A Dog's Life: Intelligence and Inbreeding

It is well known that redheads with pale skin and freckles are prone to sun damage. Now, new research from the Sanger Institute in Hinxton has shown how the gene associated with being a redhead not only increases the risk of developing skin cancer but also makes the tumour grow much faster. What's more, this gene can also be carried by those without red hair, meaning many are unaware that they are at a greater risk. In fact - it is estimated that 25% of UK adults are carriers of the gene. Redhead Claire Armstrong spoke to Dr David Adams to find out more...

David - What we were interested in in this study was exploring the link between variance in a gene called MC1R and this is the gene that's associated with being a redhead, and the effect that this has on the number of mutations that are found within a type of tumour called melanoma. A melanoma is a kind of skin tumor and they arise from cells called melanocytes which are found in the skin. Melanocytes are the cells which produce melanin and melanin is associated with tanning, so melanoma arises from those cells. If you're an individual who has no mutations in the gene MC1R, then you are someone who will tan but people who have one of these MC1R will freckle and they produce a slightly different form of melanin.

Claire - How do you know if you have these gene? I'm a redhead so I'm assuming that I have the gene but neither of my parents are redheads.

David - Right. So if you have two copies you've got a complexion like yours so red hair, probably pale skin and freckles. If you carry one copy, these people generally have pale skin and often freckles but they need not necessarily be redheads. It's generally the pale skin and freckles that would tell you carry one of these, what's known as an allele, which is a mutation in MC1R gene.

Claire - And are both of these groups in general more at risk of getting skin cancer?

David - If you are a redhead you're about four times more likely than the general population of develop melanoma. If you're one of these people who carries one of these variant form of MC1R, then you are about twice as likely. So this is further biological proof about exactly why that it is really the mutation number that is influenced by having one or two of the allele MC1R variants. So we looked in tumours that were established, so these were tumours that were removed when they were quite large. And what we found was that the number of mutations that you would find in an individual who carried one of these alleles equated to around the number of mutations that are in individuals without one of these alleles would get in 21 years.

Claire - And how did you study this? How did you study the increased mutations?

大卫-这是一个巨大的国际合作and, fortunately, genome sequences had been generated for over 400 melanomas and these melanomas came from people all over the world, so we downloaded the data and reanalysed it.

Claire - What's actually going on then at a cellular level with these gene when you have the mutation in the genome? Do you know why it's giving rise to more mutations in the tumour than when you don't have the gene?

David - So its around the ability of individuals who carry these variants to produce that mature form of melanin, so the mature form is the darker coloured melanin. So the melanin, when you carry one of these variant forms of MC1R is not fully processed through to that darker form, and so you get a type of melanin that is red in colour and this particular type of melanin is less able to protect the cells of the skin from the effects of UV radiation.

Claire - I guess in the UK where we don't have very much sunshine unfortunately, actually 10 million people are deficient in vitamin D which we get from the sun, but then at the same time we don't want to be over-exposing ourselves to the sun. So what would be the best balance - we want to get some vitamin D!

David

You may have heard of something that has been rolled out this week calledpokemon go. This is a mobile game which has people catching fictional creatures called pokemon in their local area- and it uses something called AR, or augmented reality. Augmented reality and its cousin virtual reality are coming our way - with companies racing to have their tech ready and on the shelves as soon as possible. But how does it work, and what does this mean for gaming? Naked Scientists tech wizard Peter Cowley took Georgia Mills through this new frontier of gaming...

Peter - There are two parts to those two abbreviations VR and AR. VR is virtual reality and AR is augmented reality.

First of all virtual reality is where you are effectively completely immersed in an environment, which could be real, it could be created by computers which give you sight, touch, hearing, and even smell.

Augmented reality, which is the pokemon connection is, in fact, a computer simulation on top of real life. So in the case of pokemon, you are wandering down the street, you can see an image of what's in front of you but a pokemon character - whatever they call it because I don't play the game - will appear in front of you and you are trying to find those. That has a massive adoption recently - I believe about 20 million people are playing it already. It was only released two weeks ago - phenomenal!

格鲁吉亚——是的,服务器是完全失望。我知道this because I was trying to find pokemon in the studio earlier and then it broke. So is this changing gaming?

Peter - Yes. First of all the reason it's suddenly become adopted so much is because of mobile phone technology which allows great video, accelerometer, low cost and everything. Gaming - yes I had a look at that and I'm a bit surprised. And a big survey of nearly 20,000 gamers, only 15% said they'd buy something that was virtual reality and that might be to do with cost, unlike some of the ones we're just about to look at which are £10 each, the high end ones can be many hundreds of pounds or even low thousands. But I well imagine when these prices come down in a short time, a year or two, many gamers will be using virtual reality.

Georgia - So how does it work? We've got a couple of examples with us here in the studio...

Peter - Which we are going to switch on in a moment. Basically, virtual reality works much better. Clearly when you've got binocular vision which means a screen - we're both using mobile phones - is split in two so each eye sees a different image. That method of doing it then allows you to create depth so you can actually see around. Then the accelerometer and the GPS inside the phone, and the compass allow you to move your head around so you can look up, down and it will give you a different image based on that. So rebuild the screen based on that.

Georgia - I see. So I've slipped my phone into this cardboard contraption - it's very simple. It's just folded cardboard with two little glass goggles and you stick it on your face and I've gone on a tightrope simulator. I don't know why I did that because I despise heights. But when you move your head it around it really does look like you're there. I'm looking round and I think it's the Grand Canyon I'm tightroping across at the moment.

Peter - Yeah and I'm in a different one. Excuse me if I move away from the microphone but I've just come out of a cage in a load of sharks and the sharks are swimming around me. Ooops...

Georgia - You went into the microphone there.

Peter - So looking up and down I can see divers there below me and above me and I can see sharks that are apparently going to attack me - I think!

Georgia - So apart from the perils of whacking into my microphone, and I suppose we both look quite stupid as well holding these big cardboard boxes to our heads. But what kind of things do they need to work on for this to work?

Peter - The two big ones are the fact that computing power isn't probably quite fast enough. So what's called rendering, which is rebuilding the image, can be a bit slow and when we tried it earlier with different generations of a particular phone, we found quite big differences between those but it's getting there, the technology is getting there.

另一个这是恶心或平衡sues. When you've got this on you've got no means of connecting yourself with the real environment particularly if you've got some sensing device on - gloves or something - you're completely immersed in that. In the way that some people are more affected by being on a boat, and some people are more affected by reading in a car, there will be some people who suffer more from it than others.

There are also a few other things as well. There's obviously the input devices ,which I think Graihagh's going to be talking about later, how to actually interact. And secondly possibly addiction. You know you can quite enjoy being in your virtual environment compared with normality...

Georgia - And what about outside the world of gaming what kind of use can these have?

Peter - I've used on AR effectively to read a menu recently. So this is where you point it at a menu and it's translating the food in real time in front of you. If you are in Russia are something it's very easy if you don't speak Russian. But there's lots of sensible applications. Some military, medicine, tourism, archaeology. Can you imagine architecture wandering through a building that you're designing. To be able to see it before it's actually been built.

Georgia - Save money I suppose if you didn't like the design!

Peter - Exactly. Change the design, exactly, yeah.

How did wolves turn into dogs? Humans and wolves have been interactingtogether for as long as both species have been on the planet, but the first evidence of dog-like characteristics appearing is about 15,000 years ago. But what caused this? Well, just last month a study uncovered a revelation about this domestication - it happened more than once! I spoke to Greger Larson from Oxford University to see what he had dug up...

Greger - The first big thing that we've just discovered is by sequencing a genome of a 4,800 year old dog from Ireland. From that we were then able to compare that very conclusively to all the modern genomes that have been sequenced and that then, through the analysis, through the phylogenetic trees and molecular clocks, and looking at the pattern of different genetic signatures in time and space made us think that perhaps dogs were domesticated not once as being previously suspected by a lot of geneticists, but twice.

Georgia - What are the implications of this domestication happening twice?

Greger - Well if it's happened twice that makes it go from being something like an accident - I mean anything can happen once. But as soon as it twice on several thousand miles, several thousand kilometers apart from each other, it seems like maybe it sort of lends an inevitability to this that makes it seem like there was a set of environmental circumstances that was the same over a very wide range wherein people and wolves started interacting in a way that they hadn't done for the last 150,000 years prior to that. And that interaction, and that sort of romantic dance, as it were, between the wolf population and the human population getting used to one another and partnering up in a way that they hadn't done before that led to what we now know as domestic dogs.

Georgia - Do we know about how this came about?

格雷格-我们真的不。我们可以从l猜什么ooking at comparisons and using analogues from the rest of the natural world. So, one hypothesis that we've been talking about recently is this idea that there were potentially different wolf ecomorphs, and by that I mean different populations of wolves that were specialising based upon the kind of they that they were going after. In the same way that there are killer whales off the northwest coast of North America, some pods go after salmon, some pods go after seals, and they don't really like each other, they don't really talk to each other. When calves are born they're raised in either seal eating or salmon eating and they kind of know that the other killer whales are out there but they don't really talk to them that much, and we know that wolves are very capable of this. There are very well known wolves that are on the TV every week that hunt caribou, but there's other wolf populations that don't go anywhere near the caribou and subsist of completely different resources in forested environments.

So what we suspect might be happening is that about 15,000, maybe a few thousand years before that, maybe two independent wolf populations started following people rather than following anything else, or rather than trying to get resources in any other means, and getting used to that human niche. And in doing so would start to protect that human niche and that would initiate reduction in the gene flow between that wolf population and wolf populations that were doing other things. That may have activated this process of domestication very early on which wouldn't require any initiation from people who were acting intentionally in goal directed fashion to try and generate a chihuahua puppy from a wild wolf, which of course they couldn't have known about because there were no domestic animals.

Georgia - So while one group of wolves made its living from following humans, others did not and the two groups wouldn't have interbred so started to change. The wolves who hung around humans need different characteristics t do well: having low fear and low aggression. And, over time, this relationship became more and more entrenched and people started selecting which dogs would live and which would die, and selecting for tameness also changed the wolves in other ways...

Greger - There was an experiment in the '50s in Siberia, where they were just selecting for foxes solely on the basis of how a lack of fear and a lack of aggression that the demonstrated when someone put a hand into a cage. And they only selected those animals that had the least amount of fear, or the most curious, and the most friendly and within a couple of dozen generations, those foxes started looking like a lot of the characteristics that domestic dogs have. They started getting smaller overall, they had differences in their shapes, and their coat colours, and their snouts, and they started barking. So it was a very clear demonstration that simply by selecting for a tame behaviour you can get all of these changes that we recognise as what we call the domestication syndrome.

Georgia - And so wolves started to become dogs. But why did humans tolerate these animals being around in the first place?

Greger - You are much better able to exact resources and to get calories out of an environment when you've got a wolf partner. And here are many instances where from Japan to Southern Scandinavia to even the southeast corner of the U.S in the mesolithic, prior to the advent of agriculture or at least prior to agriculture arriving in those areas, where people are burying their dogs with more grave goods than they're burying with a lot of people. I mean seriously, these dogs are being revered as very hugely important members of society - as equals, or in some cases even better than some of the people.

So there was a clear partnership there and you would only do that if those dogs were very important to your well being in those environments . There's lots of speculation about how they were used in hunting and clearly they have much better olfactory capabilities than we do. And if you were able to cut an animal with a microblade on a long stick and then the animal runs, it's hard for us to find if it runs in a dense forest but dogs have an amazing sense of smell and would be able track them down and that would lead the humans to them and boom... you've got dinner!

Georgia - Man's best friend indeed! And dog's were the very first domestication in human history. It was the start of a trend which led to life as we know it.

Greger - So until you have domestication you certainly don't have the capability of humans expanding their population sizes to afford the kinds of technological advances that we've seen over the last 10,000 years.

During the Victorian times humans started selecting for much more extreme looks and sizes for our dogs - creating so called 'pedigrees'. But this has caused problems: it has resulted in some breeds having extreme features, like short legs or long bodies, that can affect their quality of life, and what's more - when you breed from a narrow gene pool, genetic defects or inherited disease become common and widespread. And while people fork out a fortune for a pedigree dog, each breed has its own set of problems they are likely to suffer from, such as tumours, arthritis or breathing problems. Georgia Mills wanted to know more about one such disease - one suffered by pugs and bulldogs, which causes them to struggle breathing, so went to Cambridge Veterinary school, to meet Jane Ladlow, who is investigating this disease and trying to set about solving it...

Jane - The disease that we are interested in is Brachycephalic Obstructive Airway Syndrome - that seems to be an issue in the smaller dogs that have the very, very short faces. So we look at the three extreme brachycephalic dog and we think of these as the pug, the bulldog, and the French bulldog. And they've been bred to look very appealing to people and they way they do this is they make the nose shorter, larger eyes, and a little bit more like a human baby face. They have become exceptionally popular in the last few years. So it used to be that you'd expect to see 4 or 5,000 particularly French bulldogs around and now you will see 10 times that amount so a very, very, popular breed. And that means you're starting off with quite a small number of breeding stock and that your using them more and we're also getting more dogs in from different countries and we're not sure about their health. So it's a population explosion that is causing quite a lot of the problems we're seeing.

Georgia - And what are these problems causing for the dogs?

简,我们特别在呼吸,what's happened in some of these dogs is as their skull has reduced in it's length, the soft tissues within the skull have not reduced in the same way and this means they have areas of obstruction in their upper airway and you can hear this. Many people think it's normal to hear a bulldog snorting as it walks past you, but that indicates there are levels of obstruction in that airway.

Georgia - That's horrible! So all this soft tissue is crammed into this much smaller space meaning the air just finds it really hard to get through?

Jane - Exactly - that's exactly it.

Georgia - This is something you study here. How are you looking into this?

Jane - We started quite a few years ago now. So the problem with this disease is that it's a very difficult disease to measure. Doing functional breathing tests on dogs is more complicated than humans because they won't cooperate in the same way. With humans you can say breath into this tube and you can get spirometer readings but with dogs, if you handle them or put a face mask on them, you can alter their breathing. So unless you can actually measure what a normal dog is like, and what an affected dog is like, then you can't really determine how many dogs are affected, and how badly they're affected. And also, for me, I had no real idea how well these dogs were responding to treatment.

Now we used to look at owner questionnaires, and owner questionnaires are useful but many owners don't recognise the disease symptoms in their dogs. So there has been some work done that has shown 60% of owners do not really recognise the signs of obstructive airway disease

We tried lots of different techniques: we tried a treadmill and that wasn't very good because bulldogs went off the end, and we tried putting tapes round them to measure how their respiratory functions alter in the thoracic wall in the abdomen, but many of our dogs are barrel chested and the tapes move. So, after trying lots of different ways of trying to measure respiratory function in these dogs, we came up with a new technique which we call plethysmography - whole body plethysmography.

Georgia - Jane showed me the kit they used for this technique. There's a clear plastic box with a comfy doggie bag inside. The dog settles down in the box and the pressure changes inside are measured and recorded on a laptop. This then shows how much air the dog can get in and out of their lungs and how efficiently. I wanted to see the box in action so we recruited willing bulldog Ronnie...

Hello! Hello! No don't eat the microphone! Oh you are friendly and a bit smelly!

Jane - We did have one dog that we used to have a temperature probe in the chamber and one dog ate it. So all our probes now are outside the chamber...

Georgia - Once Ronnie had settled down in the box, we could watch his breathing traces in real time. This technique has allowed Jane and her team to quantifiably estimate how bad an individual case may be. And after testing over 800 dogs, it looks like up to 60% of pugs and 50% of bulldogs have this disease, which isn't good.

Jane - Unfortunately we're not sure what proportion of animals die from Brachycephalic Obstructive Airway Syndrome because they are often just recorded as acute deaths. And it's also reported as heat stroke because another thing these animals can't do if you're not panting and breathing effectively, then you're not cooling yourself down properly. So it's often put down as acute death or heat stroke, but certainly a proportion of them would be exasperated by their respiratory obstruction.

Georgia - Ah because yes, dogs can't sweat can they - they lose it all through panting?

Jane - Yes, so panting is vital and this is why you will hear a lot of information about not taking out Brachycephalics in the heat of the day, which is sensible, but it's a little bit of shame that we have to look after them so carefully because they have breathing issues.

Georgia - What else can we do about this?

Jane - Well, if you have an affected dog, then we can manage the disease in a number of different ways. So we can be careful about when we exercise, we can use coats that keep the animals cool, and then for dogs that require more help we have surgical procedures.

The other thing that we are looking at in the longer term; we have Dr David Sargan working on the genetics of this disease and we are hopeful that in the future the geneticists may be able to offer some guidance to the breeders. I don't think it will be simple yes or no affected tests, but it might be an estimated breeding value where you could look at a couple of dogs and you can say, ok well if you breed this particular dog with this particular dog then your odds of having affected progeny are so much, and that will at least give breeders a lot more of an idea of how to improve the health of the breed. So I think longer term we do need to look at trying to support the breeds and improving the health.

The other discussion is whether we bring some different blood into some of these breeds, which is a very difficult question because for a number of the pug breeders, it's the pugs we're particularly thinking of, it's a very emotive area that you shouldn't really change the breed, but maybe that's a faster way to improve the breathing. But these are questions that the Kennel Club will have to think about.

Georgia - Should people who care about animal welfare buys pugs and bulldogs if this is such a big problem?

Jane - I think you have to be exceptionally careful where you get a brachycephalic dog from. So if I was going to buy a brachycephalic dog, I would go and I would look at the mother; I would ask to look at the father and have some idea of their breathing. I wouldn't just want photo's I'd actually want to go and visit the parents. I'd want to see some other bulldogs, or French bulldogs, or pugs that have been produced by those breeders, and I'd like to see the dogs exercising and having a normal life. There are good dogs out there. However, unless you're going to do your homework very carefully, you do have a risk of having a dog that has this horrible problem.