Posts Tagged ‘genetics’
exploring meiosis
Canto: So I’m trying to get my head around meiosis in general, and how the parental chromosomes get assorted in the process. I understand that Mendel arrived at his law or principle of independent assortment by noting the resultant phenotypes from particular crosses, especially dihybrid crosses. He knew nothing about gametes and meiosis, an understanding of which didn’t get underway until a decade or more after his 1865 experiments…
Jacinta: Well, meiosis is a v v amazing process that deserves lots of attention, because if not for, etc….
Canto: But what is meiosis for, I don’t even understand that.
Jacinta: It’s for the production of gametes – the sperm and egg cells in mammals. And that’s interesting, because, according to Medical News Today, ‘Females are born with all the eggs they will ever have in their lifetime. The amount decreases until a person stops ovulating and reaches menopause’. According to a graph they present, the number of egg cells produced is at its peak long before birth, and has reduced about tenfold by the time of birth, to about one or two million. This number continues to reduce through life, though it remains relatively stable during the period of ‘optimum fertility’ from about ages 18 to 31, when the number of eggs is around 200,000, with a lot of individual variation.
Canto: So, meiosis occurs entirely while the infant is in the womb? For females at least. And what exactly is ovulation?
Jacinta: Yes, egg cells don’t regenerate like other cells. Remember, tens of billions of our somatic cells die every day, and are being replaced – mostly. As to ovulation, this occurs as part of the menstrual cycle, which occurs with females at puberty. During menstruation, mature eggs are released from the ovaries, which are on the left and right sides of the uterus and connected to it by the fallopian tubes.
Canto: What do you mean by mature eggs? Aren’t they always mature?
Jacinta: Hmmm. Detour after detour. Four phases are recognised in the menstrual cycle – menstruation, the follicular phase, ovulation and the luteal phase. It’s the follicular phase that produces mature eggs, through the release of follicle stimulating hormone (FSH) by the pituitary gland. Do you want me to go into detail?
Canto: No, let’s get back to meiosis – but I always knew there was something fshy about the menstrual cycle. So meiosis is about haploid cells producing more haploid cells? You mentioned that egg cells, which are haploid cells, are at their peak long before the birth of a female child, a peak of around 10 million. But where does the first haploid cell come from, when a child starts as one fertilised egg – a diploid cell? Haploid cells combining to form diploid cells is one amazing process, but diploid cells separating to form haploid cells?
Jacinta: Okay so here’s what I think is happening. A human being starts as a diploid cell, a fertilised egg. As cells differentiate, which happens quite early, some become germ cells. But they’re diploid cells, like all the others, not haploid cells. So meiosis starts with diploid cells.
Canto: Okay, so what differentiates a germ cell from other somatic diploid cells?
Jacinta: I don’t know, just as I don’t know what makes a pluripotent or totipotent cell become a brain cell or a blood cell or whatever. This presumably has a lot to do with genetics, epigenetics and the production of endless varieties of proteins that make stuff, including germ cells. Which presumably are not egg cells or sperm cells, which are haploid cells, or gametes. And these germ cells can undergo mitosis, to reproduce themselves, or meiosis, to produce gametes. So now, at last, we describe the process, and much of this comes from Khan Academy. There are two ’rounds’ of meiosis – M1 and M2 – each of which has a number of phases. In M1 the diploid cell is split into two haploid cells each with 23 chromosomes, and in M2 the haploid cells reproduce as haploid cells, so that at the end of the cycle you have four haploid cells. And in each of these ’rounds’ there are the four phases, prophase, metaphase, anaphase and telophase. PMAT is how to remember it. And then there’s interphase, where cells just going on being themselves and doing whatever they do – though it’s important to know what happens during interphase for these other stages.
Canto: The complexity of it all is fairly mind blowing. Molecules that have a code for making proteins that perform all these functions that produce a huge variety of cells every one of which – apart from the gametes – has a nucleus containing 23 chromosomes from your mother and 23 from your father. Trillions of them!
Jacinta: Yes, it’s certainly amazing – and billions of those cells die and are replaced every day. And not just in humans but in dogs and bonobos and cetaceans and whatnot.
Canto: But here’s a thing – we’re talking about gametes, also known as germ cells, which may be female or male – sperm cells or egg cells. But sperm are also known as spermatazoa, and they’re much tinier and less complex than egg cells, and also far more numerous. Is a spermatozoon a sperm cell, or do lots of spermatozoa live in one cell, or what? One ejaculation releases – how many of these tiddlers?
Jacinta: Well sperm counts can range from about 15 million or less per millilitre of semen (that’s a low sperm count) to somewhere between 200 and 300 million. An ejaculation can vary in volume of course – generally about a teaspoon, which might be as much as 5mls. And, yes, a single sperm or spermatozoon is a male gamete, much smaller than the female ovum. So, yes, male sperm, like male political leaders, make up in numbers for what they lack in complexity.
Canto: Okay so let’s get started with PMAT and all that.
Jacinta: Well it’s all very miraculous or mind-blowing as Salman Khan rightly emphasises – to think that this complexity comes from mindless molecules and all. But here goes, and it cannot help but be a simplified description. So we start with a germ cell – and I’m not sure how this particular type of diploid cell is distinguished from other diploid cells…
Canto: Or whether, even though it’s called a germ cell, it is essentially different in male bodies as compared to female bodies, since they produce such different gametes…
Jacinta: Yeah well I’ll keep that in mind as we progress. Now we start with the interphase, during which time the chromosomes in the nucleus are synthesised. Interphase is generally subdivided into three phases, Gap 1 (G1), Synthesis (S) and Gap 2 (G2). The cell itself experiences a lot of growth during interphase.
Canto: Too vague.
Jacinta: Well I’m just getting started, but I’m not writing a book here.
Canto: Are you going to explain how the chromosomes are ‘synthesised’?
Jacinta: Probably not, this is just a summary.
Canto: I want to know about chromosome synthesis.
Jacinta: Sigh. You’re right, it sounds pretty important doesn’t it. So let’s focus in detail on interphase, which I think is much the same whether we’re looking at mitosis or meiosis. If you consider a whole cell cycle, from its ‘birth’ – usually through mitosis – to its ‘death’ (through mitosis again? I’m not sure), 95% of its time is spent in interphase, during which it doubles in size. It is, in a sense, preparing itself for chromosomal replication and cell division. Here’s a quote from a text book, Concepts of Biology, which I found online, describing the first stage of interphase:
The first stage of interphase is called the G1 phase, or first gap, because little change is visible. However, during the G1 stage, the cell is quite active at the biochemical level. The cell is accumulating the building blocks of chromosomal DNA and the associated proteins, as well as accumulating enough energy reserves to complete the task of replicating each chromosome in the nucleus.
Canto: So it’s a clever cell, actively accumulating the material to build and replicate its particular and unique DNA – I mean unique to the particular soma that it somatically serves, along with several trillion others.
Jacinta: Actually, another source tells that the G stands for growth, which I think makes more sense. The next stage is the S or synthesis phase. Now at this stage, or the beginning of it, the chromosomes exist largely as chromatin, a kind of mixture of DNA and proteins. Histones, in particular are important proteins for packaging the DNA into a tight enough space to fit in the nucleus. I mean, 23 pairs of chromosomes doesn’t really tell you how much DNA and other molecules it all amounts to. Now, this S phase is really complicated, and summaries don’t do it justice. Here’s a quote from yet another source to kick things off:
The S phase of a cell cycle occurs during interphase, before mitosis or meiosis, and is responsible for the synthesis or replication of DNA. In this way, the genetic material of a cell is doubled before it enters mitosis or meiosis, allowing there to be enough DNA to be split into daughter cells. The S phase only begins when the cell has passed the G1 checkpoint and has grown enough to contain double the DNA. S phase is halted by a protein called p16 until this happens.
So you’re asking how these chromosomes are synthesised. Note how this says ‘synthesis or replication’, so it’s presumably about the same sort of process that occurs when cells and their chromosomes are replicated during mitosis? Here’s another passage from the same source, and I don’t pretend to understand it:
The most important event occurring in S phase is the replication of DNA. The aim of this process is to produce double the amount of DNA, providing the basis for the chromosome sets of the daughter cells. DNA replication begins at a point where regulatory pre-replication complexes are attached to the DNA in the G1 phase. These complexes act as a signal for where DNA replication should start. They are removed in the S phase before replication begins so that DNA replication doesn’t occur more than once.
Canto: Wow. That explains not much. Obviously the key to it all is the ‘regulatory pre-replication complexes’ previously attached. How could I not have known that?
Jacinta: Well let’s just say that there are known mechanisms by which DNA replication is regulated, and prevented from occurring more than once in the S phase. I’m sure all those ‘pre-replication complexes’ have been named and studied in detail by scores of geneticists. So that’s enough for now about chromosome synthesis/replication. The S phase also involves continued cell growth and the production of more proteins and enzymes for DNA synthesis. Always looking to the future. And so we move to the next phase.
Canto: Ah yes, reading ahead I see that DNA synthesis is always much the same. The DNA double helix is kind of unzipped by an enzyme called helicase, and the two single strands can be used as templates to form new and identical double strands. I’m over-simplifying of course.
Jacinta: Yes there are different processes going on to ensure that everything goes more or less smoothly, as well as to maintain cell growth outside of the genetic material. A key enzyme, DNA polymerase, binds nucleotides to the template strands using the base pairing code – A binds to T, C to G. This creates an identical new double helix of DNA.
Canto: Apparently there’s a difference between DNA replication and chromosome replication. Please explain?
Jacinta: I’m not sure if I can, but we’re talking about the replication of chromosomes in the S phase, after which each chromosome now consists of two sister chromatids (halves of a chromosome), as you see below.
In the first circle, A and B are homologous pairs. That’s to say, they’re segments of DNA, chromosomes, from each parent, though they might code differently – they might be different alleles. This is a bit complicated. Sal Khan in his video puts it this way:
Homologous pairs means that they’re not identical chromosomes, but they do code for the same genes. They might have different versions, or different alleles for a gene or for a certain trait, but they code essentially for the same kind of stuff.
Make of that what you will. I suppose it means that the homologous pair might have, say, genes for eye colour, but mum’s will code for blue, dad’s for brown. But the same kinds of genes are paired. Anyway, after replication in the S phase, you get, as above, two male and two female chromosomes, joined together in a sort of x shape. They’re joined together at that circular sort of binding site called a centromere (it’s not actually circular). The images above are misleading though, in that there are short arms and long arms leading off the centromere. You could say the centromere is off-centre. So the whole of this new x-shaped thingy is called a chromosome and each half – the right and the left – is called a chromatid. And at the four ends of the x-shaped thingy – I mean the chromosome – is a cap of repetitive DNA called a telomere.
Canto: Ah yes, I’ve heard of those and their relation to ageing…
Jacinta: Let’s not be diverted. So all of this is occurring in the nucleus, and there’s also replication of the centrosomes. Okay they’re a new structure I’m introducing, one that seems to only occur in animal-type or metazoan eukaryotic cells. They serve as microtubule organising centres (MTOCs), according to Wikipedia, which is never wrong, and which goes into great detail on the structure of these centrosomes, but for now the key is that they’re essential to the future separation of the chromatids via microtubules during prophase I. And that’s the next phase to describe. And it’s worth noting that the developments described up to now could be preliminary to meiosis or mitosis.
So, in prophase I the nuclear envelope starts to disintegrate and the pair of centrosomes are somehow pushed apart, to opposite sides of the chromosomal material, and microtubule spindles start extending from them – presumably by the magic of proteins. And another sort of magical thing happens, though I’m sure that some geneticists understand the detail of it all, which is that the homologous pairs line up on opposite sides of a kind of equator line, guided by these spindles, forming a tetrad, and this is where a process called crossing over or recombination occurs, in which the pairs exchange sections of genes. And this recombination somehow manages to avoid duplication and to maintain viability, and indeed to increase diversity. The recombination occurs at points in the chromosomes called chiasmas.
So that’s the end of prophase I. Now to metaphase 1. In this phase the nucleus has disappeared, the centromeres have completed their move to the opposite sides of the cell, and the spindle fibres of microtubules become attached to chromosomes via the kinetochores – protein structures connected to the centromeres. Here’s an interesting and useful illustration of a kinetochore.
All of this is similar to metaphase in mitosis. Then in anaphase I the homologous pairs, which remember had come together and recombined, are separated, or pulled apart, which is different from anaphase I in mitosis, where the chromosomes are split into their separate chromatids. Next comes telophase I, when the separation is complete, the facilitating microtubules break down and cytokinesis, the final separation of the chromosomes and the cytoplasm into two distinct cells, occurs. Telophase I ends with two cells and two nuclei, each containing 23 chromosomes, half of those in the original cells. They’re called daughter cells, for some reason.
Canto: Probably because son cells sounds silly.
Jacinta: Good point. So now these daughter cells start on a whole new PMAT process, which is a lot more like mitosis. Prophase II involves the disintegration of the nucleus once more, the two centrosomes start to move apart as microtubules are formed – and remember this is happening simultaneously in the two daughter cells – and then we’re into metaphase II, where the centrosomes have migrated to opposite ends of the cell, and the chromosomes line up at the ‘equator’, and the spindle fibres attach to the kinetochores of the sister chromatids. Next comes anaphase II, in which the spindle fibres draw the chromatids away from each other, as in anaphase during mitosis. And at the end of this journey they’re now treated as sister chromosomes. And all of this is happening in those two daughter cells, which start to stretch and cleave, which of course means that, in telophase II, you have cytokinesis, and the creation of new nuclear membranes, and the cytoplasm – remember that all the cytoplasm and its organelles have to be replicated too, to make, in the end four, complete haploid cells, or gametes. So that’s the potted version. There’s lots of stuff I’ve excluded, like the difference between centrosomes and centrioles, and lots of details about the cytoplasm, and there’s no doubt much more to learn (by me at least) about the crossing over that’s so essential to provide the variation that Darwin searched for in vain. Anyway, that was sort of fun and thank dog for the internet.
Canto: But I’m still confused about sperm cells and egg cells… If sperm cells are just those little tadpole things – a bunch of DNA with a flagellum, they don’t have any cytoplasm to speak of, do they?
Jacinta: Ah yes, something to look into. There’s spermatogenesis and there’s oogenesis… for a future post. It just never ends.
References
exploring genetics – Mendel, alleles and stuff
Canto: So I’d like to know as much as I can about genetics before I die, which might be quite soon, so let’s get started. What’s the difference between genetics and genomics?
Jacinta: Okay, slow down – but I suppose that’s as good a place to start as anywhere. I recently listened to a talk about the human genome project, which was completed around 2003, and the number I heard the guy mention was 3 billion genes, or something. But according to videos and other sources, each human has between 20,000 and 25,000 genes – though I’ve found another FAQ which estimates 30,000. So I gather from this that our genome is the number of genes we might possibly have – in the whole human population? Which raises the question, how do we know that the human genome project has captured or mapped all of them.
Canto: So there’s an individual genome, peculiar to each of us, and a collective genome?
Jacinta: Errr, maybe. We’re 99.9% genetically identical to each other, supposedly. And if this sounds very paradoxical, we need to zoom in on the detail. And with that, I’ve discovered that the 3 billion refers to base pairs, sometimes called ‘units of DNA’. So what’s a base pair? Well, we need to start with the structure of DNA, the genetic molecule. That’s deoxyribonucleic acid, which is made up of basic components called nucleotides. A nucleotide of DNA consists of a sugar molecule, a phosphate group and a nitrogenous base. The bases come in four types – adenine, guanine, thymine, and cytosine (A, T, G and C). The sugar and phosphate groups provide structure, allowing the bases to form a long string of DNA. Bonds form between the bases to create a double strand of DNA – hence base pairs.
Canto: Here’s how the World Health Organisation defines genomics, obviously from a health perspective:
Genomics is the study of the total or part of the genetic or epigenetic sequence information of organisms, and attempts to understand the structure and function of these sequences and of downstream biological products. Genomics in health examines the molecular mechanisms and the interplay of this molecular information and health interventions and environmental factors in disease.
Now you might think that this definition could cover genetics too, and maybe we shouldn’t be too worried about the distinction. Maybe, in general, genomics is about sequences of genes, especially in detailing whole organisms, while genetics is more about individual genes.
Jacinta: Genomics is the much more recent term, first coined in the 1980s, whereas genetics and genes date back to before we knew about DNA as the genetic molecule. Going back to Mendel and all, though I don’t think he used the term, he talked about ‘factors’ or some such.
Canto: So we know that there’s DNA, and there’s also RNA, another building block of life. How old are they, and which came first? And can species replicate without these molecules?
Jacinta: Oh dear – we’ll get there eventually, maybe. Genomics deals with the whole complement of genes in an organism, which we’ve gradually realised is necessary to evaluate, say, how prone that organism is to contracting a disease, or developing some immuno-deficiency, because individual genes often don’t tell us much. And there’s also the matter of dominant and recessive genes. Which takes us to inheritance. All those genes are combined together on chromosomes, of which there are 23 pairs in humans, which we inherit from our parents, 23 chromosomes each.
Canto: Combined together? Can you be more specific?
Jacinta: Okay, a chromosome is a thread-like structure, in which DNA is coiled around structural proteins called histones. Each chromosome has two ‘arms’, flowing from a constriction point called a centromere. These arms are labelled p and q. The p arm is shorter than the q. And these chromosomes contain genes, which may or may not code for proteins. The genes, as mentioned, consist of base pairs, which vary in number from hundreds to millions.
Canto: Okay, so what’s the difference between a gene and an allele?
Jacinta: Well, genes are codes for making proteins – and those proteins affect all sorts of things, to do with taste, smell, hair colour and type, height, and predisposition to various diseases, among many other things. You can call these things ‘traits’, which show up in our phenotype, our physical characteristics. And it should be pointed out that many of these traits are the results of not just one gene but different genes in combination. Now, as mentioned, these genes are in pairs of chromosomes – 23 pairs in humans. Now, say we isolate an area in a chromosome that codes for a particular trait. What about the other chromosome in that pair? Remember, each chromosome comes from a male or female parent, and they are different, genetically – or likely to be. That’s where alleles come in, and it takes us back to Mendel, who found that with pea plants, traits such as colour, or the alleles that carried those traits, could be dominant or recessive. So, for that trait, they could carry two dominant alleles, or two recessive alleles, or one of each. If one or both of those alleles is dominant, the trait will be expressed, but if both are recessive, it won’t be. But as I say, it’s more complicated than that, as traits expressed in phenotypes are generally carried by many genes.
Canto: So alleles are? – how to define them?
Jacinta: Google it mate. Here’s a quickly found definition: “each of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome”. So let’s continue with the work of Mendel. When we find a dominant trait, we use a capital, T. It might be paired with another dominant trait, TT, or with a recessive trait, Tt. On the other hand, both traits might be recessive, tt, and that’s all the combos you have, for single traits. Now, in noting this, and the way that alleles combine, Mendel came up with a ‘law of segregation’. Or rather, he noticed a process, which later became recognised as a law. In fact, he observed three fundamental processes, ‘segregation’, ‘independent assortment’, and ‘dominance’, which we now describe as laws. Now, I’ve used the term ‘trait’ but perhaps I should’ve used the term ‘allele’. So TT combines two dominant alleles. The law of segregation has been stated thus:
During gamete formation, the alleles for each gene segregate from each other such that each gamete formed carries only one allele for each gene.
Canto: Right. Uhhh, what’s a gamete again?
Jacinta: Sex cells, which carry only one copy of each chromosome. They’re created during meiosis, after which we end up with four cells each with only one allele for each gene. So indeed, alleles are segregated during gamete formation.
Canto: Oh dear. I’ll have to brush up on meiosis.
Jacinta: So now we have these segregated alleles, which will be recombined. The law of independent assortment comes next. This also occurs during meiosis. In the fourth or metaphase period of cell division, the chromosomes align themselves on the equatorial plane, also called the metaphase plate. This alignment is random, and that’s the key to the law of independent assortment – ‘genes for different traits assort independently of each other during gamete formation’. But obviously Mendel knew nothing about meiosis, though it was first observed in his lifetime, in sea urchins . Anyway, this law allows for many different combinations of alleles depending on how chromosomes become aligned on the metaphase plate. A dihybrid cross will provide more such combinations.
Canto: A dihybrid cross? Please explain.
Jacinta: Well, a monohybrid cross will be like this – TT x tt. Not much to be assorted there. A dihybrid cross might be like this – TtCc x TtCc, creating four different assortments for each cross. So now to the third law, of dominance. This law simply states that ‘some alleles are dominant while others are recessive. An organism with at least one dominant allele displays the effect irrespective of the presence of the recessive one’. So the phenotype will present the dominant allele regardless of whether it’s double-dominant or single-dominant. Though the terms used are homozygous (TT), or heterozygous (Tt).
Canto: So are we going to look at punnett squares now? I’ve heard of them…
Jacinta: Well it might help. They were named after a bloke called Punnett back in 1905, the early days of Mendelian genetics. They’re neat little tables, that can start to get quite complicated, for determining the genotypes of offspring, when you breed dominant with recessive, heterozygous with homozygous and so on. It’s useful for simple genotypes, but when genotypes are multifactorial, as they often are, other methods are obviously required.
Canto: Okay, that’s more than enough to absorb for now.
Jacinta: I think, since we’ve started with Mendel, we might do a historical account. Or maybe not….
References
https://www.google.com/search?client=safari&rls=en&q=alleles&ie=UTF-8&oe=UTF-8
https://byjus.com/biology/mendel-laws-of-inheritance/
https://www.yourgenome.org/facts/what-is-meiosis
returning to the race myth
‘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.
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.
Pinning down meiosis: sperm, mainly
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
a DNA dialogue 5: a first look at 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)
a DNA dialogue 3: two anti-parallel strands
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
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
A DNA dialogue 1: the human genome
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
epigenetics and imprinting 3: at the beginning
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.