What's in your genes?

14 April 2016
Presented by Kat Arney.

As the costs of DNA analysis come down, we've seen the rise of direct-to-consumer genetic testing, allowing anyone to spit in a tube, pop it in the post and get a personalised readout direct to their inbox. But what do these tests actually reveal? Plus, how advertising execs can help us talk about genes, digging up the secrets in dogs genomes, and our gene of the month is totally legless.

In this episode

01:24 - Misha Gajewski - Getting a genetic test

Kat:: Have you ever wondered what’s in your genes? Now it’s possible, thanks to home genetic tests. But what's it like to take one?

Misha Gajewski - Getting a genetic test
with Misha Gajewski, Cancer Research UK

Kat - Have you ever wondered what's in your genes? Maybe you're concerned about your risk of certain diseases, or you're keen to find out more about your ancestry. Now it's possible, thanks to direct-to-consumer genetic tests - such as those offered by 23 And Me here in the UK. But what's it like to take one of these tests? And what actually happens?

Misha - Hi. I'm Misha Gajewski and I am the person who had their genes tested.

Kat - Tell me a bit about the background of this. What was the process that led you towards getting your genome done?

Misha - It was mostly just out of intrigue and also to get my employer to pay for a gene test because I thought it would be interesting to find out if anything was lying deep within.

Kat - That sounds a bit sinister - your employer paying for it. Who is your employer and why were they asking you to do this?

Misha - Cancer Research UK is my employer but they weren't asking me to do it. I thought it would be an interesting article to write about. And so, on the premise of writing a story, I got to get my genes tested.

Kat - So how did that actually work? When people say, "I want to have my genome done" which company did you go for and what did it involve, actually the practical side of it?

Misha - The only one that you can get direct to consumer or by kind of off the shelf is 23 And Me. So that's one we used and that's also pretty cheap. Pretty much, anyone with a hundred quid can go get one at Superdrug.

Kat - What do they actually involved? Did you have to have a blood test or something like that? How did you get the DNA out of you and to them?

Misha - It comes in these little kits, almost the size of a makeup box. In it, there's a test tube in which you spit into which sounds horrendous and it is because you think like it'll just be a little bit of spit like one or two, kind of "pwuh!" But it's actually a lot and you're not allowed to eat or drink for half an hour before hand. So, you're kind of strapped with this horrendous dry mouth trying to like produce enough saliva to fill up this stupid tube. I've read a couple of articles of other journalists who had done it before and they're like, "Do not do this at work. it will be really embarrassing for you and all your colleagues will make fun of you." So, I took mine home which didn't actually turn out to be less embarrassing because my flatmate and a repairman were there staring at me awkwardly.

Kat - Were you like (making spitting sounds)

Misha - Yeah, just trying to work out the saliva to get it in the tube - and you just mail it back to them.

Kat - How long did it take to get some results?

Misha - So, it takes about 8 weeks. You kind of forget about it for a long time and then you get this email saying, "Your results are ready. Go check them out."

Kat - That's kind of a big thing because this is your genetic makeup and potentially, will tell you things about your family as well. So coming into this, what were the sort of thoughts you had about, "God, I wonder what they'll find. I hope I don't have X, Y, Z." Was there anything like that?

Misha - Yeah. So, there's a couple of scary ones. So there's the Alzheimer risk, Parkinson's and breast cancer. So, those are kind of the major scary ones that I was a bit nervous about. Because I did it through work, I talked to a genetic councillor beforehand. And so, that kind of prepped me and maybe didn't make it as scary as if I just gone and opened it without knowing what the test was really about.

Kat - Because most people who do these, they just pick it up off the shelf, spit in the tube and no one sits down and talks through it with them at all.

Misha - No, but 23 And Me does have a lot of information that kind of guides you through what the results are actually showing you especially for the scary ones like Alzheimer's and breast cancer. There's multiple steps you have to go through before you can actually see the results. So, there's kind of this 5-step process before it's like, "Are you sure? Are you really sure? Are you really, really sure you want to see this?" And then finally, they'll let you know what you have.

Kat - And obviously, our genome is something that we share with our family. Did you tell your family you're having this done? Was anyone a bit like, "God! What did she find?"

Misha - Yeah, so the genetic councillor, actually, she said, "Have you talked to your parents because your results are their results?" And so, I ended up calling up my mom and saying, "Would you want to know and then go ask my dad and my brother about this?" It was kind of funny. I got her to record it because my parents live in Canada so I couldn't be there for the physical conversation. So I got her to record this conversation. When she asked my brother, he panicked. He was like, "What? Am I adopted?" He freaked out and I realized all those years of telling him that he was adopted finally paid off for me. It was my longest prank.

Kat - When you got that email, "Here are your results, here is your genome", what was it? What were you actually looking at? Is it like a big string of A, C, Ts, and Gs? How does it kind of come to you?

Misha - So, it comes actually really nicely presented in kind of dropdown menus. So, there's four categories. You can have your traits, so that's kind of physical characteristics like hair colour and you're lactose intolerant, if you have wet or dry earwax, kind of weird stuff like that.

Kat - Aren't these things you know already? Like I kind of know what my earwax is like and I know that I can eat cheese.

Misha - Yeah. So, a lot of stuff you can find out by looking in a mirror. And so, that part isn't all that revealing. And then there's your ancestry which was actually quite interesting because it kind of shows which different parts of the world you're kind of made up of. I'm very white, so that was you know, not that revealing. You know, very typical blonde. And then there's drug response which is kind of an interesting one and that's where mine came up with some variations. So, I think one of them is like a blood pressure drug that if I take it, I don't really react to it. So, it's kind of good to know down the line if you're not getting the kind of response you should and then you'll be like, "Oh, maybe my genes have something to do with it." And then come the big genetic risk ones for diseases.

Kat - I have to ask, if you're prepared to divulge, is there anything in there that made you go, "Oh crumbs!"?

Misha - No. I was so average which was - I don't know. You don't want anything but for the sake of my story, I almost kind of wanted there to be like an increased risk of heart disease or something in there that I could write about and talk about. But everything just turned out normal.

Kat - How did you feel about it afterwards? Were you like, "Whew! I know that now"? How did you respond to having this information?

Misha - So, it took a while to actually get up the courage to open it in the first place. I faffed around for three days after I received the email before I kind of - it's like, "Okay, okay. I'll open it now." But then after, I don't know. A lot of the stuff, you kind of know from talking to your family. If your family does have a higher risk of cancer, you kind of know because your aunt might have had it, your mom might have had it. And so for me, nothing really changed and I'm not going to change any of my health behaviours based on my results. To be honest, I pretty much forgot about it after I opened it.

Kat - Some people are concerned when they have a kind of genetic analysis that potentially, it might have any knock-on effects in the future. Is that something that crossed your mind for example, if insurance companies did change their mind about not using genetic information?

Misha - So, that was kind of an interesting bit of the piece I wrote, was actually finding out the legal implications of doing a genetic test is because right now in the UK, there is a moratorium on insurance companies and employers not being allowed to use your genetic information against you. But you don't know how long that's going to last, if it's going to stick. So, it could change in the future and as like more genetic tests are being developed, it could have a scary implication. I'm not so sure about that one. That one was kind of a bit scary.

Kat - Overall, how did you find the experience? If someone else said, "Should I have this done?" What would you say to them?

Misha - Honestly, it's interesting to just see it on paper almost in print, but it's interesting in the same way taking personality tests are interesting. They tell you something you already know about yourself, but it's kind of reaffirming and kind of like very introspective in a way. But other than that, it's more of a fun thing to do than a serious thing to do.

Kat - Misha Gajewski, and you can read her account of having her genome 'done' and what she found on the Cancer Research UK blog.

10:40 - Anna Middleton - Talking about genes

How do you start talking about genetics? Anna Middleton has teamed up with ad execs to make films to get the conversation flowing.

Anna Middleton - Talking about genes
with Anna Middleton, Wellcome Trust Sanger Institute

Kat - As Misha mentioned, before she took her gene test, she wanted to discuss it with her family. But how do you go about starting conversations like this, especially if all this talk of genes, DNA and genomes is a bit confusing? To get the conversation flowing, genetic counsellor Anna Middleton, based at the Wellcome Trust Sanger Institute in Cambridge, has teamed up with advertising exec Julian Borra to make a series of short films about different genetic concepts.

Anna - I've been looking at how to start a conversation about genomics with people who know nothing about genomics. The reason being that genetic technology is being mainstreamed across healthcare services now. So, it's in paediatrics, ENT, dermatology, obstetrics, and it's moved out of the specialist clinical services, clinical genetic services across the NHS. So, more people than ever before are having to engage with the technology. You might say, "Well, it's not really very relevant to me because I'm not currently using health services" but maybe your relatives are and that's the key thing about genetics is that everybody that we're biologically related to contains information that might be relevant to us too. It's about really reaching the general public and their relatives with very generic messages about genetics really. So, I've been looking at how to do that and employing the skills of the advertising industry who are very well-versed at reaching mass populations, turning complex ideas into simple messages.

Kat - How do you go about starting a conversation about genetics? How have you been trying to get advertisers to help us with this?

Anna - We're doing something I guess quite innovative, in that we're combining methods from social science and methods used in market research and advertising. So, I've done a series of focus groups resembled as a public that are completely detached from genomics currently. So, I've met with a choir, I've met with a council residents association group, I've met with the women's guild group. I even went down and joined a Men's Curry Club. I've met some parents at the school gates and I've listened to how they naturally talk about issues to do with genetics. So, I prompted them for words like DNA, gene, genetics, genomics, and asked them what those terms mean to them and then listen to the natural conversation. I then analysed those in a qualitative sense and taken those themes to Julian Borra who is my partner from the advertising world. He's ex-Saatchi & Saatchi Creative Director. Julian and I then bounced around the themes. So see how natural conversation is happening and then to overlay a narrative on top of that. 

So we wanted to see what metaphors, memes, ideas, people are currently using and then we've given a bit of a creative makeover and turned those into series of animations. The animations, we just use them with these metaphors to try and start a conversation. We don't actually know if they work or not. This is a research project but what we're doing is we're showing animations and asking people to let us know what they think of them. If there's anything that resonates, if there's anything in there that sparks the conversation or makes people go, "Oh! That's kind of interesting. I guess I'd like to share that in some way by talking to other people about it or sharing it via social media."

Kat - Was there anything that surprised you when you started talking to people and you've got something back say, "I had no idea that people didn't understand the meaning of this word or thought about things in this way."

Anna - What was fascinating was that when you say the word 'DNA', the natural response from most of the groups was, "That's something to do with identifying bodies. Is that to do with crime scenes?" When you said that words 'gene and genetics', people said, "Is that to do with families and things that were in families and that's obviously true?" When I said the word 'genomics', there was often this sort of long pause, the silence, and most people said, "I have no clue, I haven't heard of it." And then they would start to break down the word literally. "So genomics - is it to do with gnomes by any chance?" Really taking the word literally. It's very alien concept, alien term so we really like that and we decided to capture the idea of the gnome and see if we could use that as a metaphor for the sequencing. So, the little bearded gnome with the fishing rod, sequencing, looking for information, fishing through all your DNA and seeing is there's anything useful and interesting in there. so that formed one of the animations. 

Of other things that popped up, I didn't actually ask about fears or harms or anything like that, but independently, people mentioned insurance in relation to genetics. So they felt that they could be discriminated against. They'd heard about insurance companies potentially using genetic data to formulate changes to policies. Most people don't actually know that they can't be discriminated against from the basis of a genetic test for insurance companies - they're not allowed to ask if you had a genetic result. But nevertheless, there's this misconception that there will be mass exploitation. So, we made that the heart of one of the animations as well.

Kat - What can people do if they want to see the animation and take part in it? What do ask the people to do?

Anna - What we'd really like them to do is to go to genetube.org. that's our little research website and you click in there, you can see the animations. You get asked a few questions, you can bounce around between the animations, just let us know what you think. You might love them, you might hate them, either way, it's very useful to know. You might think, "No idea what this is all about. What's the point?" So you might think, "Actually yes, that would help me start a conversation." This is just trying to do evidence-based science communication and trying to work out how to do it better. I mean, this is really just a starter, just to get some ideas. The next level would be actually to turn these into proper films and to build on the ideas, and to try and get a bit more evidence about what works and what doesn't.

Kat - It is going to be more and more important that the general public understands more about genetics. Where do you think are the key gaps? Is it at schools? Is it more widely in the media? Or is it just everywhere?

Anna - I think there is a lot of information out there about the science of genetics. You just have to go on to YouTube and you'll see thousands of films that will give you the science. What we were trying to do is just something a little bit different, a little bit more creative, trying to deliver the messages in a slightly different way. And to work out whether they work or not and if they do, then we could build that into something that is useful for schools and is useful for patients and is more widely available. So, it would take genetics out of the more niche market into the mainstream market. So, it should be really stages of trying to work out how to do that. So, if it can go mainstream then fantastic. I think we got a long way to go before we reach that point though.

Kat - You wonder if as many people would talk about genetics as talk about the football.

Anna - The wonderful thing about genetics is that it just connects us all. It's what ties us to our relatives and ties us to humanity. It's all about us. It's all about our identity. To me, that's far more exciting than the football.

Kat - Anna Middleton, and you can watch the films and contribute to her research project at  genetube.org

18:17 - Maternal gene therapy trial

Researchers have found that pregnant women would be prepared to take part in a gene therapy trial for the condition fetal growth restriction

Maternal gene therapy trial

An international group of researchers, including those at UCL and Queen Mary University of London, found that almost all of the 34 pregnant women in a small ethics survey would be happy to participate in a clinical trial for gene therapy if their unborn child is suffering from severe growth problems.

The scientists - all part of a consortium called EVERREST - are currently planning the first ever trial of this kind of maternal gene therapy, but they needed to know whether mothers-to-be will actually be happy to take part. Because if they aren't, then that's a big problem. The condition to be treated - known as fetal growth restriction - affects up to 8 per cent of all pregnancies, and is usually caused by a lack of blood flow in the womb and placenta.

At the moment, women whose babies are affected by the condition either have to deliver their baby prematurely, to give it the best shot at life, or risk the chance that it may die in the womb. So it's hoped that the new treatment will help to reduce stillbirths and babies dying shortly after birth, as well as cutting long-term complications such as cerebral palsy, diabetes and heart disease in children that do survive.

The gene therapy designed to treat it has been in development since 2013, involving putting a gene that makes a molecule called VEGF directly into the arteries in the mother's womb, where it helps to stabilise the blood vessels and encourage blood to flow. So far it's worked well in animal studies, so the time has come to take it into trials in humans in the next year or so - so fingers crossed for a successful outcome.

20:15 - Jeff Schoenebeck - Dog genetics

Humans aren’t the only animals to be getting their genomes analysed - our four-legged friends have been getting in on the act too.

Jeff Schoenebeck - Dog genetics
with Jeff Schoenebeck, Rosline Institute

Kat - You're listening to the Naked Genetics podcast with me, Kat Arney. Still to come, we'll be learning about a legless gene of the month. But first, humans aren't the only animals to be getting their genomes analysed - our four-legged friends have been getting in on the act too, as I found out when I spoke to Jeff Schoenebeck from the Roslin Institute in Edinburgh.

Jeff - The differences between pugs and great Danes and these dogs with very disparate shapes, what's remarkable is that it seems like in dogs, these things that are driving shape differences can be held in a couple of hands. So, this is quite a striking difference to other species and I think about human stature and the genetics of something like that in humans which we know from studies, there's hundreds of variants that seem to be important that are playing into this determining stature. In dogs, what we have are, at the moment, it depends on the study and how it's designed but somewhere in the 10s of variants that can be playing into this. That's a remarkable difference, but bear in mind, a lot of these variants had to be recognised by breeders in the litter. So, I think the difference between dogs and humans or other species is that the variants that are particularly affecting morphology probably have larger effects than what would typically be found in a population of humans.

Kat - Different dog breeds have been very highly selected for. They want the long ears of a basset. They want the kind of the luxurious hair of a poodle. How do you start pinning down some of these genetic differences that lead to these really quite disparate traits?

Jeff - So, we begin by comparing the skulls - the shapes and sizes of skulls across animals. Our study design is based on patients that are coming through the referral hospital, many of them coming through The Royal Dick School of Veterinary Studies. These patients are coming because there's a diagnostic purpose for them to have a CT scan. But we can take that information when a dog gets a head scan and we can use it to reconstruct the head and we can derive size and shape from those animals. And so, we can feed this information into our genome wide association studies which for all intents and purposes tell us what area of the dog genome and what piece of DNA is carrying a particular genetic change and is driving a pug to have a shorter snout. That's the first part. So, we want to find a signal that's driving a particular shape-related event and we want to identify what chromosome and what region in the chromosome that change is located on. 

And then we want to look across our data and by comparing dogs of similar shapes to those that lack that shape and identify what is the minimal region where this mutation or this genetic change could fall in. Is it a hundred thousand positions, is it 90,000? Once we have an interval defined then we leverage these whole genome sequencing technologies that have come on board in recent years. We sift through genotypes and genetic variants and we try and infer what is the best candidate there that can be causing this morphological change. Ultimately, we want to understand what is the change at the DNA level that's driving the trait. In future, we'd like to characterise the biology behind this, but it's still a bit of early days for us. We're still trying to define what are the places in the dog genome that drive size and head shape.

Kat - More broadly, looking at other studies that have been done, what sort of genes have been identified that gives some of the varieties to dogs that we see?

Jeff - I think among the morphology studies, size is where the most data exists. We see genes that make sense, things that affect insulin signalling, insulin growth factor 1 which we know in a myriad of species can affect overall animal size. Growth hormone receptor - again, this is a gene who captures signalling molecules and signals downstream to modulate growth. So, these are fantastic. They make sense in terms of why they've been selected by breeders to modulate animal size. From the skull side of things, it's still pretty wide open and this is again the interest of my lab is to put this issue to rest so to speak. We can infer that BMP signalling is probably involved, bmp standing for bone morphogenetic protein. So that makes sense. There's still a lot to be done.

Kat - One of my favourite traits in dogs is the little stumpy ones, things like corgis and dachshunds, and bassets. Is there a similarity between these kind of stumpy dogs in terms of their genetics?

Jeff - Absolutely and this is a fantastic work Heidi Parker in Elaine Ostrander's lab, wondered the same exact thing - what is driving dogs to have smaller legs? The technical term for this is asymmetric chondrodysplasia.

Kat - Cute stumpiness.

Jeff - Exactly. So she compared all the belly scraping dogs to those that stand high off the ground and looked for genetic differences between the dogs with the short legs and the dogs with the long legs. She found this beautiful signal on chromosome 18, used other tools to see, well, was there breeder mediated selection in this area on chromosome 18 and indeed, there was. And then through using sequencing and mapping technologies, she was able to find a region and it turns out that it's an additional copy of Fgf4.

Kat - What does Fgf4 do and how did an extra copy of it get into these short dogs?

Jeff - Fgf4, fibroblast growth factor and there's a large family of FGFs and they're involved in a host of different biological processes. But they have a very prominent role in development. FGF4 in particular is a gene that's required for normal limb growth. In many species, this has been demonstrated. And so, what we think occurred in dogs, and this is due to the structure, this additional FGF gene that was identified, and what we infer is that it's in fact, a copy of RNA - the message of the gene had been reverse transcribed back to DNA and that DNA got inserted back into the genome. So, the dogs wound up with an extra copy of Fgf4. Somehow, this extra copy, the overexpression of this gene is probably perturbing limb development, so it's restricting limb growth.

Kat - And then presumably, some owner of that dog went, "Wow! That's cute. Let's make more of those."

Jeff - Absolutely. Getting back to this idea of form and function, here, it's men saying, "These dogs have a form that can suit very well in the function of going into holes of badgers or rabbits and chasing out prey or unwanted pests in the farmland." And so, many of these dogs that have this FGF retrogene are dogs that are used for hunting in burrows and then the other large bodied dogs that have this are cattle herders. So, the idea being that they're so low to the ground, if a cow kicks, it'll swoop up above the head and they'll miss it. It won't connect with their head.

Kat - That was Jeff Schoenebeck from the Roslin Institute

28:15 - Gene of the Month - Pygopus

Our gene of the month is Pygopus, named after the species of Australian legless lizard.

Gene of the Month - Pygopus
with Kat Arney

And finally it's time for our gene of the month, and this time it's Pygopus. Named after the species of Australian legless lizards (not snakes - they're definitely lizards!), Pygopus was first discovered in fruit flies in 2002. Working together with genes known as Legless and Wingless, Pygopus has a range of roles in the developing fruit fly maggot, including setting up the basic body plan, guiding the development of the gut, heart and brain, along with the structures that go on to form parts of the adult fly, including the wings and - unsurprisingly given the gene's name - the legs. And it's not just flies. Versions of Pygopus have been found in other species, including humans. We have two versions of the gene, and Pygopus faults have been implicated in bowel cancers and other types of tumour too.

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