#228      24 min 06 sec
Show us your mutations: Curating genetic variation in human populations

Geneticist Prof Richard Cotton discusses the Human Variome Project, a global initiative to collect and curate all human genetic variation affecting human health.

"We have 20,000 genes and each of those genes needs to be intact for us to develop and function normally.  If one of those is wrong and has a fault in it, the embryo may not even develop or you can go right to the other extreme where the disease like Huntington's Disease in fact will only develop when the person is about 40 years old." -- Prof Richard Cotton




Prof Richard Cotton
Prof Richard Cotton

Prof Richard Cotton AM BAgSc., Ph.D, D.Sc. (Melbourne), FRCPA(Hon.) initiated the Mutation Research Centre, now renamed the Genomic Disorders Research Centre, in January 1996. He has always been interested in the biochemical genetics of human disease and has recently focussed on mutation. In 1992, he initiated the journal Human Mutation. In June 2005, he was admitted as a Member of the Order of Australia for service to science through genetic research, particularly through the development of technologies to detect gene mutations that underlie birth defects or cause disease and through efforts to document findings. In June 2006, he convened a meeting, co-sponsored by WHO, which initiated the Human Variome Project (HVP). The Human Variome Project has recently been given the status of NGO official partner of UNESCO (consultative status). Richard is currently the Scientific Director of Human Variome Project, and was till December 2012, the Director of the project's Australian node. He is also the Co-Editor of Human Mutation.

Credits

Host: Dr Shane Huntington
Producers: Eric van Bemmel, Kelvin Param
Associate Producer: Dr Dyani Lewis
Audio Engineer: Gavin Nebauer
Voiceover: Nerissa Hannink
Series Creators: Kelvin Param & Eric van Bemmel

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VOICEOVER
Welcome to Up Close, the research talk show from the University of Melbourne, Australia.  

SHANE HUNTINGTON 
I'm Shane Huntington, thanks for joining us.  In 1953, James Watson and Francis Crick unveiled the structure of the DNA double helix, ushering in an exciting and frenetic era of genetics research that continues to this day.  In 2003 the Human Genome Project published a complete draft of the more than three billion genetic letters or nucleotides that form the structural blueprint of our species.  Individuals can have their own genome sequenced inexpensively, opening up the great potential of personalised medicine.  What the Human Genome Project failed to capture was the incredible diversity that exists between each of our individual genomes.  There is significant variation from one person to the next and whether we like it or not, we all have mutations that affect us to varying degrees.  Gaining knowledge of these mutations in order to form health strategies to respond to them is a crucial next step and one that requires compiling and analysing extensive quantities of data collected from diverse human populations.  In this episode of Up Close, we speak to the founder of the world's primary data resource of genomic variations, the Human Variome Project.  Professor Richard Cotton, a geneticist, is now Scientific Director of the Human Variome Project and director of the project's Australian node.  Welcome to Up Close, Richard.

RICHARD COTTON
Well, it's a pleasure to be here and thank you very much for having me here.

SHANE HUNTINGTON
I'd like to start with the idea of mutation.  It has a negative connotation to it, but is it fair to say that we are essentially all mutants to some degree?

RICHARD COTTON
I think that's taking it a little bit to extremes.  The point is that we all have many variations in our DNA and many of those give the colour of the hair et cetera et cetera so they're not so important medically, but when we have children, you may well have a child where that mutation or faulty gene is expressed.  So yes, we all are mutants to a certain extent.  I just read this morning that there's something like 400 of these faulty genes and they will only expressed if they have children with someone who has one of those 400.

SHANE HUNTINGTON
Are human's different from other species in this regard, or is this a commonality throughout the animal kingdom?

RICHARD COTTON
It's certainly common in the animal kingdom.  You can see of course albino animals; that's a mutation.  You can also see cattle which have large rumps which have a particular mutation; it may not necessarily be a fault.  Also of course, the cattle breeders do not like to have mutations within their flock whereby some of the calves will not thrive.

SHANE HUNTINGTON
Now, hair colour and skin colour and so forth is one thing, but some of these mutations have more serious effects?  Why is that?  

RICHARD COTTON
Well, going back one step, we have 20,000 genes and each of those genes needs to be intact for us to develop and function normally.  If one of those is wrong and has a fault in it, the embryo may not even develop or you can go right to the other extreme where the disease like Huntington's Disease in fact will only develop when the person is about 40 years old.  So the time of expression of that fault in the genes is actually variable, and this is because they affect different functions.  Some affect your gut, some affect your eyes, some affect your brain, muscles, et cetera, et cetera, so therefore they are going to be different.

SHANE HUNTINGTON
We clearly have a degree of redundancy in our sort of genome in the system that our body operates under.  How does that link in with some of these mutations?  Are they in a situation where they just don't affect us because other genes are taking over that process or does that redundancy not work with regards to some of these particular mutations that are more catastrophic?

RICHARD COTTON
Yes, one of these difficult things about this field of genetics is that there are things called modifier genes, and even though a person may have two copies of a really bad fault in both copies of the gene, most people will in fact succumb to that particular disease that it usually causes, but in fact there are some people who have particular changes in another gene which protects them from those particular things.  So it makes it quite difficult for genetic counsellors because every now and then there will be a person who they think is going to develop the disease but they don't because they have one of these modifier genes.  So that is another item, if you like, that humanity has to document when doing genetic analysis.

SHANE HUNTINGTON
Now, Richard, we're obviously a very successful species and we have all these mutations flowing around.  Why do they actually occur?

RICHARD COTTON
Why do they occur?  Usually they occur spontaneously and I can't give you the numbers, but in fact in some diseases the mutation can in fact arise spontaneously within the sperm or the egg and that will be the first instance in that family and that happens quite often.

SHANE HUNTINGTON
Are there ways to protect against some of these mutations?

RICHARD COTTON
You mean stop them being formed in the first - well, I suppose avoid atomic bombs and radiation, but of course those ones are what you call somatic mutations, which are mutations of the tissues which usually cause cancer.  But no, I don't think so; they're just part of being a living organism that you will have mutations from your parents and there will also be some arising spontaneously.

SHANE HUNTINGTON
You mentioned issues like skin cancer and the like.  Obviously some mutations cause that kind of result; other mutations cause more serious problems like Huntington's disease, for example.  What determines which way they go?

RICHARD COTTON
I think that's slightly difficult to answer.  The mutations that cause disease in an inherited mode, we call those germline mutations which are in the sperm and the egg, whereas with somatic mutations which cause cancer and some other diseases, those are specific mutations that might be in one of your skin cells and therefore cause skin cancer.  So they're quite different and that may not appear in the germline or the sperm or the ovum of the person who gets the cancer, obviously.  

SHANE HUNTINGTON
Our bodies are particularly good at rejecting things that are foreign to us.  We see this when we look at things like transplant therapies and the like.  Why do we not have a similar response when one of these mutations occur in a particular cell or a part of the body?

RICHARD COTTON
Well, we do actually have a response to that, and these are called mismatch repair systems.  It's quite interesting that when this system is mutated - and one of my colleagues in the colon cancer area is dealing heavily with these, Professor Macrae in Melbourne, Australia - when these systems have a mutation in them, the person is susceptible inherited colon cancer.  So we do have mechanisms to cut out, if you like, spontaneous mutations but when they don't work we're in trouble, we get colon cancer.

SHANE HUNTINGTONI'm Shane Huntington, and you're listening to Up Close.  In this episode we're talking about mutations and genetic variation with geneticist Richard Cotton.  Richard, you founded the Human Variome Project.  Can you tell us a little bit about what this project is and what its goals are?

RICHARD COTTON
The goals are rather grand and massive but it needs to be done, and that's why there's such support around the world.  The goal is to systematically collect all of the faults or mutations in genes in all 20,000 genes from all countries.  Now, that's rather ambitious, but it has to be done systematically because people can be helped in one part of the world - say a person in Finland may have information that can help someone in New York for example, and so that's the reason it has to be done.  Even though it appears a massive task, it is actually a task which could be spread worldwide, because what we need to do is to have people collect the data within their own country as a distributed system.  So in other words, the project might actually be done by ten or 20,000 people worldwide, but the community has to decide how these people would collect it.  So that is what the project is; it is a project to systematically collect from all countries, from all genes, mutations causing disease.  In the broader sense, humanity needs to know, just like we needed to know the human genome, which you spoke about earlier, we need to know the human variome, in other words all the variations that are in those three billion bases, from base one to unit three billion.  One day in say ten or 20 years' time, we will in fact be able to index disease or variations, if you like, by clicking base 4,000,032 or something like that.

SHANE HUNTINGTON
Richard, most cities across the world struggle with electronic health records in general; this seems like an extraordinary task to put this together.  How are you going about coordinating such a big endeavour with so many countries and so many jurisdictions?

RICHARD COTTON
One path is for experts in genes to actually collect the data within their gene of interest, the one of the 20,000 or whatever, and they will form a consortium around that and that data will be put in databases.  People have doing that even for 50 years, say, since the 1950s for their own  purposes, so it's not a new thing.  The other route is through countries getting their act together and actually collecting within a country - and we call those country nodes.  At the moment we have 16 countries signed up, including the US and the UK and China, to actually collect data within their country.  That data was needed within their country to actually facilitate genetic health care so that the load is known within the country and so that the actual cost to the community is known in the country so that governments can in fact put in an appropriate amount of money.  So that's how we're doing it, and we have community members amongst those 1000 recommending to the community or putting up suggestions or standards as to how this should be done, both within the disease and within the country.  

SHANE HUNTINGTON
Presumably some of these diseases only have a few thousands of sufferers worldwide.  Is that one of the reasons why we have to do this over such a wide range?

RICHARD COTTON
Exactly.  It may be that in Australia there may be only two or three or four of a particular disease, and even in the world there may be only or two.  But yes, as a group there may be up to 20,000 of them, diseases, each with an average of say 100 to 1000 sufferers worldwide, but within each country there may be only a handful.  

SHANE HUNTINGTON
With so many possible mutations in the genome, how does a clinician go about diagnosing a baby, for example, that's born with a particular medical condition based on their genetics?

RICHARD COTTON
Based on their genetics, it's quite difficult for the general practitioner obviously, because they just don't see these very often.  What usually has to happen in the clinical world - and I'm not a clinician - is that these people usually are referred to a tertiary institution and usually they come to a genetic counsellor or a clinical geneticist and they will then look at the family to see if there are other instances in the family.  That's the first thing.  Or if there's a particular malformation which is quite striking and even if it's the first in that family, it could have been caused by an environmental effect like thalidomide or it could be the first mutation within that family, as we discussed earlier, that may have arisen in the sperm or the ovum of the family.  Today, you mentioned earlier it's very cheap to sequence these genomes now and so that child is highly likely now, a singleton child, or even a family where no cause is known, that is highly likely to be sent off somewhere to be sequenced for the actual genetic fault to be found in that family, which can then reassure the family and the family can take action based on that data.

SHANE HUNTINGTON
So we're now able to sequence a person's genome, look for these mutations.  How easy is to actually determine which gene is responsible for the problem at this point?

RICHARD COTTON
It's relatively easy but what people are saying now, it might be the $1000 genome but it might be the $30,000 analysis and that's because there's a lot of genetic analysis done.  Once they've done this sequence of the particular child's genome, there's a pipeline of informatics which is perhaps 20 steps long and out of the end of that they might get say six or eight genes that are likely ones.  Then they look carefully at that to see where they're expressed, where they're in the brain or the muscle or the bone et cetera, et cetera, and then pick one of those and then they will then perhaps make an artificial mutation in a mouse or a fly or a worm and see if that produces symptoms analogous to what's actually in that human being.  So that's how it's done, and I believe something like 30 per cent of these strategies are successful in finding the gene; others it's been too difficult.

SHANE HUNTINGTON
Providing this sort of information to an individual comes with some fairly serious ethical dilemmas.  Are we keeping up with the research in terms of the ethics with these patients?

RICHARD COTTON
I think ethics has been one of the major problems.  I think there are two major aspects of ethics.  One is that you must not allow the person's fault, if you like, be known to the general public because there may be adverse actions like discrimination of some sort in job searching or superannuation or life policies, et cetera.  The other aspect is what should be told to the patients and of course, I believe the patients need to know everything because in the end the patients need to know, they will make the decision; the family will make the decision what to do in that family.  So to some extent that clarifies the ethical dilemma from their point of view because they will make up their mind; it's their own ethics if you like within the family.  But there are on top of this there are some incredibly difficult ethical situations.  For example, in Huntington's disease do you tell the child that they're going to die of a horrible disease at the age of 40?  Do you tell them?  The other thing that's happening more recently now is what's called incidental findings.  So when in fact a child or a person might be sequenced for fun, if you like, there's lots of recreational sequencing, or even say, a particular diagnosis.  Just say they're being sequenced for some particular reason and they find a susceptibility to breast cancer, say, or a cause of breast cancer that might turn up later, do you tell them that when the DNA is being actually examined for a different reason, and there's enormous ethical discussion going around the world if these so-called incidental findings should in fact be told to the patients.  Another example which happened recently is that two sisters in a family with breast cancer were tested for a particular mutation that was in their family for breast cancer.  One of the sisters was told that she had the risk for breast cancer and she may well develop breast cancer; the other one said she didn't have the risk or gene.  The tragic thing is that those sisters never spoke to each other again.  So there are all sorts of reactions, ethical problems, et cetera, et cetera.  One of the other ethical dilemmas is do you tell other people in the family.

SHANE HUNTINGTON
I'm Shane Huntington and my guest today is Professor Richard Cotton.  We're talking about mutations and the Human Variome Project here on Up Close.  Richard, where does all the information for the Human Variome Project actually come from?  Who on the ground is doing the collecting and where is it being stored and the like?

RICHARD COTTON
On the ground it's actually happening in the tertiary hospitals where the clinical hospitals where the clinical geneticist would send the sample to the diagnostic lab and the diagnostic lab would find the result and then it comes back.  There are literally thousands of these diagnostic labs around the world doing such analyses, and these labs have the data within their records and generously many of them, particularly in the US - huge labs in the US doing a third of the analyses have actually generously put these in the public space or they are going to put them in the public space.  They also collect it in research laboratories.  These ones usually finish up in a research paper because that's the first time a particular mutation or gene has been incriminated with disease.  The collection comes from the scientific literature and it comes from the diagnostic labs, we need all of those.  Where it is finally deposited?  The Human Variome Project Consortium members and particularly Johan den Dunnen and colleagues in Leiden, Netherlands, in fact developed a particular type of software which makes it very easy for this data to be collected and many people are storing their data in that system.  It is their own data; it doesn't belong to the Leiden people, it belongs to the people.  So that is heavily used and ultimately the aim is for that data to be transferred or shared.  It is public but it is to be shared with the major facilities in the US, in Washington and also in the EBI system in the UK.  The idea is to get the flow going from those diagnostic labs and the research labs into the system so it can be readily identified and found without extensive searching by the clinician who has a particular fault in a patient in front of them at the time.

SHANE HUNTINGTON
Richard, when you're taking the data from individuals, what ethical requirements are there to then include that in the global database?  Do you need permission?

RICHARD COTTON
The consortium has been quite active in this area, and in fact what we did was to take the guidelines from UNESCO, OECD, WHO et cetera, et cetera and found which of those which were directly relevant to curation of this data in databases and actually it was a clinical geneticist that did that, not a professional ethicist because that's where the buck will finish.  Of course, the data has to be de-identified, especially in the public world.  You can have grades of protection whereby interested clinicians may be able to get a better view to be able to help their patients and in the Australian system here we have got very sophisticated scrambling mechanisms to actually allow the patient to be re-identified for clinical purposes but not possibly for prying purposes, if you like.

SHANE HUNTINGTON
You're including developing countries in this study as well.  I understand the need for a large cohort across the world, but why is there a need for such a distributed cohort into all regions of the globe?

RICHARD COTTON
Within those countries, they need to develop the methodology, which is one of the things we're trying to help them with, to develop the methodology so they can in fact find the mutations within their country and make the proper strategies within their country.  But of course, because there's much migration, if a person from South America, for example, is seen with a genetic disease in Melbourne we need to know what are the predominant diseases in the South American population.  It's widely known that in the Mediterranean countries thalassemia is one of the key diseases; they need to be tested for that.  Within the Ashkenazi Jewish population, because there are particular mutations, which we call founder mutation, almost all the children I believe do know in fact if they do carry a disease before they're married - not have the disease but carry it - and therefore cause the disease in a child if they marry another carrier and have children.  Those are the sort of needs.  It needs to be global because of migration; it needs to be global because each country needs to have its data on a plate.  

SHANE HUNTINGTON
Is there a point at which this project is complete?

RICHARD COTTON
In some ways it will never be complete because there will always be new mutations found, firstly.  There will always be new mutations being caused in the community.  I would say that completeness might be when all of the flow is coming from each country instantaneously to be publicly viewable.  I think that is the time of completion, which is obviously a big ask but that's what is being aimed at I would say by the community.  

SHANE HUNTINGTON
Richard, what sort of things do we expect to be seeing from the variome project in the coming years?

RICHARD COTTON
I think it's hard to say.  I think governments now are starting to realise, particularly in Europe and the US, that this field does need some attention.  There are some major initiatives which are taking place and we are part of those.  I think there is a movement now, mainly coming from the rare disease parents, which have pushed things, particularly in Europe and the US.  The Human Variome Project activity, which we have initiated with many probably hundreds and hundreds of colleagues around the world is in fact driven by the diagnostic labs and the clinicians who have to look at the mutation or the fault they've found and say is that causing the disease or not?  That's a major, major problem.In fact, in the colon cancer initiative that I spoke about earlier there was one example where they have an organised group of about 50 people that look at these faults or genes and try to decide whether it's disease-causing or not.  The actual data they look at is quite hair-raising in some ways because five labs have tried say six different systems of trying to decide if it is in fact a mutation causing the disease.  Half of the tests have shown it's not pathological and not causing disease and half have said it has.  So I think this underlies the real reason why expert curation is needed, and fortunately the Cancer Society in Victoria, Australia, has in fact facilitated hook-ups if you like for many of these 50 experts to look at these mutations on a case by case basis.  One of the most difficult things to fund is in fact this expert curation, but because it's going to affect people's lives it's essential and I think that's one of the things we're pushing to do at the moment.  We're fortunate that the Chinese government have in fact promised to fund such curation activities, and there's a philanthropic effort in Australia which has funded some of the curation activities for this colon cancer group.  So there's plenty of room for the philanthropists, governments and rare diseases groups to support the project.

SHANE HUNTINGTON
Professor Richard Cotton, Scientific Director of the Human Variome Project, and director of its Australian node.  Thank you for being our guest on Up Close today and talking with us about this important research and diagnostic resource.

RICHARD COTTON
It's been a pleasure and thank you very much for including me.

SHANE HUNTINGTON
Relevant links, a full transcript and more info on this episode can be found on our website at upclose.unimelb.edu.au.  Up Close is a production of the University of Melbourne, Australia.  This episode was recorded on 13 December 2012.  Our producers for this episode were Kelvin Param and Eric Van Bemmel.  Associate producer Dyani Lewis.  Audio engineer Gavin Neighbour.  Up Close is created by Eric Van Bemmel and Kelvin Param.  I'm Shane Huntington; until next time, goodbye.  

VOICEOVER
You have been listening to Up Close.  We’re also on Twitter and Facebook.  For more info visit upclose.unimelb.edu.au. Copyright 2013 The University of Melbourne.


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