Why humans are so different

05 January 2016

Interview with

Professor Hugh Montgomery, UCL

We share almost all of our genes with one and other yet, we're totally different. Ifcrowd you get a combination of your parents genes - what determines what traits you get from which parent? Professor Hugh Montgomery took Graihagh Jackson through her A, T, Gs and Cs...

Hugh - Well fairly straightforwardly you've got your genes.  You probably know roughly 20,000 genes is what you've got, and it's that common inheritance of 20,000 genes that are pretty much the same that makes you a human being - that's what determines your species.  But you inherit half of those genes from your mum and half of them from your dad and what determines the way you are is the combination of those genes that you inherited, the gene variants in them, and the environment that you expose them to.  And that's why you're different from your brother, or indeed from any human that's ever lived before or who will ever live in the future.

Graihagh - When you say gene variants - what do you mean?

Hugh - Well there are subtle variations in that sequence that means that those genes differ very slightly.  Now some of those variants don't do anything functional at all, but some of those little changes are in areas that regulate the way the gene is expressed - so you could imagine that as being a slightly twitchier brake or accelerator pedal in the bits that control the gene.  So those gene variants can make no difference or they can make quite big differences, and those variants come in different flavours.  There are big differences where you can have an extra bit of a chromosome tacked on the bottom end, or you could have a bit missing which is called deletion variance, or you can have copying errors where pretty much an entire block of a gene has been copied several times, so you end up with repeat sequences.  So lots of ways in which it can vary.  Not much of it's variable though.  You are very, very similar to other human beings in your genetics but you are very different in who you are.

Graihagh - This is quite a staggering thought - we share almost all of our genes with one and other yet we're totally different. So your environment must be a pretty important factor in shaping you, just how much though?

Hugh - The rest of its environment and, as a rough rule of thumb - and it is rough, you could say that roughly 30% of the variation in any particular trait, any particular way you are, will be down to the genes you've got and sometimes it's a lot more.  So, if you look for instance at how fat teenagers are - 13/14 year olds - oddly enough more than 70% of the variation in that is due to genes.  And that applies to everything - it applies to whether you drink alcohol, if so how much, how tall you'll grow, how fast you'll run.  So, if you think of the alcohol thing, there's strong genetic traits whether you choose to drink and, if so, how much but a very, very strong environmental signal.  So, if you're in a country where you cannot buy alcohol then you can't drink any, and it it's priced to a point where it's massively expensive, alcohol consumption will be low, and that's an environmental factor interacting with the genetics you've inherited that predisposes you to choosing to drink.

Graihagh - Hmm... My brother and I, we grew up together and experienced the same environmental pressures, so does that mean Charlie has a six pack gene?! Is there even such a thing? As it turns out, there are actually very few 'fitness genes' that we know of...

Hugh - If you don't know where to look it's a needle in a haystack.  There are probably another three or four for which there is solid evidence; there are good data to say its influential.

Graihagh - You discovered the first fitness genes - the ACE gene. I wonder whether you can just unpick what that is and, actually, how you discovered it, because you've already mentioned there's 20,000 genes.  How did you just identify that one gene as being really key in your fitness ability?

Hugh - Well I suppose it's probably fair to say we found that, to a degree, by chance.  There are many ways in which you can try to identify the relationship of one gene or gene variant with a physical trait.  We took what's known as a candidate gene approach.  So it's where you have a suspicion that a gene or a gene variant is doing something and then you look to see whether it is.  Now in this particular case, this gene called ACE which encodes something called angiotensin-converting enzyme - that's why is known as ACE, and we wanted to know whether this gene and its product Ace regulated heart growth in humans.

So I asked the Army if I could ultrasound scan the hearts of army recruits at the start of training and at end of 10 weeks of training.  If we could relate the size of their heart to the gene they carried.  So in principle exercising makes you heart grow stronger - it's like any muscle, if you exercise it, it will grow.  In this case, the recruits are all basically the same age and race and in those days the same sex as well - all men, and they were all undergoing exactly the same physical training, and they were eating the same food, drinking the same water.  So in this case, we controlled for the environment.  So they were all getting the same environmental drive for the heart to grow and, therefore, pretty much all of the difference in heart growth will be genetic.  So we have taken the environmental bit out and what we found was we were right.

Graihagh - Now, remember how Hugh talked about how genes variants and how genes express themselves differently? In the case of the ACE gene you could you could have few extra base pairs tacked on to the end, which they called the I variant;

Hugh - Or you could have missing, which is called deletion variance.

Graihagh - The deletion variant form of ACE is called simply called, D.

Because you get one gene from your mum, and one from your dad you can be DD, II or DI.

If you have the DD, you produce much more of this muscle making protein, ACE. The army folk grew bigger hearts but they actually worked harder too.

If you're II, you may work less hard, but as a result, you're much better at conserving your energy and thus, endurance sports...

Hugh - And what we found that people with two D versions of genes, hearts grew many, many tens of times more than the people with two insertion bits, the bits present where they had low expression of this ACE.  Now one of the obvious confounders of that would be to say, well yes, Hugh but that's rubbish isn't it, it's just that the DD people worked harder and their heart had to work harder to do the same exercise.  And we thought, well that's not true, but we'll look and see and it turned out that it was true.  That to get the same external workout on a bike, if you measure how much people were pedalling to get the same external workout, the poor old DDs were having to do a lot more mechanical work and their hearts were having to work a lot harder too.  Anyway, to cut a very long story short that told us that ACE was important with fitness, and what we found was that the I version of the gene tracks with endurance performance.  So, this is if you're wanting to do something that involves fatigue resistance or very long very long distance running, you want the I version, and if you want to build up strength or do a power sport like swimming or sprinting, then you want the D version.

Graihagh - What are you?

Hugh - Well I'm a DD.  I should put a caveat on this - this is a very personal view - I don't think it's a good idea to be genetically tested but, as it was back in the day, I did run mine for experimental reasons and I know that I'm a DD.  Now it fits with my sporting history; I was a strong swimmer, so all of that tracks well with that genotype.  The bit that doesn't is mountaineering.  Mountaineering is very strongly skewed towards IIs.  DDs - there aren't many amongst elite mountaineers.  Only about 5% of the elite mountaineers we've looked at are DD.  I'm not elite; I can certainly get up big mountains though, and I suppose the point about that is most things in life aren't down to just one gene variant - there are many gene variants.

Graihagh - I'm starting to think everything about my life might be slightly predetermined and I have no choice in where I'm going or what I'm doing.

Hugh - Well it's certainly true that part of it is.  I mean the part of you, you have not been able to regulate what colour you hair was unless you get a bottle and dye it.  You couldn't regulate how tall you chose to grow, you just grew didn't you?  You ate and you grew.  If I told you; if you really, really, really, really starve yourself to the point of ridiculous, you wouldn't end up a few inches shorter.  You might have had some control over it but beyond that you wouldn't.  So a lot of what you are; you just need to think of some of things like your behaviours as being like hair colour, they are strongly genetically influenced but you have some control over them.

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