effect, but it appears to be minimal and short-term.
Of course, it isn’t the fear of determinism that concerns me, but the lack of acknowledgment of its factual basis. Pinker goes on a long and rather facile discourse about lawyers, medicos and neurologists seeking to get wrong-doers off the hook on the basis of defective genes and/or brain processes. Note that Sapolsky admits to having offered his services in this way, generally to no avail. I would note, just in passing, that the USA has the highest per capita incarceration rate in the WEIRD world, by a huge margin. It’s the land of free will after all. No excuses.
Some of Pinker’s ‘analyses’ here really miss the mark badly. For example, he references Dennett, who…
points out that the last thing we want in a soul is freedom to do anything it desires. If behaviour were chosen by an utterly free will, then we really couldn’t hold people responsible for their actions. That entity would not be deterred by the threat of punishment, or be ashamed by the prospect of opprobrium, or even feel the twinge of guilt that might inhibit a sinful temptation in the future, because it could always choose to defy those causes of behaviour….
And so on. But this is obvious bullshit – even if you fully believed in free will, the threat of imprisonment would be a massive deterrent, especially given the horrific private prisons of the US. And so would the opprobrium directed at you for your wrong-doing, given that we’re the most socially constructed mammalian species on the planet. Others’ opinions of us massively matter. Free will doesn’t preclude a sense of right and wrong. It should also be obvious that we are determined, by evolution, to survive and thrive as best we can – so in a world of severe punishments, such as exists in the USA, we’ll obviously be determined to avoid such punishments as best we can, even given a deprived background or a shrunken amygdala.
But where Pinker goes wrong in a way that is, to me, more offensive, is in his mockery of what he calls environmental determinism. It’s the typical upper middle class response, I must say:
The most risible pretexts for bad behaviour in recent decades have come not from biological determinism but from environmental determinism: the abuse excuse, the Twinkie defence, black rage, pornography poisoning, societal sickness, media violence, rock lyrics, and different cultural mores….
This little parade of glibness doesn’t, of course, begin to address any real issues. Firstly, there’s little real difference between biological and environmental determinism. Our biology evolves in adaptation to changing environments, as every evolutionary biologist knows, and, to be fair to Pinker, there has been a revolution in our understanding of environmentally-induced gene expression (epigenetics) in the two decades since The blank slate was published. Even so, my experience of growing up in a profoundly working-class environment, in which classroom illiteracy was commonplace, as well as vandalism, neglect and police harassment, makes me flare up when I hear the life-shattering experiences of kids in the street where I lived being dismissed in terms of ‘the abuse excuse’. I also note that in mocking these ‘excuses’ his target is invariably the lawyers (his own class) that bring these claims, rather than the accused themselves, about who’s background he appears to be indifferent. It’s the same clubbish elitism that I found in the dated Berofsky collection I re-read recently, but more focussed on law than philosophy.
Another of the irritations I found in revisiting Pinker’s determinism-free will piece, is that he focusses almost exclusively on crime, ignoring the much larger issues of lives lived in struggle because of determining forces beyond their control – a Palestinian in modern Israel, a woman in Afghanistan, a Dalit in India, an Australian Aboriginal at the time of the British colonisation of that island, a Jew growing up in Germany in the 1930s, the Tainos visited by the Spanish horror in the late 15th and 16th centuries, the Scots massacred in the reign of Edward I, the East Timorese massacred by Indonesian forces, the isolated old women burned as witches… millions of people who found themselves members of the wrong gender or ethnicity at the wrong time – murdered, raped, enslaved, or simply deprived of the means to live a life in which there’s some hope of an upward trajectory. None of us got to choose our ethnicity, our class (yes it does exist), our early upbringing, our parentage, even our level of intelligence, and this is so obvious, and so overwhelming a fact, that it seems to me almost embarrassing to have to point it out. And all of this is profoundly determining. That’s why reading history, as I often do, can be such an affecting experience. It is so full of innocent victims. And of course it continues….
So, finally, it isn’t the fear of determinism that should concern us – it’s the very fact of determinism.
I’ve been lucky, on balance. I was brought, as a five-year-old, to live in one of the richest and most peaceful nations in the world. I can’t praise or blame myself for this. Certain aspects of my treatment both at home and at school resulted in, for me, a fairly extreme anti-authoritarianism, and something of an over-self-reliance, which has its positives and negatives. But I benefitted from a world-full of books in our house, which took me to places of wonder outside myself. And I’ve benefitted from a nation with a strong social safety net, a minimum wage which is the highest of any nation outside of Luxembourg, a justice system that eliminated the death penalty nationwide almost 60 years ago, and a political system that was the first in the world to grant votes, and the right to stand for parliament, to women. It also rates as one of the least religious nations on earth – which for me is a godsend.
More on determinism from me, no doubt, as I plough into the second half of Sapolsky’s Determined.
References
Steven Pinker, The blank slate, 2002
Bernard Berofsky, Free will and determinism, 1963
Robert Sapolsky , Determined, 2023
reading matters 7
She has her mother’s laugh, by Carl Zimmer , science author and journalist, blogger, New York Times columnist, etc etc
content hints – inheritance and heredity, genetics and epigenetics, Darwin and Galton, the Hapsburg jaw, eugenics, Hugo de Vries, Theodor Boveri, Luther Burbank, Pearl and Carol Buck, Henry Goddard, The Kallikak Family, Hitler’s racial hygiene laws, morons, the five races etc, Frederick Douglass, Thomas Hunt Morgan, Emma Wolverton, PKU, chromosomal shuffling, meiosis, cultural inheritance, mitochondrial DNA, Mendel’s Law, August Weismann, germ and soma, twin studies, genetic predispositions, mongrels, Neanderthals, chimeras, exosomes, the Yandruwandha people, IVF, genomic engineering, Jennifer Doudna, CRISPR, ooplasm transfers, rogue experiments, gene drives, pluripotency, ethical battlegrounds.
Epigenetics 8: some terms
The gene is not more ‘basic’ than the organism, or closer to ‘the essence of life’, whatever that means. Organisms have DNA codes, and they maintain external forms and behaviours. Both are equal and fundamental components of being. DNA does not even build an organism directly, but must work through complex internal environments of embryological development, and external environments of surrounding conditions. We will not know the core and essence of humanity when we complete the human genome project.
Stephen Jay Gould, ‘Magnolias from Moscow’, in Dinosaur in a Haystack, 1996
I remember ages ago promising that I’d start every blog piece with a quote, then I more or less immediately forgot about it. Anyway the above quote kind of refers to epigenetics, and anticipates, in a way, the disappointment that many have felt about the human genome project and its not-quite-revelatory nature. As we learn more about the complexities of epigenetics, more about the relationships between genotype and phenotype will be revealed, but the process will surely be very gradual, though relentless. But I can’t talk, knowing so little. In this post, I’ll look at a very few key terms to help orient myself in this vast field. Not all will be specifically related to epigenetics, but to the whole field of DNA and genetics.
nucleosome: described as ‘the basic structural form of DNA packaging in eukaryotes’, it’s a segment of DNA wound round a histone ‘octamer’, a set of eight histones in a cubical structure. All of this is for fitting DNA into nuclei. Nucleosomes are believed to carry epigenetic info which modifies their core histones, and their positions in the genome are not random. Each nucleosome core particle consists of approximately 146 base pairs.
chromatin: a complex of DNA and protein, which packages DNA protectively, condensing the whole into a tight structure. Histones are essential components of chromatin. Chromatin structure is affected by methylation and acetylation of particular proteins, which in turn affects gene expression.
nucleotides: the basic building blocks of DNA and RNA, they consist of a nucleoside and a phosphate group. A nucleoside itself is a nitrogenous base (also known as a nucleobase) and a five-carbon sugar ribose (a ribose – these explanations always need more explaining – is a simple sugar, the natural form of which is D-ribose, and which comes in various structural forms). DNA and RNA are nucleic acid polymers made up of nucleotide monomers.
nucleobase: a nitrogenous base (e.g. adenine, cytosine, thymine, guanine, and uracil which replaces thymine in RNA), the fundamental units of our genetic code. Also simply known as a base.
base pairs: a base pair, in DNA, is one of the pairings adenine-thymine (A-T) or cytosine-guanine (C-G). They are pyrimidine-purine pairings. Adenine and guanine are purines, the other two pyrimidines. Due to their structure pyrimidines always pair with purines.
CpG islands: regions of DNA with a high frequency of CpG (C-G) sites, i.e. sites where a cytosine nucleotide is followed by a guanine nucleotide in linear sequence in a particular direction.
histones: highly alkaline proteins, the chief proteins of chromatin, and the means of ordering DNA into nucleosomes. There are four core histones, H2A, H2B, H3 and H4. These form an octamer structure, around which approximately 146 base pairs are wound.
Obviously, I’m very much a beginner at comprehending all this stuff, but I note that the number of videos on epigenetics seems to increase almost daily, which is raising my skepticism more than anything. I try to be selective in checking out these videos and other info on the topic, as there’s always this human tendency to claim super-solutions to our problems, as in super-foods and super-fitness regimes and the like. I’m more interested in the how of things, which is always a more complicated matter. Other information sources tend to assume knowledge or to skate over obvious complexities in a facile manner, and then of course there’s the ‘problem’ of being a dilettante, who wants to learn more about areas of scientific and historical knowledge often far removed from each other, and time’s running out, and we keep forgetting…
So anyway, I’ll keep plodding along, because it’s all quite interesting.
epigenetics and imprinting 7: more problems, and ICRs
the only image I can find that I really understand
In the previous post in this series I wrote about the connection between two serious disorders, Angelman syndrome and Prader-Willi syndrome, their connection to a missing small section of chromosome 15, and how they’re related to parental inheritance. These syndromes can sometimes also be traced back to uniparental disomy, in which the section of chromosome 15 is intact, but both copies are inherited from the mother (resulting in PWS) or the father (resulting in AS).
So the key here is that this small section of chromosome 15 needs to be inherited in the correct way because of the imprinting that comes with it. To take it to the genetic level, UBE3A is a gene which is only expressed from the maternal copy of chromosome 15. If that gene is missing in the maternal copy, or if, due to uniparental disomy, both copies of the chromosome are inherited from the father, UBE3A protein won’t be produced and symptoms of Angelman syndrome will appear. Similarly, PWS will develop if a certain imprinted gene or genes aren’t inherited from the father. Other imprinting disorders have been found, for example, one that leads to Beckwith-Wiedemann syndrome, though the mechanism of action is different, in that both copies of a gene on chromosome 11 are switched on when only the paternal copy should be expressed. This results in abnormal growth (too much growth) in the foetus. It too has an ‘opposite’ syndrome, Silver-Russell syndrome, in which the relevant protein expression is reduced, resulting in retarded growth and dwarfism.
But now to the question of exactly how genes are switched on and off, or expressed and repressed. DNA methylation, briefly explained in my first post on this topic, is essential to this. Methyl groups are carbon-hydrogen compounds which can be bound to a gene to switch it off, but here’s where I start to get confused. I’ll quote Carey and try to make sense of it:
… it may be surprising to learn that it is often not the gene body that is methylated. The part of the gene that codes for protein is epigenetically broadly the same when we compare the maternal and paternal copies of the chromosome. It’s the region of the chromosome that controls the expression of the gene that is differently methylated between the two genomes.
N Carey, The epigenetics revolution, 2011 p140
The idea, I now realise, is that there’s a section of the chromosome that controls the part of the gene that codes for the protein and it’s this region that’s differently methylated. Such regions are called imprinting control regions (ICRs). Sometimes this is straightforward, but it can get extremely complicated, with whole clusters of imprinted genes on a stretch of chromosome, being expressed from the maternally or paternally derived chromosomes, and not simply through methylation. An ICR may operate over a large region, creating ‘roadblocks’, keeping different sets of genes apart, and affecting thousands of base-pairs, not always in the same way. Repressed genes may come together in a ‘chromatin knot’, while other, activated genes from the same region form separate bundles.
Imprinting is a feature of brain cells – something which, as of the writing of Carey’s book (2011), is a bit of a mystery. Not so surprising is the number of expressed imprinted genes in the placenta, a place where competing paternal-maternal demands are played out. As to what is going on in the brain, Carey writes this:
Professor Gudrun Moore of University College London has made an intriguing suggestion. She has proposed that the high levels of imprinting in the brain represents a post-natal continuation of the war of the sexes. She has speculated that some brain imprints are an attempt by the paternal genome to promote behaviour in young offspring that will stimulate the mother to continue to drain her own resources, for example by prolonged breastfeeding.
N Carey, The epigenetics revolution, 2011. pp141-2
This sounds pretty amazing, but it’s a new epigenetic world we’re exploring. I’ll explore more of it next time.
References
The epigenetics revolution, by Nessa Carey, 2011
epigenetics and imprinting 6: when things go wrong
So imprinting involves parent-of-origin effects of which we find evidence in certain segments of certain chromosomes, in which genes are switched on or off, depending on inheritance. It often seems that these parent-of-origin effects counter-balance each other, as both parents have their own mutually exclusive way of trying to ensure the continuation of their genetic line.
It’ll be tough (for me) to take this down to a molecular level, but I’ll rely heavily on Nessa Carey’s book. It describes work on chromosome 7 in mice. I should first mention that there’s a convention in naming genes using italics, and the proteins they code for without italics. So there’s a gene in chromosome 7 called insulin-like growth factor 2 (Igf2) which promotes embryonic growth, and is usually expressed from the paternal copy. When researchers introduced a mutation which prevented the gene from effectively coding for the Igf2 protein, the offspring of this mutation were unaffected when the mutated gene was inherited from the mother, but the litter of offspring were much smaller when the gene was mutated in the father, showing that it was the paternal copy of the Igf2 gene that was required for foetal growth.
Fascinatingly for this ‘battle of the sexes’, there’s a gene in mouse chromosome 17 – Igf2r – which acts against the Igf2 protein, stopping it from promoting growth. This gene is also imprinted, from the maternal side. And so it goes.
According to Wikipedia, we now know of at least 80 imprinted genes in humans, mostly related to embryonic and placental growth and development. This is almost twice the amount Carey reported on less than a decade ago, so discoveries in this area are moving fast. As Carey writes, it’s uncertain whether there’s less imprinting in humans than in other mammals (we know of about 150 imprinted genes in mice) or whether they’re just harder to detect. Imprinting evolved about 150 million years ago (how do they know that? – as the much-treasured Bill Bryson would say), and is particularly prevalent amongst placental mammals.
This post was supposed to be about the mechanisms involved in imprinting, but my vast readership will have to wait awhile. I’m going to follow Carey, because I’m learning a lot from her, into the next area she writes about – ‘when imprinting goes bad’. She describes two very different conditions from birth, Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Researchers separately studying these conditions found that the parents of the sufferers were usually healthy, yet everything pointed to something genetic going on, presumably during the production of eggs or sperm.
The separate work on the origins of these two permanently debilitating but very different conditions eventually converged, when it was found that in both AS and PWS, the patients were missing a small, identical stretch of chromosome 15. What caused the two entirely different results of this defect was whether it was inherited from the mother (resulting in AS) or the father (resulting in PWS). So the disorder is epigenetically inherited, a further example of a parent-of-origin effect.
Yet some children inherit these disorders without any deletions to chromosome 15. They have two normal copies of chromosome 15 but not from each parent. Instead they have two copies from the mother and none from the father – called uniparental disomy. In another variation on the theme it was later discovered that AS was in some cases caused by the opposite form of uniparental disomy, in which two normal copies of the chromosome were inherited from the father. So, because the particular region of the chromosome is normally imprinted, it’s essential, for healthy offspring, that the region is inherited in the ‘correct’ way, from each parent.
I’ll be looking at more examples of problematic inheritance and imprinted genes next time.
References
https://en.wikipedia.org/wiki/Genomic_imprinting
Nessa Carey, The epigenetics revolution, 2011
epigenetics and imprinting 5: mouse experiments and chromosome 11
So we were looking at how we – mammals amongst others – are engaged in a kind of battle for the best way to ensure our genetic survival into the future, beyond our insignificant little selves. This battle begins in the very early phase of life, as zygotes multiply to form a blastocyst.
Remember from my last post on this topic, the male mammal is interested in the offspring above all else. He’s even happy to sacrifice the mother for the sake of the child – after all there’s plenty more fish in the sea (or mammals in the – you know what I mean). The female, on the other hand, is more interested in self-preservation than in this pregnancy. She wants more than one chance to pass on her genes.
So, by the blastocyst stage, cells have differentiated into those that will form the placenta and those that will form the embryo itself. Experiments on mice have helped to elucidate this male-female genetic struggle. Mouse zygotes were created which contained only paternal DNA and only maternal DNA. These different zygotes were implanted into the uterus of mice. As expected, the zygotes didn’t develop into living mice – it takes DNA from both sexes for that. The zygotes did develop though, but with serious abnormalities, which differed depending on whether they were ‘male’ or ‘female’. In those in which the chromosomes came from the mother, the placental tissues were particularly underdeveloped. For those with the male chromosomes, the embryo was in a bad way, but the placental tissues not so much.
In short, these and other experiments suggested that the male chromosomes favoured placental development while the female chromosomes favoured the embryo. Thus, the male chromosomes are ‘aiming’ to build up the placenta to drain as many nutrients as possible from the mother and feed them into the foetus. The female chromosomes have the opposite aim, resulting in a ‘fine balance’ in the best scenarios.
Further work in this area has identified particular chromosomes responsible for these developments, and some of the epigenetic factors involved. For example, mouse chromosome 11 is important for offspring development. When the offspring inherits a copy of chromosome 11 from each parent, the offspring will be of normal size. If both copies come from the mother it will abnormally small, while if both come from the father it will be abnormally large. These experiments were carried out on inbred mice with identical DNA. Nessa Carey summarises:
If you sequenced both copies of chromosome 11 in any of the three types of offspring, they would be exactly the same. They would contain the same millions of A, C, G and T base-pairs, in the same order. But the two copies of chromosome 11 do clearly behave differently at a functional level, as shown by the different sizes of the different types of mice. Therefore there must be epigenetic differences between the maternal and paternal copies of chromosome 11.
So this means that chromosome 11 is an imprinted chromosome – or at least certain sections of it. This is the same for other chromosomes, some of which aren’t imprinted at all. But how is it done? That’s the complex biochemical stuff, which I’ll try to elucidate in the next post on this topic.
Footnote: the photo above shows a bi-maternal mouse with healthy offspring, and further work in deleting imprinted genetic regions has allowed researchers to create healthy bi-paternal mice too. There’s a fascinating account of it here.
References:
Nessa Carey, The epigenetics revolution, 2011
https://www.the-scientist.com/news-opinion/first-mouse-embryos-made-from-two-fathers-64921
epigenetics and imprinting 4: the male-female thing
Gametes are gametes because of epigenetic modifications in their pro-nuclei, but they have to lose these modifications, or transform them, when they come together to form zygotes. The male pro-nucleus DNA methylation is stripped away immediately after sperm penetrates egg. The egg pronucleus undergoes the same process, but more gradually. It’s like a wiping away of epigenetic memory, creating totipotency, which becomes a more limited pluripotency as the blastocyst, with its inner cell mass (ICM), forms.
The ICM cells begin differentiating through the regulation of some key genes. For example, a gene codes for a protein that switches on a set of genes, which code for proteins in a cascading effect. But it’s not quite a matter of switching genes on or off, it’s rather more complex. The process is called gene reprogramming, and it’s of course done effortlessly during every reproductive cycle. Artificial reprogramming of the kind carried out by Yamanaka and others, an essential part of cloning, hasn’t come close to this natural process that goes on in mammals and other species every day.
Clearly, though the epigenetic reprogramming for the female pronucleus is different from that carried out more swiftly in the male. As Carey puts it, ‘the pattern of epigenetic modifications in sperm is one that allows the male pronucleus to be reprogrammed relatively easily.’ Human researchers haven’t been particularly successful in reprogramming an adult nucleus by various methods, such as transferring it to a fertilised egg or treating it with the four genes isolated by Yamanaka. The natural process of gene reprogramming eliminates most of the epigenetic effects accumulated in the parent genes, but as the reprogramming is a different process in the male and female pro-nucleus, this shows that they aren’t functionally equivalent. There is a ‘parent-of-origin effect’. Experiments done on mice to explore this effect found that DNA methylation, an important form of chromatin modification (and the first one discovered), was passed on to offspring by the female parent. That’s to say, DNA from the female was more heavily methylated than that from the male. Carey describes the DNA as ‘bar-coded’ as coming from the male or the female. The common term for this is imprinting, and it’s entirely epigenetic.
Imprinting has been cast by Carey, and no doubt others, as an aspect of the ‘battle of the sexes’. This battle may well be imprinted in the pronuclei of the fertilised egg. Here’s how Carey puts the two opposing positions:
Male: This pregnant female is carrying my genes in the form of this foetus. I may never mate with her again. I want my foetus to get as big as possible so that it has the greatest chance of passing on my genes.
Female: I want this foetus to pass on my genes. But I don’t want it to be at the cost of draining me so much that I never reproduce again. I want more than this one chance to pass on my genes.
So there’s a kind of balance that has developed in we eutherian mammals, in a battle to ensure that neither sex gains the upper hand. Further experiments on mice in recent times have explored how this battle is played out epigenetically. I’ll look at them in the next post in this series.
Reference
The Epigenetics Revolution, by Nessa Carey, 2011