Identical Twins: Not Identical?

This month: mutations in early development, selfish genes in sperm, and COVID vaccine booster shots...
15 January 2021
Presented by Phil Sansom
Production by Phil Sansom.

BABIES

Two twin babies sleeping.

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Meet the small DNA differences that make their mark by existing in the magical period of early development. We’ll hear how mutations in the very first stages of human embryos have bizarre consequences for identical twins; and how even earlier in the process, sperm use selfish genes to get ahead of the competition. Plus, an immunologist untangles mRNA COVID vaccines, from efficacy numbers to delayed booster shots...

In this episode

Twin babies in bunny outfits.

00:29 - Identical twins have early genetic differences

A new study shows how identical twins are not genetically identical - even in the first week of development...

Identical twins have early genetic differences
Kari Stefansson, deCODE; Robert Plomin, King's College London

A new study has shown that identical twins… are not actually identical! Researchers already knew that they had certain differences, because everyone’s DNA mutates throughout their lives - that’s why some people get cancer. But those kinds of mutations seem to be restricted to the body, and don’t get passed on through sperm or eggs. Now though, human genetics company deCODE in Iceland have used the genomes of nearly 400 pairs of twins to show that they often have a few differences that they actually pass on to their kids - a result that could have implications for other parts of genetics research. Phil Sansom heard from Kari Stefansson, head of deCODE...

Kari - There are certain differences in the genome of identical twins. And the reason that is important is that we have always assumed, when we are trying to separate the facts of the environment from the fact of genetics, that the genomes of identical twins are identical. So finding these mutations changes, a little bit, the way in which we can use identical twins for the purpose of separating environmental effects from genetic effects.

Phil - How is that possible, that identical twins are not identical? Because I thought they come from the same egg, don't they?

Kari - They come from the same fertilised egg. But when an egg is fertilised, it divides several times before there is a beginning of the formation of twin. And the cell divisions can lead to what is called replication error; when a cell divides, the genome in the cell is duplicated. And even though this process of duplication is a very good one, it's not flawless. And we call the flaws 'mutations'. So there is an opportunity for mutations to take place, and what we document in this paper is that they indeed do take place and they have a significant impact on differences between genomes in the twins.

Phil - When are they taking place? How big is the embryo at this point?

Kari - It is very small - around 16 to 20 cells or so.

Phil - And how can you tell that this is going on? Were you looking at these embryos at this early stage yourself?

Kari - No, the way in which we can do this is by sequencing the whole genome of the twins, of their parents, of the children, and of their spouses. We can infer when the mutations take place. If a mutation happens very early in the embryo, you will find that mutation not only in the children - because they have made it into the cells that lead to sperms in the male or eggs in the female - they will also end up in the body. And when a mutation is found both in the body and in the children, we know that mutation happened before they're differentiated. So it helps you to time it, and the timing is all-important when it comes to development.

Phil - They must also be happening only in one twin as well, right, for you to get the difference?

Kari - Yeah, because the cell that leads to one of the twins may not lead to the other. In some instances, both of the twins are developed from the descendants of the same cell; sometimes they're descendants of different cells. And if they are formed from descendants of different cells, then they will harbour different mutations.

Phil - Is it totally random which one of those you get?

Kari - I think it is very close to being random.

Phil - Now how big do these differences actually get?

Kari - These differences are not big. On average you will find about five mutations of this short that differ between identical twins, but there can be more than that.

Phil - So what does that mean for twin studies in genetics? You alluded to this earlier, because geneticists use twins all the time to try and separate out the genetics from the environment for a particular trait, or disease, or something.

Kari - We should definitely demand that people sequence the whole genomes of both of the twins before we ascribe differences between them to the environment, because indeed these mutations that are different between them could be the reason that they are different.

Phil - Does it affect the results of twin studies that people have done in the past?

Kari - It should caution people, but it should only affect differences that are rare. For example, when one twin develops a disease and the other does not, if the disease is very rare then we should definitely re-explore whether that is explained by a mutation and not just environmental effect.

Phil - Finally, I just want to ask: do you know if these differences between twins ever translate into something visible, like you might get two identical twins with something visibly different between them?

Kari - I am absolutely certain that occasionally it does. Because occasionally you'll see differences between identical twins that will not be explained by the environment.

Phil - It's pretty amazing, I think, for people to imagine that identical twins are not actually identical!

Kari - Yeah. Monozygotic, but not identicals.

Is this information a blow to the types of experiments known as “twin studies”? Geneticist Robert Plomin says no. He runs one of the largest such experiments, called the Twins Early Development Study, and he explained to Phil how they normally work...

Robert - A twin study is a design that's been around for over a hundred years, that uses a natural experiment. About 1% of all births are twins, and a third of those are what we call identical or monozygotic twins. They're clones of one another because they're derived from the same fertilised eggs; s,o when an egg and sperm get together and produce a zygote, that zygote sometimes splits in the first few days of life. The other type of twins - two thirds of all twin births - are non-identical twins or fraternal twins. Like any brother and sister they're 50% similar genetically. So the essence of the twin design is that: if a trait - say musical ability - is influenced by inherited DNA differences, you have to predict that identical twins are more similar than non-identical twins. And the extent to which that's true is an index of what we call heritability - how much of a difference does genetic differences make in the trait that you're studying.

Phil - So you're separating genes from environment. Nature from nurture, basically.

Robert - Yes, that's the idea. We've known forever that things run in families, but the question is, do they run in families for reasons of nature - that is inherited DNA sequences, genetics - or nurture - that is systematic effects of the family environment?

Phil - Can you talk me through maybe an example of a twin study so that I can picture how one might work?

Robert - Yeah. There are literally thousands of twin studies that have been reported throughout the life sciences. If you take a trait like musical ability - for which only recently do we have any twin studies at all, because it's kind of hard to measure musical ability - what we do is we get a large group of twins. We then correlate the identical twin pairs, and you say, "how similar are they?" Their correlation might be, say, 0.5; whereas non-identical twins, if they correlated at 0.5 for musical ability, that would mean there's no genetic influence. If the identical twin correlation is 0.5 and the fraternal twin correlation is 0.25, that suggests genetic influences account for about 50% of the differences that we observe in musical ability. But as always our studies are limited to the samples we described, so we're only describing a particular population at a particular time.

Phil -
Now Kari Stefansson in his paper is seemingly saying that identical twins are, in fact, not identical. Is that a shock to you?

Robert - No, I think we've known that for a long time. His study is great in terms of having a large sample and very systematically looking at this, because he actually sequences all 3 billion base pairs of DNA. But the twin method depends on inherited DNA differences. That's what we call genetic. It's a very narrow definition of genetic, because there are many biological and even DNA factors that are not included in that definition; they would be called environmental. In Kari's study particularly, what I'm afraid people will take away from it is the idea, "well, the twin method's no good because identical twins have differences." But in fact, we've known that we all get mutations as we go through life - cancers are often due to mutations - but these are not inherited DNA differences. And we know from lots of studies using a technology called SNP chips, and they focus on inherited DNA differences. They don't show any differences between identical twins. So identical twins don't differ in terms of the DNA differences they inherit from their parents.

Phil - You're saying that for the purpose of twin studies, these genes are not inherited from the twins' parents; they're eventually passed on, but that still doesn't disrupt the way the studies work.

Robert - Yeah. And it's always a problem in science when a word like 'inherited' or 'transmitted' is used in such different ways. But in genetics, what we're talking about is: the twins we're talking about as the offspring. That is, did they inherit these DNA differences, or are they spontaneous mutations. Inherited DNA differences is a very narrow definition, but it's a precise one, and it helps us understand things like Kari's finding.

Phil - So are twin studies safe?

Robert - Yeah, I think without doubt!

Sperm surrounding an egg cell.

11:02 - How sperm succeed: widespread selfish genes

Sperm are supposed to all act the same, with a few genes as exceptions. Turns out it's more than just a few...

How sperm succeed: widespread selfish genes
Robin Friedman, Ohana Biosciences

Each human sperm cell has a very random combination of DNA, taken from each of the two copies of each chromosome the person carries. Genetics orthodoxy would say that it’s therefore random which genes make it into the baby, with a few exceptions: genes that make the sperm themselves quicker and better. But scientists from Ohana Biosciences in the USA have recently discovered that this far more than a few exceptions - and the results reveal a deep conflict going on inside our own bodies. Phil Sansom spoke to author Robin Friedman...

Robin - Genes come in two copies, one from your mother and one from your father; we call those alleles. And each sperm has one of those copies of every gene. It's random chance that determines which of those two alleles gets passed on to my offspring, right? So I have a 50% chance of passing on my father's version of a gene, and a 50% chance of passing on my mother's version of a gene. But if you think about the sperm, it requires those sperm to be functionally equivalent, regardless of what genes they have; they have to swim the same, they have to fertilise the egg the same. And what we've found in this work is a mechanism by which sperm are not all created equal, and by which the genetics can actually have an effect on their function, and thereby the probability that they're going to pass that gene onto the next generation.

Phil - These are genes then that are actually good for one sperm over another?

Robin - That's right, yeah. So it can lead to sperm competition, where the sperm that are more fit might have better genetics that underlie that ability.

Phil - Is that surprising?

Robin - Yes! It's been known for a long time that there are very rare exceptions to this rule, discovered by Mendel, that you pass on genes at a 50:50 ratio to the offspring; but those exceptions are thought to be extremely rare. There are only a tiny handful that have been discovered in mammals. And in this study we used single cell RNA sequencing to look at individual spermatids - that's developing sperm in the testis - in a variety of mammalian species, to find that there are far more of these differences than we expected between sperm that could lead to this sperm competition.

Phil - How many more?

Robin - There are thousands of genes that fall into this category. It's about a third to a half of genes that are expressed in the testis. We call these genes 'genoinformative markers', or GIMs for short.

Phil - Thousands is a heck of a lot more than the few exceptions that you talked about. How are these genes getting away with favouring only one sperm, when you've just told me that actually sperm normally have got to be functionally the same - they do the same things?

Robin - First you have to understand that although sperm have only one copy of each gene, when they're developing they're actually connected by bridges, so the actual cells are sharing their contents back and forth. Now what we've found is that this class of genes - that we call GIMs - actually is not completely shared; they're not going across these bridges completely. And so that's the mechanism by which these sperm start to get functionally different.

Phil - These genes are basically sitting in their sperm and they're going, "I don't want to go to the other sperm . I don't want to send my products everywhere else. I'm happy here. Stop making me share."

Robin - Yeah, that's exactly right.

Phil - What physically are they then doing to make the sperm any better?

Robin - So we haven't actually been looking at individual sperm and studying their function. Instead we've been looking at the evolutionary traces of what these GIMs are doing over the long haul. And what we can see is that it causes an evolutionary conflict, where sperm are optimising their function, and the genes might be selfish genetic elements, because their function in the rest of your body might not be the same as the function in sperm.

Phil - Right, they're selfish in the sense that they want to get ahead in the place they are right now - AKA the sperm - no matter what bad thing it might do for you when you're grown up.

Robin - That's right, yeah. And one way that we can find evidence for this is that evolution will want to avoid these selfish elements being in conflict with the function of these genes in a human. These genes will tend to evolve to become more sperm specific over time, and you will get things like gene duplication, where a gene becomes sperm specific, and another copy of it becomes expressed in the rest of the organism. And we think this is a big reason why there are so many genes that are specific to the testis compared to other tissues, which has been a mystery for a long time.

A needle and bottle of the COVID-19 vaccine.

17:25 - COVID vaccines: efficacy explained

Viral immunologist Zania Stamataki breaks down questions about the vaccine rollout...

COVID vaccines: efficacy explained
Zania Stamataki, University of Birmingham

At the time of publishing, around fifty countries worldwide - albeit none in Africa, South Asia, or Australasia - have begun administering a variety of COVID-19 vaccines. That is, by all accounts, astonishing progress. So are we in the home stretch? Is everything going to plan? Or could something still go drastically wrong? Viral immunologist Zania Stamataki helped take apart some of the specifics behind these questions - in an interview with Phil Sansom that first aired on the Naked Scientists podcast...

Zania - Well, aren't we fortunate. We've got over 200 vaccines in development, a handful already approved in different parts of the world. The data from clinical trials are pouring in and guess what? The vaccines work. We now need to get the logistics right, to protect our vulnerable and then the rest of us. And it's important to note of course that while vaccinated, although we are protected, we may still transmit the virus to others.

Phil - This Oxford vaccine - can you remind us, what exactly is it?

Zania - The Oxford vaccine has used a harmless chimpanzee virus to infect our cells and pass on a message, the genetic information, so that we can make coronavirus spike protein ourselves. This stimulates our immune system and we prepare our defenses, which takes a couple of weeks to happen. And after that, our body's ready, and if infected with the coronavirus, our immune system can stop it in its tracks before we get COVID.

Phil - We've got a question for you about it as well, from listener James who asks: "Can you explain the Oxford COVID vaccine approval by MRHA, the UK regulator and what new data is now available since their," and I quote from him, "horrendous first reporting in early December? Seems as though the UK population is being offered a 62% minimally effective solution to me." What is he talking about and what is your opinion?

Zania - Well first of all, we need to separate the vaccine effectiveness from efficacy data. Efficacy is the 62% number that your listener was quoting. And he's talking about the outcomes of clinical trials that are very short and contain a small number of people. Now don't get me wrong, the vaccine has been given to thousands and thousands of people before the clinical trials concluded, but only a small proportion of these people have become infected. So we are getting data back from a small amount of people. Now the Oxford vaccine was given to people in two different doses; some of them showed 62% efficacy in that arm of the trial; others that received a lower dose at the beginning of the trial showed up to 90-odd percent efficacy, which is all very good. But let's remind ourselves that the FDA had said that they will approve any vaccine with efficacy above 50%. And for flu vaccinations, we accept vaccines from 20 to 60% efficacy every year. So the Oxford vaccine we expect to be highly effective, and the effectiveness data is going to change as the vaccine is rolled out and we get data from real life people.

Phil - What would you say to someone who said, “no, I want the Pfizer vaccine, that one's got a higher number. That looks better to me."

Zania - We can't really make that decision based on the data that we have because we haven't compared vaccinations side-by-side, and as scientists, that's how we make comparisons: we get the same population, we vaccinate them with the same preparations, and then we expose them to the disease and we get data back. So this has not happened. And what I can say to people that are worrying about which vaccine is going to be more effective is, I would personally accept any vaccine that was given to me that was approved by MHRA - and I'll be grateful for it as well! I think a vaccine that is approved, that works, is tremendous news. We, as a population, are going to respond differently; but if the vaccine works, take it.

Phil - There are other concerns arising that I'd like to address with you. People are a little bit worried about the UK delaying the second dose of the Pfizer vaccine to people who've received the first one; the manufacturer said three weeks, the UK is saying could be more like months. What's behind that, and is that scientifically sound?

Zania - Well as scientists that work in the lab, we get very nervous when we deviate from a protocol. And Pfizer has only tested their vaccine with a booster within the three weeks, like you said. The Oxford vaccine was tested with later booster jabs too. Now we know however from experience that vaccination boosters continue to work well after several weeks. In the UK we have an urgent public health need, with one in 50 of us currently infected, and we are losing around 900 people a day to COVID. This decision was made to save more lives. But it is important for us to gather data to inform future vaccination protocols for different patient groups.

Phil - One other thing from listener Richard who asks: "What I'd like to know is, what are the risks of developing a serious disease if you catch COVID on the same day as having the first dose of a vaccine? Is there any reduction in your risk of serious disease?"

Zania - Within the day that you are vaccinated, you have not had enough time to generate protective immune responses. As a rule of thumb, you calculate about a week until your responses start to kick off. And then beyond that up to two weeks, when you're mounting decent memory cells, that will protect you from re-infection. So within the first couple of weeks, I would say, take utmost care. You are not protected yet - and this is in your little pamphlet as well that you receive when you become vaccinated - so it takes a little while for the immune system to develop immunity. And this is the whole idea behind vaccination: by getting our jab, we are giving our immune system a sort of stimulation early on so that when we come into contact with the real thing we'll be good to jump to it.

Phil - Zania, if I can ask you to make some predictions for me, how long do you see this pandemic lasting?

Zania - Well it depends on ourselves, really. It depends on our personal behaviour. You do need the vaccine to generate immunity for a population, so that we can protect each other for a long period of time. But if you keep to the rules, as they have been advised to: mask yourself so that you can protect others from infection if you are asymptomatic; keep your distance, so you don't catch the virus yourself; wash your hands; avoid touching your face, like I do all the time without realising - I've become so used to my sanitiser now because I just can't stop touching my face! If you stick to the rules you can protect yourself. And in fact we know from countries around the world that have been very, very strict at sticking to the rules, that they can control infection. And this way, when you have outbreaks that are small, they can quash them very, very quickly. So it is possible for us to have good news, even in the absence of vaccination; but for us to eradicate the virus as a problem, we do need to vaccinate ourselves.

An Indian meal moth.

24:35 - Science From Home update: a moth infestation

When we last spoke to Zenobia Lewis, she had taken home about 800 moths. You can guess what happened next...

Science From Home update: a moth infestation
Zenobia Lewis, University of Liverpool

Here's an update to a story from April 2020 about scientists who had brought their science home with them during lockdown. When we last spoke to insect ecologist Zenobia Lewis, she had taken about 800 moths and stored them in her downstairs bathroom, effectively bringing home her whole lab. You might be able to guess what happened next. Phil Sansom caught up with Zenobia…

Zenobia - It's been an interesting few months, Phil, I have to say. For the first few weeks or months it was great not having to commute to work; I've got my experimental moths literally three metres from where I usually sit. And then they invaded my house. This species, the Indian meal moth, are well known for just being a disaster for working on because they are so hardy and they're so good at invading things; but I'll be perfectly honest, that day when I walked into the lab and there was just hundreds of moths all over the ceiling of the room, I had to close the door, sit down, pour a glass of wine, and calm myself before I could go back in there!

Phil - How bad was it in the end?

Zenobia -
It was pretty bad for a reasonable length of time; I think two months maybe. I was having to go in and do a sweep every single day, and there would be somewhere between 50 and 200 moths somewhere in the room. If that wasn't bad enough, they also contaminated their own food supply.

Phil - As in they pooed in it?

Zenobia - No, they laid eggs in it.

Phil - Oh!

Zenobia - And so these rogue moths were eating the food supply that I was using to keep the lines alive. We literally had moths coming out of the woodwork for weeks. I think we've largely controlled it now, and we've got it down to a handful of adult moths appearing each night.

Phil - Is there any silver lining here?

Zenobia - Our plan is to examine some of their traits, like body size, and compare to some historic data that we've got, and see what this period of stress has done to them. Because it has been stress: they've been in fluctuating temperatures; they haven't had their densities controlled, which is something that we usually do; they haven't been getting standardised amounts of food. And we'd like to see what that has done to them.

Phil - I don't know how long a moth lives for. Are they the same exact moths that were there at the start of the pandemic? Or is this a new generation?

Zenobia - It's been several generations since they first came home, but because they'd been at a lower temperature, and also fluctuating temperatures, it's massively stretched their development period - well, the whole of their life cycle really. Rather than four to five weeks to go through their life cycle it's been taking them two to three months, which is a massive change.

Phil - Okay. If you had to put a guess or a hypothesis on it, would you say that the stress might've made them smaller?

Zenobia - That's also an interesting question. Usually the longer they take to develop the bigger they are, literally just because they've got more time to eat. And so in contrast to what you would expect - given they've been in pretty weird conditions - they are much, much larger than they would usually be, because they're taking so long to develop.

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