Episode 149      31 min 50 sec
Out of Africa: What human genomics is revealing about us

Professor of genomic medicine Vanessa M. Hayes discusses our African genomic origins and how exploring global genetic diversity can help us understand and address human disease. With science host Dr Shane Huntington.

"We know that genetics and our genetic background and our profile and that variation that makes us different from one person to another, is going to impact to how we respond to disease." -- Professor Vanessa M. Hayes




           



Prof Vanessa M. Hayes
Professor Vanessa M. Hayes

The work of geneticist, Professor Vanessa M Hayes, has revealed genetic causes of HIV/AIDS susceptibility in Southern Africa and made major contributions to understanding genetic susceptibility to prostate cancer in Australian men. Her work has also defined the extent of population diversity in the cancer-threatened Australian icon, the Tasmanian devil.

Influence and experience
South African-born Vanessa headed a cancer genetics group at the Garvan Institute for Medical Research and then a similar group at the Children’s Cancer Institute Australia in Sydney. Following this she joined the research institute of genomicist, J Craig Venter, as Professor of Genomic Medicine in San Diego.

Vanessa moved to the United States in August 2010, to continue her efforts to determine the extent of human genome diversity and use this knowledge for phenotypic correlations related to human evolution and disease impact. She considers that we have only touched on our understanding of the extent and significance of human genome diversity.

Credits

Host: Dr Shane Huntington
Producers: Kelvin Param, Eric van Bemmel
Audio Engineer: Gavin Nebauer
Episode Research: Dr Dyani Lewis
Voiceover: Dr Nerissa Hannink
Series Creators: Eric van Bemmel and Kelvin Param

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VOICEOVER
Welcome to Up Close, the research, opinion and analysis podcast from the University of Melbourne, Australia.

SHANE HUNTINGTON
I'm Shane Huntington.  Thanks for joining us on this episode, which is brought to you by the Melbourne Festival of Ideas, for more info go to ideas.unimelb.edu.au.  In 2001 the first draft sequence of the human genome was published, representing a collaborative scientific effort on a global scale.  Since then the field of genomics has expanded rapidly, drawing in expertise from a variety of scientific domains.  Our understanding of the genetic structure of numerous species has reached the point where sequencing of new species seems, indeed, no longer newsworthy.  Despite this lack of popular interest in genomes the implications for us and the environment in which we live are staggering.  To tell us more about genomic research and why it matters we are joined by Vanessa Hayes, Professor of Genomic Medicine at the J. Craig Venter Institute in San Diego, California.  Welcome to Up Close, Vanessa.

VANESSA HAYES
Thank you very much; thank you for having me.

SHANE HUNTINGTON
Now, why don't we start by just talking about the term, human genome; could you give us an idea of what we're referring to here?

VANESSA HAYES
When we talk about the human genome we're talking about essentially three billion building blocks.  We call them building blocks of DNA, that's the A, G, Ts and Cs that make up our inheritance, but actually we should talk more correctly about six billion building blocks, because we inherit three billion from mum and three billion from dad and that is our code.  It's our code that makes us who we are.

SHANE HUNTINGTON
Now, the draft sequence of the human genome was published back in 2001 and a complete sequence in 2003, how have we benefited from this information over the last decade?

VANESSA HAYES
Well, the benefit has been astronomical.  Prior to the stage publication of the draft sequence of the human genome, we really only had about two per cent of our human DNA to work from.  This was the two per cent driven by the fact that was what we had knowledge about.  It's the two per cent that code for proteins and therefore that limited our research but, as I mentioned, we're not made up of two per cent, we're made up of 100 per cent.  So now it has opened the field dramatically, because we can start looking at ourselves as a whole being and not just a little bit of us.

SHANE HUNTINGTON
Now, when we talk about the human genome, we have this complete sequence that we developed some years ago now.  Why do we keep sequencing more people, what's missing in that complete sequence that we already have?

VANESSA HAYES
I think one has to bear in mind that the human genome projects, both the public and the private project were not an individual; it was what we call a mosaic, a pool of individuals that were put into a test tube and their DNA extracted and sequenced.  Now, the reason for this was ethical reasons, we did not know the implications as a scientific community to put in an individual genome sequence out there for everybody to have access to.  So the decision was made to sequence a pool but, of course, there was a limitation to this because it doesn't tell us the story of an individual, it tells us just the story of a sequence, which is not to minimise that effort, it was an astronomical effort and because of that the field genomic medicine has really developed.  Genetics has changed into genomics and an advancement on medical disease has happened as a result of that but, of course, we needed to generate more sequences, because one, we needed to look at an individual, which lead to the 2007 publication of the first individual, being J. Craig Venter, which is often referred to as HuRef and that was our first look, not only at how a DNA sequence affects a single individual whom we had knowledge about and a name placed to the sequence, also his background, his medical conditions attached to that sequence.  But it was also what we call the first diploid genome, where we actually looked at mum and dad and generated six billion bases.

SHANE HUNTINGTON
When you talk about the variability between the various sequences you see, what sort of things are you observing in terms of differences between that generic mosaic that you spoke about and a single person, in this case J. Craig Venter's sequence.  How do they differ?

VANESSA HAYES
So if we look at a single individual, what we learned from Craig Venters' genome is that we're different than we actually expected, that we are about three per cent different from each other.  It was expected to be a little bit less.  That was one of the unique findings which we could not do looking at a mosaic of an individual.  What we learned from Craig Venters' genome is that on average a single individual will have around three million DNA variance.  But what happened preceding that we had the 2008 publication of James Watson, the noble laureate's discovery of The Double Helix, which was then preceded by a number of genomicists sequencing their DNA.  The problem was these were all European individuals, all men as well, so that limited our perspective on how variable we can be; how make change can a human genome tolerate or how much variation is there possible within a human genome and a global pattern of humans.  We are a global species; we are unique in the fact that we have populated the entire globe.

SHANE HUNTINGTON
When we talk about sequencing the genome of an individual, can you talk us through what this actually means?  What's actually happening in the laboratory?  Does it start with a blood sample, for example?  How do you go about it?

VANESSA HAYES
Well, what the field has really done, is you don't only have to start with the blood sample, that's one of the advantages of the new technology.  We had the dominance of what we call Sanger sequencing, which was the technology used to sequence the first human genome project.  To put it into perspective, this was a $3 billion project that took 13 years to complete.  It's often associated with the task of putting man on moon, is similar to the task of sequencing the human genome.  What that meant was that it was still too expensive to sequence a whole lot of individuals at $3 billion.  So what happened in around 2006 was the development of what we call shotgun sequencing, which was a new approach developed by J. Craig Venter's team at the time.  This really changed the field, because it led to competition, it led to companies coming out with new technologies to do what is called shotgun sequencing.  This then brought the cost down, sequencing, at that time to $10 million, the Watson genome $2 million and then down to what we have today, which is around $10,000 and obviously the prospects are bringing that down even further to the $1000 genome.  What this actually means technically is taking blood, extracting DNA - we still have to obtain DNA.  One can take this from hair, nails, bone, teeth, so it allows us to also look back in time, but essentially taking the sample, extracting the DNA out of that sample and then read in the code.  The new wave of technology doesn't even amplify what we say is making more of their DNA; we can do it straight from a single cell.  So this is how the revolution of the technology is taking place.  So you have to read every single base, as was done in the past, but the cost now to read every single base has dramatically come down by these technical advances.

SHANE HUNTINGTON
So my understanding then, from what you're saying, is that you can take a single cell that has a complete strand of our DNA and produce the entire genome of that life form from that one cell.  Whereas I seem to recall a term Polymerase chain reaction that was used in the past where you would duplicate the DNA into millions of strands; is that right?

VANESSA HAYES
Correct.  So the next generation sequencing was still based on a PCR method, which is an amplification method and those are the technologies that most of the labs are still using today, but there is a new wave of technology called single-molecule sequencing where the amplification step is removed and you just keep sequencing around in a circle, so you don't need that amplification step.  Why that is important is one, yes, it leads us to sequencing single cells, which is important to understanding diseases like human cancers, but also it allows for generation of what we call longer read lengths.  At the moment shotgun sequencing, I try to explain to lay people, it's like taking a huge mirror and then smashing it on the ground and then trying to piece it all together.  So you're generating a lot of amplifications of little pieces.  So you take the whole DNA sequence, break it down into tiny little pieces and make lots of copies of these tiny pieces and then you've got to piece all the puzzle together.  That has become now the bottleneck of genome sequencing, is the informatics, the computer people that sit in front of computer piecing bits of puzzle together.  We have removed genomics largely from the lab and it has moved now into a computer room and that's what we need to generate, a lot of very brainy people that can work in front of a computer and work with terabytes of data.

SHANE HUNTINGTON
Now, Vanessa, there's two terms that we often here that I'd like you to unpack and tell us how they interact.  One is the term genetic diversity, but then at the same time we're often referred to as being very similar to other animals, chimpanzees, whatever else.  How are those two things consistent? 

VANESSA HAYES
They're very consistent in the sense that we have a new field in genomics that's really come about, it's a great field called comparative genomics.  What comparative genomics essentially means is you take a genome of any species; any organism and you compare it with another species and organism.  What we learn from that is essential to understanding who we are, what species are and what DNA can do, because we look for parts that are similar and there's a lot of similarities.  One of the great questions asked is, is this similarity between chimp and human, or human and a mouse, or human and a single-celled organism, because there are lots of similarities.  These similarities have been maintained through species evolution and these are important things, because they tell us about what it is to live and to survive.  So that's the one aspect.  On the other aspect, what my particular group and my particular interest is to understand the diversity, the area of differences.  Those differences can be on a species level, or it can be within a specific species, namely the humans.  I mentioned at the beginning what we learned from Craig Venter's genome is that there was about three per cent diversity within humans.  It may not sound like a lot, but that three per cent is essential to making us healthy or not, making us respond to a drug or not, whether we're going to be resistant or not resistant, or are we going to die from HIV faster than someone else.  These are just examples, but we know that genetics and our genetic background and our profile and that variation that makes us different from one person to another, is going to impact to how we respond to disease.

SHANE HUNTINGTON
This is Up Close coming from the University of Melbourne, Australia.  I'm Shane Huntington.  Our guest today is Professor Vanessa Hayes and we are discussing human genomics.  Vanessa, your work is focused very much on the people of southern Africa, is there some reason why you've chosen those particular population to work on and for example, why you haven't chose Asian populations, or people from Papua New Guinea, or anywhere else in the world?

VANESSA HAYES
Africa has played an incredibly important role in the evolution of the human species, right back from the divergence from our common ancestor the chimp, seven million years ago, to the divergence of the hominid species to archaic hominids about 500,000 years ago to modern humans 200,000 years ago.  How do we know that this happened within Africa?  We use archaeological findings, linguistics, as well as genetics to map where our origins of mankind lie and they clearly lie within Africa.  The debate is raised whether that location is east Africa or southern Africa and that depends on whether you want to follow archaeological trends or whether you want to follow linguistic or genetic data.  But the disciplines are now coming together to actually talk to each other and start combining their data and the field of genomics has allowed us to use the tools of what was called genetics a lot better, to start to unravel who we are and where we come from.  So that's the one reason.  The second reason for Africa is, Africa's a complex continent and I always use linguistics as my tool, although it is just a tool and a proxy.  Someone can learn a language, but they can't learn their DNA, I say.  But linguistically there are 2000 different languages in Africa.  These are not dialects these are languages, so with that you have 2000 different cultures.  If you just look at the region of southern Africa, 500 different Bantu groups, or 30 different Khoesan groups that are still alive today.  What this tells us is the amount of diversity that's within Africa and on a genetic level, we believe that Africa holds one third of the world's diversity.  So Africa was really an important place to go and particularly for me, southern Africa, because that's where the genetic linguistic data is pointing to as a possible birthplace of mankind. 

SHANE HUNTINGTON
Earlier you mentioned that for the human genome project, in the first version of it, the mosaic part was from people who were anonymous essentially, the names of those who were involved were not made public.  Your work in southern Africa however involves specific people and their names have been made public.  Why the difference?

VANESSA HAYES
We thought it was essential that the names of the individual be released and there was a couple of reasons for this.  Yes, we could have sequenced anyone off the street, but we decided not to.  We didn't just sequence any Bantu individual off the street, we sequenced not only a person and named that person, we sequenced someone of a very high profile, namely Archbishop Desmond Tutu.  The reasons for sequencing Archbishop Desmond Tutu was he could be a voice and be a voice for indigenous people, because he is the spokesman.  He's the head of the Global Elders, which is a group put together and includes people like Nelson Mandela, Graca Machel, they act as a voice if abuse occurs, or indigenous societies feel that they have been abused.  That has happened in the past, scientists have not had a very good reputation when it comes to indigenous research and one had to change this profile.  It also is important though that indigenous communities, or communities in Africa start to benefit from medical research, which they don't, they always get the last end of the straw.  You've got to remember at the time that the Archbishop Desmond Tutu's genome was sequenced, no African had been sequenced and named, only one individual to represent the whole of Africa in the early 2010 and that's only a year ago.  So the Archbishop represented a voice and without naming him, that obviously could not be done.  It also made his genome then accessible for 20 years - 30 years from now people will be still be looking at his genome, because there's enough information about him and who he is.  So it's what we call correlating phenotype with genotype. And of course, being a very outspoken man, a very honest man, very open about his life, we know a lot of about him.  We know that he's survivor of TB, we know he's a survivor of polio and we know that he has suffered from prostate cancer.  So straight away we do not only have a genome of an individual who represents Bantu culture through his mother and his father's line, but we have a person who represents a disease profile as well that we can continue to use over and over.  So it makes how the genome becomes more valid by naming the individual so much more.

SHANE HUNTINGTON
Vanessa, can you clarify for us what you mean by phenotype and genotype and how the two interact?

VANESSA HAYES
This is an area that we really need to work on, 10 years after the publication of the human genome.  It was the area that we really thought we would advance the most and what I mean by that is a phenotype is a characteristic, a trait, a disease.  It's some sort of phenotype that we can correlate with your inherited genetic profile, that's what we call a genotype and that's ultimately what we want to do.  It's pointless just having the DNA sequence and then it's a DNA sequence, well, that's nice and pretty, but what does it mean?  We've got to interpret the code and that's what correlating phenotype with genotype is, making sense of that code and what it actually means to the individual. 

SHANE HUNTINGTON
In terms of these sequences of people like Desmond Tutu and others that you have had involved in this study, what sort of things have you learned thus far from having sequenced them?

VANESSA HAYES
The first thing that we able to provide with the Archbishop and with !Gubi who by the way is a Khoesan click-speaking individual from the Kalahari Desert. It's a desert region in southern part of Africa, it lies mainly in Namibia, which is the country on the south-west coast of southern Africa, north of South Africa and Botswana.  Those two countries are the main countries where the Kalahari region lies.  It also lies a little bit into Angola, South Africa and Zimbabwe, but essentially it's Namibia and Botswana.  !Gubi is a hunter gatherer gentleman, who still lives as much as he can, a hunter gatherer lifestyle.  So he truly represents what we all were, we were all hunter gatherers and 10,000 to 12,000 years ago the human species converted to agriculture.  So he provided an opportunity, a window into our past, because he represents, we believe, around 100,000 years by the Khoesan people and therefore into the past of all of us.  What did we find?  We found if we compared to J. Craig Venter who had, as I said in the beginning, three million DNA variance, after the human genome project we had the development of HapMap Project, the goal of that project was to map all the variation in the human genome.  That project was fantastic, because we used those differences to map disease.  The problem once again, they were biased to Europeans, Asians and Yoruba people from Nigeria.  What that means was how informative is this information for people from southern Africa.  So what we found by sequencing the Archbishop and !Gubi and just partly sequencing three additional Khoesan speakers, was 1.3 million new DNA variance that weren't out there.  So we certainly had not discovered the extent of what it is to be human.  Also what we discovered was the most variable genomes, as I mentioned Craig Venter having three million DNA variance, the Archbishop Desmond Tutu having 3.6 million DNA variance and then !Gubi having over four million DNA variance.  What this tells us is something about the age of the population, the more DNA variation in an individual, the indication of the age of the population. 

SHANE HUNTINGTON
Vanessa, when you look at the differences between various groups within parts of Africa, how does that genetic difference compare to, say, White Anglo-Saxons to people from China, for example?

VANESSA HAYES
Well, there the probably most dramatic thing we found in the sequencing of the Archbishop Desmond Tutu and the Kalahari bushman, was that if we took two Khoesan speakers they're click-speakers, they live approximately 500 kilometres from each other maximally.  To our eye they looked exactly the same, both hunter gatherers, physical features the same and we call then Khoesan bushmen or San, there's multiple words used.  To them they look different; to them they speak different languages.  We found more genetic difference between these two individuals than we did between a European and an Asian, or a European and a say and individual from Yoruba, so this is dramatic.

SHANE HUNTINGTON
I'm Shane Huntington and my guest today is Professor Vanessa Hayes.  We're talking about human genomics here on Up Close, coming to you from the University of Melbourne, Australia.  Vanessa, in terms of the knowledge that we have around what the different parts of the genome actually do, are we able to make full use of the sequence that we now have?

VANESSA HAYES
We certainly haven't made full use, there is still a lot to learn and that's why the field is really, what I call, at an exciting stage.  We're 10 years past the initial human genome and there was a lot of predictions that the field would completely revolutionise in 10 years time.  We are now at the 10 years time point and we haven't met all those expectations, but they were pretty high.  We certainly haven't failed, but we do have a long way to go, but it's exciting stage now and I believe that excitement is due to the fact that we able now to start generating a truly pure human genome sequence by having multiple, what we call reference genomes to look at, multiple data, multiple technologies, which has actually made the field almost more difficult, because remember in the past because we only had one technology we comparing all these apples with apples, apples with apples, now we're comparing apples with pears, with peaches and bananas.  So there there's a lot more noise to get through.  Also we're learning things about the human genome and about genomes in general, that in the past many years back about 98 per cent of the human genome we didn't look at.  Some people called it junk DNA and we certainly know it's not junk.  So we're discovering all sorts of things about the genome.  You'll hear people in the field talk a lot about single-nucleotide polymorphisms, SNPs changes, that single-nucleotide changes where one letter, one building block changes.  But there's more than that, there's what we call structural variance, where large pieces of the genome are changed, or duplicated, or inverted.  These are all important, so it's a very, very exciting time in the field. 

SHANE HUNTINGTON
At this point in time are we seeing our approach to the production of drugs, vaccines and the like changing as a result of the genetic information we have?

VANESSA HAYES
Absolutely.  So where we're making real advances is discovering a couple of aspects of disease.  One is what puts someone at risk of a disease.  If we know someone's risk profile, we can start to do preventative medicine, that's the one aspect.  The second aspect is we need to discover outcome, what makes an individual progress in their disease in a certain way as opposed to another.  That way clinicians can actually use the genome information to direct the patient and say, look, you're more likely to progress to full phage breast cancer, so we advise you have a mastectomy.  Or we advise, if you have a man and you have prostate cancer, you don't need to have a prostatectomy, you don't need to have your prostrate removed and live with the consequences, because you're less likely to actually develop aggressive prostate cancer.  So these are the questions that the clinicians really need the tools for us to develop.  The third really important area is what we call pharmacogenomics. And what we mean by that is facilitate the clinicians into making the decision of what drugs, what treatment regimes an individual requires for their disease and that is also dependent on the genome profile.

SHANE HUNTINGTON
As many societies across the globe become more multi-cultural, especially in Australia this is true, how does genomics as a field adapt to this, given that I guess in many of the early instances you were looking at a specific population, limited both in geography but also in that genetic diversity.  How does the field adapt to this changing level of diversity, I guess I should say?

VANESSA HAYES
I call this two names.  I call it one, the modern society, which is an admix - we use the term admixed in genomic terms, society and I also like to call it the rainbow world.  I've kind of taken that from the Archbishop Desmond Tutu who called South Africa the Rainbow Nation, because of all the different cultures living in one place.  That is what the globe is becoming; we're becoming a rainbow mixture.  So yes, it's very essential to understand the modern man, the modern human, which is admixed human all around the globe.  That's why need to now cultivate and study what it is to be certain ethnic groups before that is lost, which it will, I believe, eventually be lost with global travel it's not likely to be sustained, so that we can understand our past.  But yes, it's absolutely important that we understand the admixed individual and that's where the term personal genomics comes in.  So in the past and still today, many drugs or treatments are based on, for lack of better term, a racial group or an ethnic group and that may not be possible in the future.  So we want to move away from that categorisation and just call it personal genomics, where actually you need to know your genome profile and that is personal to you and your treatment must be based on you.  But of course, we couldn't do that in the past, because it was too expensive to look at each individual, so we did the next best that we could and we grouped individuals.  As humans we're very good at grouping people, I call it visual genomics.  You see a visual thing and you group someone and we can't do that anymore, so the genomic world will open a new tool of personalised medicine.

SHANE HUNTINGTON
I understand that there's some speculation that early humans and the Neanderthals actually interbred at some stage.  Is there any genetic evidence of this scenario?

VANESSA HAYES
Yes, there is.  So the belief was that humans and Neanderthals did not mix and this data was based on mitochondrial data.  What do I mean by that?  Mitochondrial data is part of the human genome that's only inherited through your mother, its 16,500 bases in length.  The reason why the original studies, mostly studies were lent by Svante Paabo from the Max Planck Institute in Leipzig in Germany was because they were limited by the DNA that they could extract from the Neanderthal bones that were found.  By limiting the analysis, one could only look at the mother's line.  What happened last year, Svante Paabo and his team published in a landmark paper the publication of the first Neanderthal genome, where they were able to look 1.2 times across the over three billion bases of Neanderthal sequence, therefore this wasn't biased just to the mother, they were able to look at both the paternal and maternal contribution.  Doing this they discovered that 1.1 to 4 per cent of all Europeans and Asians have a Neanderthal component.  This is a likely scenario; we know that Neanderthals diverged in Africa around 500,000 years ago.  We know that Neanderthal remains were found in Europe and we know that Neanderthals died out approximately 25,000 to 30,000 years ago.  We know modern man left Africa around 50,000 to 70,000 years ago, that they must have come into contact with one another.

SHANE HUNTINGTON
Vanessa Hayes, Professor of Genomic Medicine at the J. Craig Venter Institute in San Diego, California, thank you for being our guest on Up Close today and for giving us a much better understanding of human genomics.

VANESSA HAYES
My pleasure. 

SHANE HUNTINGTON
Relevant links, a full transcript and more info on this episode can be found at our website at upcloase.unimelb.edu.au.  Up Close is a production of the University of Melbourne, Australia.  This episode was recorded on 14 June 2011.  Our producers for this episode were Kelvin Param and Eric van Bemmel.  Audio engineering by Gavin Nebauer.  Background research by Dyani Lewis.  Up Close is created by Eric van Bemmel and Kelvin Param.  I'm Shane Huntington, until next time, goodbye.

VOICEOVER
You've been listening to Up Close.  For more information visit upclose.unimelb.edu.au.  Copyright 2011, the University of Melbourne.


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