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Posts Tagged ‘chromosomes

exploring meiosis

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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

https://www.thoughtco.com/stages-of-meiosis-373512

https://www.albert.io/blog/what-occurs-in-the-s-phase/
https://en.wikipedia.org/wiki/Centrosome
https://www.thoughtco.com/kinetochore-definition-373543
https://opentextbc.ca/biology/chapter/6-2-the-cell-cycle/
https://www2.nau.edu/lrm22/lessons/mitosis_notes/meiosis.html
https://www.genome.gov/genetics-glossary/Chromatin
https://sciencing.com/difference-between-centriole-centrosome-13002.html

Written by stewart henderson

June 8, 2022 at 10:25 pm

epigenetics and imprinting 7: more problems, and ICRs

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This image has an empty alt attribute; its file name is screen-shot-2020-02-02-at-10.11.35-pm-1.pngthe only image I can find that I really understand

 

In the previous post in this series I wrote about the connection between two serious disorders, Angelman syndrome and Prader-Willi syndrome, their connection to a missing small section of chromosome 15, and how they’re related to parental inheritance. These syndromes can sometimes also be traced back to uniparental disomy, in which the section of chromosome 15 is intact, but both copies are inherited from the mother (resulting in PWS) or the father (resulting in AS).

So the key here is that this small section of chromosome 15 needs to be inherited in the correct way because of the imprinting that comes with it. To take it to the genetic level, UBE3A is a gene which is only expressed from the maternal copy of chromosome 15. If that gene is missing in the maternal copy, or if, due to uniparental disomy, both copies of the chromosome are inherited from the father, UBE3A protein won’t be produced and symptoms of Angelman syndrome will appear. Similarly, PWS will develop if a certain imprinted gene or genes aren’t inherited from the father. Other imprinting disorders have been found, for example, one that leads to Beckwith-Wiedemann syndrome, though the mechanism of action is different, in that both copies of a gene on chromosome 11 are switched on when only the paternal copy should be expressed. This results in abnormal growth (too much growth) in the foetus. It too has an ‘opposite’ syndrome, Silver-Russell syndrome, in which the relevant protein expression is reduced, resulting in retarded growth and dwarfism. 

But now to the question of exactly how genes are switched on and off, or expressed and repressed. DNA methylation, briefly explained in my first post on this topic, is essential to this. Methyl groups are carbon-hydrogen compounds which can be bound to a gene to switch it off, but here’s where I start to get confused. I’ll quote Carey and try to make sense of it:

… it may be surprising to learn that it is often not the gene body that is methylated. The part of the gene that codes for protein is epigenetically broadly the same when we compare the maternal and paternal copies of the chromosome. It’s the region of the chromosome that controls the expression of the gene that is differently methylated between the two genomes.

N Carey, The epigenetics revolution, 2011 p140

The idea, I now realise, is that there’s a section of the chromosome that controls the part of the gene that codes for the protein and it’s this region that’s differently methylated. Such regions are called imprinting control regions (ICRs). Sometimes this is straightforward, but it can get extremely complicated, with whole clusters of imprinted genes on a stretch of chromosome, being expressed from the maternally or paternally derived chromosomes, and not simply through methylation. An ICR may operate over a large region, creating ‘roadblocks’, keeping different sets of genes apart, and affecting thousands of base-pairs, not always in the same way. Repressed genes may come together in a ‘chromatin knot’, while other, activated genes from the same region form separate bundles.

Imprinting is a feature of brain cells – something which, as of the writing of Carey’s book (2011), is a bit of a mystery. Not so surprising is the number of expressed imprinted genes in the placenta, a place where competing paternal-maternal demands are played out. As to what is going on in the brain, Carey writes this:

Professor Gudrun Moore of University College London has made an intriguing suggestion. She has proposed that the high levels of imprinting in the brain represents a post-natal continuation of the war of the sexes. She has speculated that some brain imprints are an attempt by the paternal genome to promote behaviour in young offspring that will stimulate the mother to continue to drain her own resources, for example by prolonged breastfeeding.

N Carey, The epigenetics revolution, 2011. pp141-2

This sounds pretty amazing, but it’s a new epigenetic world we’re exploring. I’ll explore more of it next time.

References

The epigenetics revolution, by Nessa Carey, 2011

Epigenetics, video: SciShow

Written by stewart henderson

February 2, 2020 at 10:33 pm