Archive for the ‘mitochondria’ Category
understanding genomics 1 – mitochondrial DNA
Canto: So maybe if we got humans to mate with bonobos we’d get a more promising hybrid offspring?
Jacinta: Haha well it’s not that simple, and I don’t mean just physiologically…
Canto: Okay those species wouldn’t be much attracted to each other – though I’ve heard that New Zealanders are very much attracted to sheep, but that just might be fantasy. But seriously, if two species – like bonobos and chimps, can interbreed, why can’t bonobos and humans? And they’d don’t have to canoodle, you can do it like in vitro fertilisation, right?
Jacinto: Well, bonobos and chimps are much more closely related to each other than they are to humans. And if you think bonobo-human hybridisation will somehow create a female-dominant libertarian society, well – it surely ain’t that simple. What we see in bonobo society is a kind of social evolution, not merely a matter of genetics. But having said that, I’m certainly into exploring genetics and genomics more than I’ve done so far.
Canto: Yes, I’ve been trying to educate myself on alleles, haplotypes, autosomal and mitochondrial DNA, homozygotism and heterozygotism (if there are such words), single nucleotide polymorphisms and…. I’m confused.
Jacinta: Well, let’s see if we can make more sense of the science, starting with, or continuing with Who we are and how we got here, which is mostly about ancient DNA but also tells us much about the past by looking at genetic variation within modern populations. Let me quote at length from Reich’s book, a passage about mitochondrial DNA – the DNA in our mitochondria which is somehow passed down only along female lines. I’ve no idea how that happens, but…
The first startling application of genetics to the study of the past involved mitochondrial DNA. This is a tiny proportion of the genome – only approximately 1/200,000th of it – which is passed down from mother to daughter to granddaughter. In 1987, Allan Wilson and his colleagues sequenced a few hundred letters of mitochondrial DNA from diverse people around the world. By comparing the mutations that were different among these sequences, he and his colleagues were able to construct a family tree of maternal relationships. What they found is that the deepest branch of the tree – the branch that left the main trunk earliest – is found today only in people of sub-Saharan African ancestry, suggesting that the ancestors of modern humans lived in Africa. In contrast, all non-Africans today descend from a later branch of the tree.
Canto: Yes, I can well understand the implications of that analysis, but it skates fairly lightly over the science, understandably for a book aimed at the general public. To be clear, they looked at the same stretches of mitochondrial DNA in diverse people, comparing differences – mutations – among them. And in some there were many mutations, suggesting time differences, due to that molecular clock thing. And I suppose those that differed most – from who? – had sub-Saharan ancestry.
Jacinta: Dating back about 160,000 years, according to best current estimates.
Canto: The science still eludes me. First, how does mitochondrial DNA pass only through the female line? We all have mitochondria, after all.
Jacinta: Okay, I’ve suddenly made made myself an expert. It all has to do with the sperm and the egg. One’s much bigger than the other, as you know, because the egg carries nutrients, including mitochondria, the only organelle in your cytoplasm that has its own DNA. Your own little spermatozoa are basically just packages of nuclear DNA, with a tail. Our mitochondrial DNA appears to have evolved separately from our nuclear DNA because mitochondria, or their ancestors, had a separate existence before being engulfed by the ancestors of our somatic or eukaryotic cells, in a theory that’s generally accepted if difficult to prove. It’s called the endosymbiosis theory.
Canto: So mitochondria probably had a separate, prokaryotic existence?
Jacinta: Most likely, which could take us to the development, the ‘leap’ if you like, of prokaryotic life into the eukaryotic, but we won’t go there. Interestingly, they’ve found that some species have mitochondrion-related organelles with no genome, and our own and other mammalian mitochondria are full of proteins – some 1500 different types – that are coded for by nuclear rather than mitochondrial DNA. Our mitochondrial DNA only codes for 13 different types of protein. It may be that there’s an evolutionary process going on that’s transferring all of our mitochondrial DNA to the nucleus, or there might be an evolutionary reason for why we’re retaining a tiny proportion of coding DNA in the mitochondria.
Canto: So – we’ve explained why mitochondrial DNA follows the female line, next I’d like to know how we trace it back 160,000 years, and can place the soi-disant mitochondrial Eve in sub-Saharan Africa.
Jacinta: Well the term’s a bit Judeo-Christian (there’s also a Y-chromosomal Adam), but she’s the matrilineal most recent common ancestor (mt-MRCA, and ‘Adam’ is designated Y-MRCA).
Canto: But both of these characters had parents and grandparents – who would be somehow just as common in their ancestry but less recent? I want to know more.
Jacinta: To quote Wikipedia…
… she is defined as the most recent woman from whom all living humans descend in an unbroken line purely through their mothers and through the mothers of those mothers, back until all lines converge on one woman.
… but I’m not sure if I understand that convergence. It clearly doesn’t refer to the first female H sapiens, it refers to cell lines, haplogroups and convergence in Africa. One of the cell lines used to pinpoint this convergence was HeLa, the very first and most commonly used cell line for a multiplicity of purposes…
Canto: That’s the Henrietta Lacks cell line! We read The Immortal Life of Henrietta Lacks! What a story!
Jacinta: Indeed. She would be proud, if she only knew… So, after obtaining data from HeLa and another cell line, that of an !Kung woman from Southern Africa, as well as from 145 women from a variety of populations:
The published conclusion was that all current human mtDNA originated from a single population from Africa, at the time dated to between 140,000 and 200,000 years ago.
Canto: So mt-MRCA is really a single population rather than a single person?
Jacinta: Yeah, maybe sorta, but don’t quote me. The Wikipedia article on this gives the impression that it’s been sheeted home to a single person, but it’s vague on the details. Given the way creationists leap on these things, I wish it was made more clear. Anyway the original analysis from the 1980s seems to be still robust as to the time-frame. The key is to work out when all female lineages converge, given varied mutation rates. So, I’m going to quote at length from the Wikipedia article on mt-MRCA, and try to translate it into Jacinta-speak.
Branches are identified by one or more unique markers which give a mitochondrial “DNA signature” or “haplotype” (e.g. the CRS [Cambridge Reference Sequence] is a haplotype). Each marker is a DNA base-pair that has resulted from an SNP [single nucleotide polymorphism] mutation. Scientists sort mitochondrial DNA results into more or less related groups, with more or less recent common ancestors. This leads to the construction of a DNA family tree where the branches are in biological terms clades, and the common ancestors such as Mitochondrial Eve sit at branching points in this tree. Major branches are said to define a haplogroup (e.g. CRS belongs to haplogroup H), and large branches containing several haplogroups are called “macro-haplogroups”.
So let’s explain some terms. A genetic marker is simply a DNA sequence with a known location on a chromosome. A haplotype or haploid genotype is, as the haploid term suggests, inherited from one rather than both parents – in this case a set of alleles inherited together. SNPs or ‘snips’ are differences of a single nucleotide – e.g the exchange of a cytosine (C) with a thymine (T). As to the rest of the above paragraph, I’m not so sure. As to haplogroups, another lengthy quote makes it fairly clear:
A haplogroup is…. a group of similar haplotypes that share a common ancestor with a single-nucleotide polymorphism mutation.More specifically, a haplogroup is a combination of alleles at different chromosomal regions that are closely linked and that tend to be inherited together. As a haplogroup consists of similar haplotypes, it is usually possible to predict a haplogroup from haplotypes. Haplogroups pertain to a single line of descent. As such, membership of a haplogroup, by any individual, relies on a relatively small proportion of the genetic material possessed by that individual.
Canto: Anyway, getting back to mt-MRCA, obviously not as memorable a term as mitochondrial Eve, it seems to be more a concept than a person, if only we could get people to understand that. If you want to go back to the first individual, it would be the first mitochondrion that managed to synthesise with a eukaryotic cell, or vice versa. From the human perspective, mt-MRCA can be best conceptualised as the peak of a pyramid from which all… but then she still had parents, and presumably aunts and uncles…. It just does my head in.
References
https://www.genome.gov/genetics-glossary/Mitochondrial-DNA
https://en.wikipedia.org/wiki/Mitochondrial_Eve
https://en.wikipedia.org/wiki/Haplogroup
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.
HIT, mitochondria and health
and for a gentler form of exercise…
Jacinta: Well now, I know you’re dying to explore the recently touted benefits of your favourite exercise, so let’s have it.
Canto: Yes, I’m very much a HIT man, that’s high intensity interval training, highly recommendable because it takes so little time and only requires an exercise bike. I was put onto it by one of Michael Mosley’s documentaries, though I’ve been a rather theoretical enthusiast in recent times, having trouble overcoming my laziness and my pain-avoidance tendencies, because though it’s short exercise it is a little painful.
Jacinta: So the recent Catalyst episode has brought your enthusiasm surging back?
Canto: Naturellement, especially as it brings with it some new research to focus on. Mitochondria – what do you know about them?
Jacinta: That they are organelles in our cells, believed to have originated as bacteria but to have united with our eukaryotic cells way back in time in a process known as endosymbiosis. They’re also responsible for producing ATP, the energy molecules… though I’ve no idea how, or what an energy molecule actually is.
Canto: That’s music to my ears.
Jacinta: The dulcet tones of ignorance?
Canto: In the country of the blind the one-eyed science pundit is king, and I’d rather be a king than a commoner, so hear ye, my subject.
Jacinta: I may be blind but I’m all ears, Your Majesty.
Canto: Well, as the Catalyst program tells us, mitochondria are about a billion times smaller than a grain of sand, but the world at nanoscales has really opened up to us in recent decades. Mitochondria are good for us, and the more the merrier. And the evidence is that HIT exercise can not only increase the production of mitochondria but increase their function.
Jacinta: So how do we produce mitochondria?
Canto: Are you going to keep interrupting me with questions? Okay, the production of mitochondria relies on our oxygen intake. The story goes that we fill our lungs with oxygen and it enters the bloodstream for a specific purpose…
Jacinta: Hang on, we fill our lungs with air, not just oxygen, so how does the oxygen get separated, and how does the blood take up the oxygen? Aren’t you skipping a few steps here?
Canto: Yes, go and research it yourself and you can report on it next time. The destination of this inhaled oxygen is the mitochondria. There are billions of these mitochondria in our musculature, though the more fit and trained up you are, the more you’re likely to have. Mitochondria apparently comprise some 10% of our body mass, which I’m sure will come as a surprise. Now oxygen, as you know, acts as a corrosive through the process known as oxidation, which involves the loss of electrons…
Jacinta: Hang on…
Canto: Please shut up. So oxygen can have a negative effect on proteins, enzymes and even our DNA, but mitochondria uses this corrosive electron-stripping power to break down nutrients and to create energy in the form of adenosine triphosphate (ATP). Don’t ask! Of course this doesn’t just happen in humans but in all other mammals and complex creatures, and in plants. And that brings us to physical fitness, and the VO2 Max, which is, essentially, the measure of the fitness of our mitochondria. The term stands for volume (V), oxygen (O2), and of course maximum, though generally those concerned with aerobic fitness don’t make the association with mitochondria, they’re just looking at increasing their maximum oxygen consumption levels. Now it’s not an easy thing for impoverished nonentities like us to find out what our VO2 Max is, but it’s probably pretty pathetic. It’s something that endurance athletes tend to obsess about as they try to improve their performance – I believe rowers in particular have some of the highest levels. I notice there’s at least one VO2 Max app on the market – going very cheap too – but I’d be very sceptical about its reliability. In the testing facility shown on Catalyst they measure it via a version of HIT. They get the subject to ride an exercise bike, building up speed till she’s going as fast as she can, and she can go no faster and starts slowing down. That peak represents her VO2 Max. She will be tested 16 weeks later, after a mere 6 minutes of HIT a week, and you can bet your rented house that her VO2 Max will have substantially improved.
Jacinta: So for us low-lifes – excuse my interruption – who can’t easily or cheaply measure improvements in our VO2 Max or, say, our fat to muscle ratio, we just have to feel the difference in aerobic fitness, mitochondrial health and the like…
Canto: Yeah, and your weight will go down too, if you’re carrying a bit extra, as we both are. And the exertion will make you feel better and healthier, I guarantee it. We all know that the placebo effect is real after all. But seriously, I’m sure if we keep to a regime of HIT – say 3 bursts of 20-second full-pelt pedalling interspersed with a minute or so of more relaxed pedalling, or even if we start with 10-second bursts and then 15-second bursts, maybe eventually getting up to 30-second bursts, we’ll feel it getting easier, and it won’t be purely subjective even if we have no way of objectively measuring it.
Jacinta: But shouldn’t we consult a doctor beforehand? I already feel a heart-attack coming on.
Canto: I know you’re joking, but certainly anyone who has any kind of heart condition, or are diabetic or pre-diabetic or have any other serious chronic condition should discuss it with their GP, but really, apart from your couch potato tendencies, there’s nothing wrong with you.
Jacinta: You’re right, and I’m looking forward to the challenge, even though I’m already a to-die-for, effortlessly slim, perpetually twenty-two year old intellectual beauty..
Canto: And I’m the ultimate metrosexual hipster of indeterminate age and shoe size, discreetly tattooed and tucked…
Jacinta: Ah, yuck, you stupid twat, tattoos are the most repugnant fashion development of all time. At least you’re not a spornosexual, yuk, stay away from the gym or I’ll never speak to you again .
Canto: Promise? Anyway, around 35 is the average VO2 Max, but that’s a bit meaningless for us low-lifes as you say. Top athletes have levels in the 60s and 70s, with the highest ever recorded being around 96 or 97 for humans, but some mammals – like racehorses and Siberian sled dogs – can reach much higher levels. But there’s also going to be a big improvement in your fat-to-muscle ratio with regular bouts of HIT. In the Catalyst episode, the reporter took a DEXA body composition scan to measure this ratio. It also measures bone density. DEXA stands for Dual Energy X-ray Absorptiometry, that means you’re subjected to 10 minutes of very low-dose x-radiation at two different energy levels. It measures the relative densities of the different tissues. You can get this scan done in Adelaide, for a baseline measure, but it’ll probably cost an arm and a leg.
Jacinta: One way to lose weight. Cheaper to just take it for granted that you’re getting more muscular with every HIT.
Canto: Spoken like a true scientist. But generally, inactivity itself is a health problem, and anything that raises your metabolism, as HIT most definitely does, will be good for you, if it doesn’t kill you. And of course one of the most exciting findings in recent times is that your VO2 Max can be raised, with all the associated health benefits, without spending crazy amounts of time and money at the gym.
Jacinta: So how did they make this discovery?
Canto: Well I suppose they were doing a lot of experimenting and testing around the health benefits of exercise, but one test, a Wingate test, involved 30 seconds of all-out pedalling on an exercise bike, repeated a few times between periods of rest, to make up to two or three minutes of full-on exercise per session.
Jacinta: And this was for already-athletic types, right?
Canto: Yes – not advisable for middle-aged or post-middle-aged couch potatoes to start on that regimen. I’m currently doing three fifteen-second bursts, building up to 20-second bursts, then up to 30 seconds and no more. So researchers found that endurance levels can be dramatically improved after just six minutes or so of this kind of exercise. A doubling of endurance capacity, no less. Compare this to the current recommendations of 150 minutes a week. Who ever does that, apart from gym junkies?
Jacinta: So, it’s like this incredible short-cut to health.
Canto: Well of course it isn’t the solution to all ills, but among other things such a quick turn-around is a great motivator towards a healthier lifestyle all round. And it doesn’t have to be an exercise bike – you can adapt it, for example you can get yourself outside and do interspersed 30-second sprints, but I hate running and I’ve got a gammy knee so I’ll stay on the bike.
Jacinta: So, have they looked more into the actual science of this? What’s happening here?
Canto: Well again it seems to be about sucking in oxygen and providing a drug hit to the mitochondria. They did this rather nasty experiment with mice, genetically modifying them so that their mitochondrial DNA wasn’t functioning properly – their mitochondria were getting worn out. They looked pretty sorry-looking compared to the control mice, prematurely ageing as evidenced in their fur, their neural activity, heart function and sensory abilities. Their life-span was about half that of normal mice, and no drugs improved the situation. Then they set them on a treadmill regularly, 3 times a week, at a brisk pace, for 45 minutes each session, which you might think would’ve killed them off all the more quickly, but the result was a spectacular improvement in mitochondria production and overall health and energy levels.
Jacinta: And this was in genetically modified mice?
Canto: Apparently so. The program didn’t go into detail about that, except to say that the bad mitochondria were apparently being selected against. Now of course we’re talking about mice here, and this was looking at endurance fitness rather than HIT, but it’s been shown that HIT does all the right things, and in some areas performs better than endurance training. Reductions in blood pressure, improvements in insulin sensitivity, in muscle to fat ratio, in VO2 max all in a matter of weeks, but the really interesting finding was that with HIT, improvement in mitochondrial function was significant – which wasn’t the case after endurance training.
Jacinta: How do they know that?
Canto: They took muscle samples and measured the ability of the muscles to produce oxygen – basically a measure of mitochondrial function. After just four weeks of HIT, mitochondrial function improved by up to 30%, while endurance training over the same period showed little or no change.
Jacinta: Wow. Doesn’t say much for endurance training.
Canto: Well endurance training does improve your VO2 max and it’s hardly bad for you. But the thing with these quick sprints is the difference at the muscle level. Sports medicine distinguishes between fast-twitch, slow-twitch and intermediate muscle fibres. HIT uses a wider range of muscles and muscle types than endurance work, and that seems to be the key. Improvement in mitochondrial function confers a heap of benefits, so this kind of exercise wards off neurological and other conditions, including muscle weakness and epidermal deterioration, the tell-tale signs of ageing. In fact all exercise does this. Ever heard of the stratum corneum?
Jacinta: Mmmm, corneum, cornea, isn’t that part of the eye?
Canto: Excellent guess but wrong in this case. The stratum corneum is the top layer of the epidermis, the skin. It starts to thicken as you age, and the layer underneath gets thinner as your mitochondrial function reduces. You can slow down that process quite significantly with regular exercise. They did skin biopsies of sedentary people over 65 before and after endurance training. After just 3 months the skin showed great improvement – a 20 to 30 ‘youthening effect’, according to one researcher. The dead outer layer thinned, and the dermis, full of collagen fibres, thickened. So, clearly, you’re never too old to start.
Jacinta: Or never too young. So okay I’ll start.
Canto: Great, but let me describe one more impressive study, being done on menopausal women using HIT. Menopause is about a major decline in estrogen, which has serious vascular, heart and metabolic effects, as well as insulin resistance. You tend to produce a lot of bad visceral fat which negatively affects the liver, due to the over-production of cytokines – but that’s another story. Anyway, the women were given a sprint regime, of just a short period of fast peddling interspersed with more relaxing peddling, amounting to eight minutes of fast but not hard exercise all up. The results of this research haven’t been published yet, but the women’s self-reporting is all very positive, which isn’t surprising. The research is also based on previous research with obese young men, and the exercise proved very effective. Visceral fat is generally much easier to reduce than subcutaneous fat.
Jacinta: Okay, so we’re going to do this?
Canto: Absolutely. And finally, here are some links.
The Catalyst episode, http://www.abc.net.au/catalyst/stories/4319131.htm
https://newsroom.unsw.edu.au/news/health/sprint-fight-fat
High-Intensity Training and Changes in Muscle Fiber, [www.springerlink.com/content/1137px7x66667132]