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Posts Tagged ‘genetics

returning to the race myth

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‘My own personal view is that today we over-privilege and fetishise the concept of identity’.

Mark Thomas,  Professor of evolutionary genetics, University  College, London (quoted in  Superior: the return of race science, by Angela Saini, 2019)

A couple of years ago I tackled issues of race and identity politics in a post which focussed on ‘blackface’ among other things. I don’t think there’s much I’d change about it, but my current reading of Angela Saini’s above-mentioned book, in particular the chapter ‘Roots’, which relates what anthropology has found regarding the first indicator of race amongst those who tend to obsess over it, namely skin colour, has updated my knowledge without really changing my outlook.

When we think of ‘white’ people one of the most obvious examples would be the pale, cold-weather Scots, of which I’m one. We’re not called WASPs for nothing. I was amused as an adult to find paperwork indicating that I was baptised as a Presbyterian. WTF is that? Another funny thing about my waspness is the fact that I’ve lived in sunny Australia since the age of five, my skin darkening quite splendidly every summer in the pre-sunblock era. Needless to say my intelligence dipped sharply during those months.

Saini relates a story about a 1903 archaeological discovery in Somerset, of one of the oldest human bodies ever found in Britain. Dating back some 10,000 years, he was given the name Cheddar Man as he was discovered in caves at Cheddar Gorge, and much more recently he was analysed by genetic sequencing. There was naturally a lot of interest in the genetics of this fellow, as English, or British, as cheddar cheese.

… what came as a real shock to many was that his bones… carried genetic signatures of skin pigmentation more commonly found in sub-Saharan Africa. It was probable, then, that Cheddar Man would have had dark skin. So dark, in fact, that by today’s standards he would be considered black.

Superior, Angela Saini, p167

Visual reconstructions based on the genetics also showed him to be far less WASP-looking than genteel society might condone. It was front-page news stuff, but experienced geneticists such as Mark Thomas were unfazed. The fact is that modern genomics has probably done more than anything else to scuttle the notions of fixed identities relating to blackness, whiteness, Europeaness, Asianess, Africaness, Scandinavianess or Irishness. In short the necessity of ness-ness ain’t necessarily so.

This has everything to do with genetic drift. As Thomas explains it, in pre-civilisation times, humans migrated in small groups, and would have varied physically (and of course in other ways) from those they separated from. Later, as groups grew and became more stable, there would have been an opposite effect, a greater homogeneity. Thus we see ‘Asians’, ‘Africans’ and ‘Europeans’, from our limited perspective, as near-eternal categories when in fact they’re relatively recent, and of course disintegrating with globalisation – an extremely recent phenomenon, genomically speaking.

On ‘blackness’ itself, that may have been a more recent phenomenon in our ancestry than ‘whiteness’. My good friends the bonobos, and their not-so-nice chimp cousins, tend to have light skin under their dark hair. As we moved forward in time from our ancestral link with chimps and bonobos, losing our body hair and increasing the number of sweat glands as we became more bipedal and used our speed for hunting, there would have been a selection preference for darker skin – again depending on particular environmental conditions and cultural practices. There is of course a quite large gap in our knowledge about early hominids (and there is controversy about how far back we should date the bonobo-human last common ancestor – identifying Graecopithecus as this ancestor tends to push the date further back) considering that Homo Habilis, which dates back, as far as we know, to 2.3 million years ago is the oldest member of our species identified so far. Beyond H habilis we have the Australopithecines, Ardipithecines, Sahelanthropus Tchadensis and Orrorin tugenensis, among others, which may take us back some 7 million years. DNA analysis can only take us back a few thousand years, so I don’t know how we’re ever going to sort out our deeper ancestry.

In any case, the new racial ‘ideas’, given impetus by various thugocracies in the former Yugoslavia as well as today’s Burma/Myanmar, China, India and the USA (where it may yet lead to civil war) are an indication of the fragility of truth when confronted and assaulted by fixed and fiercely held beliefs. Social media has become one of the new and most effective weapons in this assault, and when thugocracies gain control of these weapons, they become so much more formidable.

Truth of course, is, and should be its own weapon against identity politics. Knowledge should be the antidote to these supposedly indelible identities, of blackness, whiteness, Jewishness, Hindu-ness and so on. Unfortunately, too many of us are interested in confirmation than in truth. In fact, according to the psychologists Hugo Mercier and Dan Sperber, in their book The enigma of reason, we use reason more often to confirm beliefs that we want to be true than for any other purpose. And when enough of the ruling class are concerned to confirm erroneous beliefs that happen to advantage them, as is the case for the current Indian Hindu government, the result is a thugocracy that oppresses women as well as the so-called ‘untouchables’ and other victims of the two-thousand year old caste system.

But having just read the chapter entitled ‘Caste’ of Angela Saini’s book, I should modify those remarks. The current Indian government is only reinforcing a system the disadvantages of which are more clear to ex-pats like Saini (and some Indian students I’ve had the pleasure of teaching) than it is to those that remain and ‘belong’. It involves more than just caste and religion, as it’s practiced by Christians and others, and enforced by families and broader relational and cultural units. My own detachment from family and cultural constraints makes it easy for me to judge this rather harshly. And in faraway Australia we hear of the horrors of in-group fealty without feeling its comforts. And naturally as a working-class lad and anti-authoritarian my sympathies are definitely with the underclass.

So how do we overcome the inwardness of caste and class systems, which are ultimately destructive of genetic diversity, not to mention causing the immiseration of millions? The answer, also provided by Mercier and Sperber’s thesis, is interaction and argument. They argue that reason developed as a social rather than an individual phenomenon. Evidence of course also must play a part. Saini’s book provides an excellent example of this, and the scientific community generally does too. Mercier and Sperber give an interesting example of how the marketplace of ideas can produce effective results over time:

The British abolitionists didn’t invent most of the arguments against slavery. But they refined them, backed them with masses of evidence, increased their credibility by relying on trustworthy witnesses, and made them more accessible by allowing them to see life through a slave’s eyes. Debates, public meetings, and newspapers brought these strengthened arguments to a booming urban population. And it worked. People were convinced not only of the evils of slavery but also of the necessity of doing something about it. They petitioned, gave money, and – with the help of other factors, from economy to international politics – had first the slave trade and then slavery itself banned.

The enigma of reason: a new theory of human understanding, H Mercier & D Sperber, p314

Some would say, of course, that slavery is still flourishing. I’ve even heard the claim that Jeff Bezos is the quintessential modern slave-owner. But nobody is credibly claiming today that slavery is reasonable. It has long ago lost the argument. That’s why evidence-based argument is our best hope for the future.

References

Superior: the return of race science, Angela Saini, 2019

The enigma of reason: a new theory of human understanding, Hugo Mercier & Dan Sperber, 2017.

 

Written by stewart henderson

June 17, 2021 at 8:51 pm

reading matters 7

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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.

Written by stewart henderson

July 28, 2020 at 12:22 pm

Pinning down meiosis: sperm, mainly

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the reassortment of DNA during meiosis 1

Canto: Not very long ago I was reading Carl Zimmer’s book She has her mother’s laugh, and he was explaining meiosis. It was exciting, because I think I understood it. Being a regular science reader I’d read about meiosis and mitosis before but I could never remember, or perhaps I never clearly knew, the difference. But this time was different, and I thought ‘Yes!’, or maybe ‘Eureka!’ sounds better, because not only did I get it, or thought I did, but I thought ‘this is a new weapon against those who say they don’t believe in evolution’. There’s a fellow-teacher at my college who actually says this, but I’ve never really confronted her on it, apart from some mutterings.

Jacinta: So please explain yourself. Meiosis and mitosis are about cell division aren’t they?

Canto: Well I can’t explain myself, but at the time I thought ‘here’a new one-word response to those who say they don’t believe in evolution’. The other one-word responses being ‘genes’, ‘genetics’, ‘genomics’ and other variants. Well okay, I can give a partial explanation. Most everyone believes in evolution, that’s why they use smart phones rather than the earlier types of mobile phones or landlines or whatever. That’s why they use dishwashers and modern washing machines and modern computers, and drive modern cars instead of a horse-and-carriage, because evolution just means progressive development. What my fellow-teacher really should be saying is she doesn’t believe in the Darwin-Wallace theory of natural selection from random variation, but she doesn’t say that because I strongly suspect she doesn’t have a clue what that means.

Jacinta: Right, so she doesn’t believe in the particular theory…

Canto: Which is proven by genes, the essential mechanism of random variation, which of course Darwin was completely unaware of. And by meiosis, another essential source of variety.

Jacinta: So, meiosis. It’s quite complex. Zimmer gives a brief explanation as you say, and there’s also a number of videos, from Khan Academy, Crash Course Biology and others, so let’s try to describe it for ourselves, with emphasis on variety or variation, which is the essential thing.

Canto: Mitosis, and hopefully I now will never forget this, is the cell division and replication that goes on in our bodies at every moment, and which enables us to grow from a foetus to a strapping lad or lassie, to heal wounds and even to have multiple times more neurons than old fatty Frump, maybe. It occurs among the somatic cells, and it essentially does it by replicating cells exactly, like replacing or adding to like.

Jacinta: But not exactly, otherwise we’d just be a growing blob of undifferentiated body cells, not liver, brain, blood, skin and other cells. That takes epigenetics, as I recall. Mitotically-created cells are identical as to chromosomes, but not as to expression. But anyway, meiosis. That’s how our germ cells are replicated.

Canto: Egg and sperm cells, together known as gametes. Khan Academy begins its article on meiosis with this:

meiosis in humans is a division process that takes us from a diploid cell—one with two sets of chromosomes—to haploid cells—ones with a single set of chromosomes. In humans, the haploid cells made in meiosis are sperm and eggs. When a sperm and an egg join in fertilization, the two haploid sets of chromosomes form a complete diploid set: a new genome.

All fine, though this division process is damn complicated as we’ll discover. But what interested me in Zimmer’s account was this, and I’ll quote it at length, because it’s what got me excited about variation:

In men, meiosis takes place within a labyrinth of tubes coiled within the testicles. The tube walls are lined with sperm precursor cells, each carrying two copies of each chromosome, one from the man’s mother, the other from his father. When these cells divide, they copy all their DNA, so that now they have four copies of each chromosome. Rather than drawing apart from each other, however, the chromosomes stay together. A maternal and paternal copy of each chromosome line up alongside each other. Proteins descend on them and slice the chromosomes, making cuts at precisely the same spots.

As the cells repair these self inflicted wounds, a remarkable exchange can take place. A piece of DNA from one chromosome may get moved to the same position in the other, its own place taken by its counterpart. This molecular surgery cannot be rushed. All told, a cell may need three weeks to finish meiosis. Once it’s done, its chromosomes pull away from each other. The cell then divides twice, to make four new sperm cells. Each of the four cells inherits a single copy of all 23 chromosomes. But each sperm cell contains a different assembly of DNA.

Think of this last line – each sperm cell contains a different assembly of DNA.

Jacinta: Yes, and there can be up to a billion sperm cells released in each ejaculate, but who’s counting? And are they all different?

Canto: Apparently so. Even the Daily Mail says so, so it must be true. And when you think of it, if there weren’t differences, each offspring born from that man’s sperm would be a clone…

Jacinta: Not necessarily – what about the egg cells?

Canto: Yes, I believe it’s the same meiosis process with them, though not quite. Anyway, there’s the same mixing of chromosomes, so the chances of any two egg cells, or I should say their chromosomal complement, being identical is extremely small.

Jacinta: So, meiosis – I’ve been trying to pin it all down, but I don’t feel I’ve succeeded. Here goes, anyway. Meiosis is a special type of reproduction, confined only to our germ cells, the sperm and egg cells. The gametes. The haploid cells. As opposed to the diploid cells which make up all the somatic or body cells we have. That’s to say, those cells reproduce differently from diploid, somatic cells. But before I try to explain the complex process of their reproduction, what about their production? Where do these haploid cells come from? Now I might answer glibly that the egg cells, also called oocytes, come from the ovaries, and the spermatozoa come from the testes, but that’s not really my question.

Canto: In fact I’m not even sure if you’ve got it right so far. The egg cell is called an ovum. An oocyte is a precursor egg cell I think. I’m not sure if it matters much, but we’re looking at the production of these gametes. Presumably the kinds of gametes we produce depends on our gender, which is determined at conception? Of course, in these gender-bending days, who knows.

Jacinta: Oh dear. Let’s try not to get confused. Assume an embryo or foetus is straightforwardly male or female, or potentially so. I seem to recall that males only start producing sperm at puberty, whereas females produce all their egg cells before that, and only have a fixed number, and egg cells are quite huge in comparison to sperm, and even compared to your average somatic cells – though some neurons have super-long axons. When females reach the stage of menstruation, that’s when they start releasing eggs.

Canto: Okay in the above quote from Zimmer, sperm precursor cells are mentioned. They’re also called spermatocytes, and the labyrinth of coiled tubes he also mentions are the seminiferous tubules. This is where the meiosis happens, in males. There are two types of spermatocyte, primary and secondary. The primary spermatocytes are diploid, and the secondary, formed after the first meiosis process (meiosis 1), are haploid.

Jacinta: To possibly confuse matters further, there’s a multi-stage process happening in those seminiferous tubules, a process called spermatogenesis. It starts with the spermatogonia (and maybe we’ll leave the spermatogonium’s existence for another post), which are processed into primary spermatocytes, then into secondary spermatocytes, then into spermatids, then to sperm.

Canto: Yes, so the first step you mention is mitotic, with diploid cells creating diploid cells, the primary spermatocytes…

Jacinta: And mitosis has those four steps or phases – PMAT, as students recall it; prophase, metaphase, anaphase and telophase, while meiosis has the same but in two parts, PMAT for meiosis 1 and PMAT for meiosis 2. So as we’ve already pointed out, this double-doubling process has a final result of four new cells. Now, before meiosis 1, the cells go through interphase, but I won’t detail that here. In prophase 1, chromosomes are brought together in pairs, called homologues. Their alleles are aligned together, but then this more or less random ‘crossing over’ occurs, presumably with the aid of some busy little proteins, which mixes the chromosomes up. Each homologue pair can have many of these crossovers. More mixing happens during metaphase 1, when homologue pairs, with their crossings-over, line up randomly at the metaphase plate. I’m not pretending to fully understand all this, but the main point is that the variety we find in the final product, the sperm cells, is brought about essentially during prophase and metaphase in meiosis 1 of the double cycle.

Canto: It does get me more interested in understanding meiosis more fundamentally though, as well as mitosis. The phases and the processes that bring them about, the proteins, the chromatin, the centromeres, the metaphase plate, and of course oogenesis, polar bodies and much much more.

Jacinta: Yes – I think meiosis does point to a lot of the variation in the world of organisms, but it would be hard to get those who ‘don’t believe in evolution’ to think about this and its relevance. They tend not to listen to explanations or to want to make connections.

Canto: You can give up on them or keep plugging away with the ‘what about this?’ or ‘can you explain that?’ Or demonstrate to them directly or indirectly, the results of those powerful explanations, in medicine, in astronomy, in our technology, and in our human relations.

References

She has her mother’s laugh: the powers, perversions and potential of heredity, by Carl Zimmer, 2018

https://en.wikipedia.org/wiki/Meiosis

https://www.khanacademy.org/science/biology/cellular-molecular-biology/meiosis/a/phases-of-meiosis

https://www.yourgenome.org/facts/what-is-meiosis#:~:text=Meiosis%20is%20a%20process%20where,to%20form%20four%20daughter%20cells.

Written by stewart henderson

May 31, 2020 at 9:18 pm

a DNA dialogue 5: a first look at DNA replication

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schematic of ‘replisome’ structures involved in DNA replication

 

Jacinta: So let’s scratch some more of the surface of the subject of DNA and genetics. A useful datum to remember, the human genome consists of more than 3 billion DNA bases. We were talking last time about pyrimidines and purines, and base pairs. Let’s talk now about how DNA unzips.

Canto: Well the base pairs are connected by hydrogen bonds, and the two DNA strands, the backbones of the molecule, run in opposite, or anti-parallel, directions, from the 5′ (five prime) end to the 3′ (three prime) end. So, while one strand runs from 5′ to 3′ (the sense strand), the other runs 3′ to 5′ (the antisense strand). 

Jacinta: Right, so what we’re talking about here is DNA replication, which involves breaking those hydrogen bonds, among other things. 

Canto: Yes, so that backbone, or double backbone whatever, where the strands run anti-parallel, is a phosphate-sugar construction, and the sugar is deoxyribose, a five-carbon sugar. This sugar is oriented in one strand from 5′ to 3′, that’s to say the 5′ carbon connects to a phosphate group at one end, while the 3′ carbon connects to a phosphate group at the other end, while in the other strand the sugar is oriented in the opposite direction. 

Jacinta: Yes, and this is essential for replication. The protein called DNA polymerase should be introduced here, with thanks to Khan Academy. It adds nucleotides to the 3′ end to grow a DNA strand…

Canto: Yes, but I think that’s part of the zipping process rather than the unzipping… it’s all very complicated but we need to keep working on it…

Jacinta: Yes, according to Khan Academy, the first step in this replication is to unwind the tightly wound double helix, which occurs through the action of an enzyme called topoisomerase. We could probably do a heap of posts on each of these enzymes, and then some. Anyway, to over-simplify, topoisomerase acts on the DNA such that the hydrogen bonds between the nitrogenous bases can be broken by another enzyme called helicase.

Canto: And that’s when we get to add nucleotides. So we have the two split strands, one of which is a 3′ strand, now called the leading strand, the other a 5′ strand, called the lagging strand. Don’t ask.

Jacinta: The leading strand is the one you add nucleotides to, creating another strand going in the 5′ to 3′ direction. This apparently requires an RNA primer. Don’t ask. DNA primase provides this RNA primer, and once this has occurred, DNA polymerase can start adding nucleotides to the 3′ end, following the open zipper, so to speak.

Canto: The lagging strand is a bit more complex though, as you apparently can’t add nucleotides in that other direction, the 5′ direction, not with any polymerase no how. So, according to Khan, ‘biology’ adds primers (don’t ask) made up of several RNA nucleotides.

Jacinta: Again, according to Khan, the DNA primase, which works along the single strand, is responsible for adding these primers to the lagging strand so that the polymerase can work ‘backwards’ along that strand, adding nucleotides in the right, 3′, direction. So it’s called the lagging strand because it has to work through this more long, drawn-out process.

Canto: Yes, and apparently, this means that you have all these fragments of DNA, called Okazaki fragments. I’m not sure how that works…

Jacinta: Let’s devote our next post on this subject entirely to Okazaki fragments. That could clarify a lot. Or not.

Canto: Okay, let’s. Goody goody gumdrops. In any case, these fragments can be kind of sewn together using DNA ligase, presumably another miraculous enzyme. And the RNA becomes DNA. Don’t ask. I’m sure all will be revealed with further research and investigation.

References

Leading and lagging strands in DNA replication (Khan Academy video)

https://www.quora.com/What-is-DNA-unzipping

https://www.yourgenome.org/facts/what-is-dna-replication

Written by stewart henderson

February 26, 2020 at 10:59 pm

a DNA dialogue 3: two anti-parallel strands

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but why the twist? – we don’t know yet

Jacinta: Ok so these two strands of DNA are described as anti-parallel. Is this just intended to confuse us?

Canto: Apparently not, in fact it’s quite essential. The useful q&a site Quora has good info on this, and understanding it in all its complexity should help us to understand DNA general – it’s one of a thousand useful entry points.

Jacinta: Yes, and I’ll try to explain. It became clear to us last time that the strands or ribbons twisted round in a double helix, called the backbone of the molecule, are made from phosphate and deoxyribose sugar, covalently bonded together. That means tightly bonded. Between the two strands, connecting them like ladder rungs, are nitrogenous bases (this is new to us). That’s adenine, thymine, guanine and cytosine, bonded together – A always to T, and C to G – with weak hydrogen bonds. We’ll have to look at why they must be paired in this way later.

Canto: It’s called Chargaff’s base pairing rule, which doesn’t tell us much.

Jacinta: And, according to a respondent from Quora, ‘the two strands of DNA are anti-parallel to each other. One of them is called leading strand, the other is lagging strand’. But I don’t quite get this. How are there two strands of DNA? I thought there was one strand with two sugar-phosphate backbones, and a rung made up of two – nitrogenous nucleobases? – weakly connected by hydrogen bonds.

Canto: I think the idea is there are two strands, with the attached bases, one next to another on the strand, and weakly attached to another base, or set of bases each attached to another phosphate-sugar backbone. As to why the whole thing twists, rather than just being a straight up-and-down ladder thing, I’ve no idea. Clearly we’re a couple of dopey beginners.

Jacinta: Well, many of the Quora respondents have been teaching molecular biology for years or are working in the field, and just skimming through, there’s a lot be learned. For now, being anti-parallel is essential for DNA replication – which makes it essential to DNA’s whole purpose if I can call it that. I’ll also just say that the sugars in the backbone have directionality, so that the way everything is structured, one strand has to go in the opposite direction for the replication to work. If for example the strands were facing in the same direction, then the base on one side would connect to a hydrophobic sugar (a good thing) but the base on the other side would be facing a hydrophilic phosphate (a bad thing). Each base needs to bond with a sugar – that’s to say a carbon atom, sugar being carbon-based – so one strand needs to be an inversion of the other. That’s part of the explanation.

Canto: Yes, I find many of the explanations are more like descriptions – they assume a lot of knowledge. For example one respondent says that the base pairs follow Chargaff’s rule and that means purines always pair up with pyrmidines. Not very helpful, unless maybe you’re rote-learning for a test. It certainly doesn’t explain anti-parallelism.

Jacinta: Well, although we don’t fully understand it yet, it’s a bit clearer. Anti-parallelism is an awkward term because it might imply, to the unwary, something very different from being parallel. The strands are actually parallel but facing in the opposite direction, and when you think about the structure, the reason for that becomes clearer. And imagining those backbone strands facing in the same direction immediately shows you the problem, I think.

Canto: Yes and for more insight into all that, we’ll need to look more closely at pyrmidines and purines and the molecular structure of the backbone, and those bases, and maybe this fellow Chargaff.

References

https://www.quora.com/Why-are-DNA-strands-anti-parallel

https://slideplayer.com/slide/13304243/

Written by stewart henderson

January 21, 2020 at 2:38 pm

epigenetics and imprinting 5: mouse experiments and chromosome 11

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something new, since Carey’s book was published – a healthy mouse, from entirely maternal DNA, with healthy offspring – and in 2018 a healthy bi-paternal mouse was created

 

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

Written by stewart henderson

January 19, 2020 at 12:26 pm

A DNA dialogue 1: the human genome

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what genomics tells us

Canto: I’m often confused when I try to get my head around all the stuff about genes and DNA, and genomes and alleles and chromosomes, and XX and XY, and mitosis and meiosis, and dominant and recessive and so on. I’d like to get clear, if only I could.

Jacinta: That’s a big ask, and of course we’re both in the same boat. So let’s use the magical powers of the internet to find answers. For example, here’s something that confuses me. The Human Genome project, which ended around the year 2000, involved a mapping of the whole human genome, and that includes coding and non-coding genes, and I think it was found to contain 26,000 or so – what? Letters? Genes? Coding genes? Anyway there’s a number of questions there, but they’re not the questions that confuse me. I don’t get that we now, apparently, have worked out the genetic code for all humans, but each of us has different DNA. How, exactly, does our own individual DNA relate to the genome that determines the whole species? Presumably it’s some kind of subset?

Canto: Hmmm. This article from the Smithsonian tells us that the genetic difference between human individuals is very tiny, at around 0.1%. We humans differ from bonobos and chimps, two lineages of apes that separated much more recently, by about 1.2%….

Jacinta: Yes, yes, but how, with this tiny difference between us, are we able to use DNA forensically to identify individuals from a DNA sample?

Canto: Well, perhaps this Smithsonian article provides a clue. It says that the 1.2% difference between us and chimps reflects a particular way of counting. I won’t go into the details here but apparently another way of counting shows a 4-5% difference.

Jacinta: We probably do need to go into the details in the end, but clearly this tiny .1% difference between humans is enough for us to determine the DNA as coming from one individual rather than 7 to 8 billion others. Strangely enough, I can well believe that, given that we can detect gravitational waves and such – obviously using very different technology.

Canto: Yeah the magic of science. So the Human Genome Project was officially completed in April 2003. And here’s an interesting quote from Wikipedia:

The “genome” of any given individual is unique; mapping the “human genome” involved sequencing a small number of individuals and then assembling these together to get a complete sequence for each chromosome. Therefore, the finished human genome is a mosaic, not representing any one individual.

Of course it would have to be a mosaic, but how can it represent the whole human genome when it’s only drawn from a small number? And who were these individuals, how many, and where from?

Jacinta: The Wikipedia article does give more info on this. It tells us that the project isn’t really finished, as we’ve developed techniques and processes for faster and deeper analyses. As to your questions, when the ‘finished’ sequencing was announced, the mosaic was drawn from a small number of anonymous donors, all of European origin.

Canto: But we all originated from Africa anyway, so…

Jacinta: So maybe recent ‘origin’ isn’t so important. Anyway, that first sequencing is now known as the ‘reference genome’, but after that they did sequence the genomes of ‘multiple distinct ethnic groups’, so they’ve been busy. But here are some key findings, to finish off this first post. They found some 22,300 protein-coding genes, as well as a lot of what they used to call junk DNA – now known as non-coding DNA. That number is within the mammalian range for DNA, which no doubt surprised many. Another blow for human specialness? And they also found that there were many more segmental duplications than expected. That’s to say, sections of DNA that are almost identically repeated.We’ll have to explore the significance of this as we go along.

Canto: Yes, that’s enough for starters. Apparently our genome has over 3 billion nucleobase pairs, about which more later no doubt.

References

http://humanorigins.si.edu/evidence/genetics

https://en.wikipedia.org/wiki/Human_Genome_Project

Written by stewart henderson

January 13, 2020 at 11:48 pm

epigenetics and imprinting 3: at the beginning

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stuff that can be done with iPS cells

A zygote is the union of two gametes (haploid cells), the sperm and the egg. It’s the first diploid cell, from which all the other diploid cells – scores of trillions of them – are formed via mitosis.

What’s interesting about this from an epigenetic perspective is that gametes are specialised cells, but zygotes are essentially totipotent – the least specialised cells imaginable – and all this has to do with epigenetics.

I’m not entirely clear about what happens to turn specialist gametes into totipotent zygotes, and that’s what I’m trying to find out. I’m not sure yet whether zygotes immediately start differentiating as they divide and multiply or whether the first divisions – in what is called the zygote phase, which eventually forms the blastocyst – form an identical set of zygotes. 

The two-week period of these first divisions is called the germinal phase. During this phase zygotes divide mitotically while at the same time moving, I’m not sure how, from the fallopian tube to the uterus. Apparently, after the first few divisions, differentiation starts to occur. The cells also divide into two layers, the inner embryo and the outer placenta. The growing group of cells is called a blastocyst. The outer layer burrows into the lining of the uterus and continues to create a web of membranes and blood vessels, a fully developed placenta.

But, as Nessa Carey would say, this is a description not an explanation. How does this initial cell differentiation – into the outer layer (trophectoderm), which becomes the placenta and other extra-embryonic tissues, and the inner cell mass (ICM) – come about? Understanding these mechanisms, and the difference between totipotent cells (zygotes) and pluripotent cells (embryonic stem cells) is clearly essential for comprehending, and so creating, particular forms of life. This PMC article, which examines how the trophectoderm is formed in mice, demonstrates the complexity of all this, and raises questions about when the ‘information’ that gives rise to differentiation becomes established in these initial cells. Note for example this passage from the article, which dates to 2003:

It is now generally accepted that trophectoderm is formed from the outer cell layer of the morula, while the inner cells give rise to the ICM, which subsequently forms the epiblast and primitive endoderm lineages. What remains controversial, however, is whether there is pre-existing information accounting for these cell fate decisions earlier than the 8-cell stage of development, perhaps even as early as the oocyte itself. 

The morula is the early-stage embryo, consisting of 16 totipotent cells. The epiblast is a slightly later differentiation within the ICM. An oocyte is a cytoplasm-rich, immature egg cell.

Molecular biologists have been trying to understand cell differentiation by working backwards, trying to turn specialised cells into pluripotent stem cells, mostly through manipulating their nuclei. You can imagine the benefits, considering the furore created a while back about the use of embryonic stem (ES) cells in medical treatments. To be able to somehow transform a liver or skin cell into this pluripotential multi-dimensional tool would surely be a tremendous breakthrough. Most in the field, however, considered such a transformation to be little more than a pipe-dream.

Carey describes how this breakthrough occurred. Based on previous research, Shinya Yamanaka and his junior associate Kazutoshi Takahashi started with a list of 24 genes already found to be ‘pluripotency genes’, essential to ES cells. If these genes are switched off experimentally, ES cells begin to differentiate. The 24 genes were tested in mouse embryonic fibroblasts, and, to massively over-simplify, they eventually found that only 4 genes, acting together, could transform the fibroblasts into ES-type cells. Further research confirmed this finding, and the method was later found to work with non-embryonic cells. The new cells thus created were given the name ‘induced pluripotent stem cells’, or iPS cells, and the breakthrough has inspired a lot of research since then.

So what exactly does this have to do with epigenetics? The story continues.

Written by stewart henderson

January 6, 2020 at 5:28 pm

epigenetics and imprinting 2: identical genes and non-identical phenotypes

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I’ve now listened to a talk given by Nessa Carey (author of The epigenetic revolution) at the Royal Institution, but I don’t think she even mentioned imprinting, so I may not mention it again in this post, but I’ll get back to it. 

The talk was of course easier to follow than the book, and it didn’t really teach me anything new, but it did hammer home some points that I should’ve mentioned at the outset, and that is that it’s obvious that genetics isn’t the whole story of our inheritance and development because it doesn’t begin to explain how, from one fertilised egg – the union of, or pairing of, two sets of chromosomes – we get, via divisions upon divisions upon divisions, a complex being with brain cells, blood cells, skin cells, liver cells and so forth, all with identical DNA. It also doesn’t explain how a maggot becomes a fly with the same set of genes (or a caterpillar becomes a butterfly, to be a little more uplifting). These transformations, which maintain genetic inheritance while involving massive change, must be instigated and shaped by something over and above genetics but intimately related to it – hence epigenetics. Other examples include whether a crocodile hatchling will turn out male or female – determined epigenetically via the temperature during development, rather than genetically via the Y chromosome in mammals.   

So, to add to the description I gave last time, the histone proteins that the DNA wraps itself round come in batches or clusters of eight. The DNA wraps around one cluster, then another, and so on with millions of these histone clusters (which have much-studied ‘tails’ sticking out of them). And I should also remind myself that our DNA comes in a four-letter code strung together, out of which is constructed 3 billion or so letters.

The detailed description here is important (I hope). One gene will be wrapped around multiple histone clusters. Carey, in her talk, gave the example of a gene that breaks down alcohol faster in response to consumption over time. As Carey says, ‘[the body] has switched on higher expression of the gene that breaks down alcohol’. The response to this higher alcohol consumption is that signals are generated in the liver which induce modifications in the histone tails, which drive up gene expression. If you then reduce your alcohol consumption over time, further modifications will inhibit gene expression. And it won’t necessarily be a matter of off or on, but more like less or more, and the modifications may relate to perhaps an endless variety of other stimuli, so that it can get very complicated. We’re talking about modifications to proteins but there can also be modifications to DNA itself. These modifications are more permanent, generally. This is what creates specialised cells – it’s what prevents brain cells from creating haemoglobin, etc. Those genes are ‘tightened up’ or compacted in neurons by the modifying agents, so that, for example, they’re permanently unable to express the haemoglobin-creating function.

All of this is extremely fascinating and complex, of course, but the most fascinating – the most controversial and headline-creating stuff – has to do with carrying epigenetic changes to the next generation. The inheritance of acquired characteristics, no less. Next time.

References

What is epigenetics? with Nessa Carey – The Royal Institution (video)

The Epigenetics Revolution, by Nessa Carey, 2011

Written by stewart henderson

January 3, 2020 at 3:58 pm

epigenetics and imprinting 1 – it’s complex

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A useful summary - not explained in the text

The last book I read was The Epigenetics Revolution by Nessa Carey, though I’m not sure if I’ve really read it. So much of it was about persisting with the next sentence though I hadn’t fully understood the previous one. Biochemistry does that to me – too many proteins, versions of RNA, transposons, transferases, suppressors, catalysers, adjuvants and acronyms. And in the end I’m not at all sure how much progress we’re making in this apparently tantalising field.

So I’m going to pick out imprinting for starters, as a way of familiarising myself a little more with the epigenetic process of leaving tabs or marks on specific genes.

I know nothing about imprinting. Isn’t it what female birds do with their offspring, even when they’re still in the shell? Here’s how Wikipedia introduces it :

Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. As of 2014, there are about 150 imprinted genes known in the mouse and about half that in humans. Genomic imprinting is an inheritance process independent of the classical Mendelian inheritance. It is an epigenetic process that involves DNA methylation and histone methylation without altering the genetic sequence. These epigenetic marks are established (“imprinted”) in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism.


This suggests that it’s not something life-forms do, it just happens. But there are a number of mysterious terms here that need exploring – ‘a parent-of-origin-specific manner’, ‘DNA methylation’ and ‘histone methylation’.

Briefly, to get all that DNA (between 2 and 3 metres to each nucleus) to fit inside that tiny space you need some expert packaging, and that’s where histones come in. They’re proteins that DNA gets wound around, like cotton reels, and together the histones and the DNA are called chromatin. They’re also divided into sections called nucleosomes.

DNA methylation is when a methyl group, derived from methane (CH3), is added to the DNA, affecting its activity, including repressing gene transcription. Histone methylation is when methyl groups are added to amino acids in histone proteins. Again these can repress or enhance gene transcription, depending on the amino acids and how they’re methylated.

The parent-of-origin thing is most interesting to me, and needs a bit more explaining. When a human sperm cell enters an egg cell, as the first step in fertilisation, it carries its load of 23 chromosomes in what is called a pro-nucleus. In a sense a sperm cell, much smaller than an egg, is nothing but a pro-nucleus surrounded by a membrane, with a tail for motility. Once inside the egg, the tail and the membrane are shed. The egg cell also has its load of 23 chromosomes in its pro-nucleus, but this is considerably larger than the male – and the human egg cell in its entirety has about 100,000 times the volume of a sperm cell. The point is that the differences in the male and female pro-nuclei have a lot to do with epigenetic effects including imprinting, which affect phenotypic traits, including disease prone-ness and structural effects in animals and plants. Tracing these effects in molecular terms to either parent therefore becomes a priority.

So, this is a little starter in what is an overwhelmingly complex topic. I shall return to it.

Written by stewart henderson

December 31, 2019 at 10:11 am