Well, thanks Jonathan. I ... in fact, I was pleasantly surprised
to learn that our research has been successful! [laughter]
And I would like to talk with you a little bit about -- actually, mostly
about the science, some of our findings, and then toward the end move on
to some of the reactions to those findings, and Professor Naidu will talk
further about the collaboration and about some of the reactions to our
findings in India.
But I'd like to start by addressing, I think, a more general issue,
as a scientist. Why are we interested in studying human genetic variation?
What is it that motivates us? And I can think of several reasons
why we do what we do. One does involve the biomedical applications
of genetic variation, studying genetic variation in populations, understanding
the reasons for the variation that we see in the distribution and prevalence
of genetic diseases. Why is cystic fibrosis so common in northern
European populations? Why is sickle cell disease so common in African
populations? We are understanding better and better the mechanisms
responsible for that variation, the evolutionary forces contributing to
that variation. So I think that's important in terms of understanding
the genesis of those diseases, and in some cases, can contribute to our
understanding of the etiology of diseases. Studying genetic variation
is important in terms of understanding our reactions to environmental agents.
One of the most interesting of these is reactions to prescription drugs.
According to an article published in the Journal of the American Medical
Association last year, over a hundred thousand Americans die each year
as a result of adverse reactions to prescription drugs. One of the
things that we are interested in is target -- or understanding how genetic
variation contributes to those adverse reactions, which it clearly does,
in many cases. So there are enormous health benefits right there
from understanding genetic variation in human populations.
The second area, and one that I've been involved with now for a few
years, is in the forensic applications of human genetic variation.
DNA profiling has been used in thousands of court cases now, both to successfully
prosecute guilty individuals, and also -- just as importantly -- to exonerate
innocent individuals. One of the reasons that that evidence, when
used properly, is successful, is that we have come to understand the nature
of variation in human populations. By understanding that variation
and how it is distributed, we can better estimate, match probabilities,
and come up with reasonable estimates that are admissible in the courtroom.
And finally, an area that many of us are interested in is the elucidation
of population history. Our, every major event that affects human
populations -- migrations, bottlenecks, selective events -- leaves an imprint
on our genome. And it's a fascinating exercise to look at our genome,
to look at genetic variation, to deduce those events. So what I'll
be talking about today is sort of a test case, in which we've used a known,
established mating system to test how well our predictions of genetic variation
hold up when we actually look at the results of our genetic analysis.
Have I got the slides on? You've got the focus, okay.
So here are some of the research questions that we've been addressing
in our studies in south India. First of all, is there significant
between-population genetic variation, and we've been looking thus far primarily
at caste variation, and what is the pattern of between-caste genetic distances?
What are the likely origins of south Indian castes and tribal populations?
And finally, is there evidence of a sex-biased gene flow between castes?
And this is essentially the system that we were testing with mitochondrial
and Y-chromosome genetic markers, and I'll talk a little bit more about
that as we go along.
Now, we can summarize -- and this is a very, very oversimplified summary
of major historical events in India, but it gives us at least a framework
from which to proceed -- Paleolithic settlement of probable African origins,
migrations of proto-Dravidian speakers from the Fertile Crescent area about
nine or ten thousand years ago. And then most recently, a third major
event, migrations of Indo-European-speaking, so-called Aryans from West
Asia, about 3500 years ago, and it was these individuals who established,
who are thought to have established, the caste system. And I'll be
referring to these waves of migration as we go through the talk.
Now the Hindu marriage patterns prescribed by the caste system are of
significant interest, and have been for many decades, to a variety of researchers.
Primarily, marriages occur between individuals of equal caste status, but
men from higher varna or groups of castes may occasionally marry women
from lower varna or groups of castes, but the opposite is very, very strongly
discouraged. So basically, we have a system in which males very seldom
change caste, but females occasionally do, and most typically when that
happens, they would change to a caste of slightly higher status or rank.
So that provides us with a mating system, one that's been going on for
more than a hundred generations, that predicts certain kinds of patterns
of genetic variation. So what we're interested in is seeing whether
those historical patterns are indeed reflected in the genetic systems we're
The study populations that we have used thus far -- these numbers are
actually a little bit old, but from the upper, so-called upper castes,
about 60 individuals, middle, 160, and lower 73, and those are further
subdivided into these groups shown here, so I won't go into that in detail.
Our primary comparisons have actually been between these three groups of
castes, and these are all males [who we've typed?]. This shows the
location. Actually [inaudible place name] is down in this part of
India, south India, and then we've also collected a number of samples from
throughout the region, but I won't really be talking about those collections
Now the genetic systems we've looked at -- I won't go into great detail
about this, but primarily we've looked at sequence variation in the mitochondrial
DNA. This is DNA that you inherit only from your mother, so it gives
us an idea of the maternal lineage of a population, and we can look at
differences in mitochondrial DNA to deduce the degree of relationship,
the degree of genetic similarity, between individuals in this maternal
lineage. We've also looked at Y-chromosome variation, and of course
that gives us the other side of the picture. The male, the paternally
inherited lineage. In addition to these Y systems, we've now, we're
now in the middle of or nearly done with typing 30 systems in the autosomes,
but again I won't be referring to those today.
So if we look at variation among the cast populations, this statistic
tells us what percentage of the genetic variation is the result of subdivision
into castes. So if we look at the mitochondrial DNA, the maternal
lineage, we see that about 1.5% of the variation exists between castes.
The vast majority exists within castes, but about 1.5% is seen between
castes. If we look at the Y chromosome systems, about 10% of the
variation that exists is observed between castes, 90% within. So
one important point here, of course, is that the vast majority of variation
occurs within castes, rather than between. But something I want to
stress here is that 6 or 7 times more variation is seen for the Y chromosome
polymorphisms, the Y chromosome systems, than for the mitochondrial systems.
That will be an important point, one we'll come back to later.
If we look at genetic distances between caste groups for our mitochondrial
systems, our maternally inherited systems, what we've done is to color
the different groups, the upper castes here in green, middle castes in
blue, and lower castes in yellow. And one of the things that we see
is that there's a fairly good grouping by caste, by caste ranking, when
we look at differences in mitochondrial variation. In other words,
what this tree tells us, it tells us how closely related these individual
-- these populations are, in terms of their mitochondrial DNA, their maternally
inherited DNA. And we're seeing a clustering of populations according
to caste ranking, so those castes that are more similar in traditional
ranking are more similar in terms of their mitochondrial DNA. We
can compare that to Y chromosome genetic distances, and now we see that
there's really very little association between caste ranking and genetic
distance. In other words, caste ranking has no relationship, really,
with the degree of paternal similarity, the degree of similarity in that
paternally inherited lineage. And if we look at the...
So that result, I think, is a very interesting one, because it's exactly
what we would predict, based on the known history of the caste system.
Females do switch castes occasionally; they can move up. And so castes
that are more similar in rank are going to be genetically more similar,
just like populations that are geographically closer to one another tend
to be more similar to one another, because they exchange mates. So
this laddering effect is what we would expect for mitochondrial DNA.
Now, for Y chromosome DNA, for paternally inherited DNA, because that DNA,
because males seldom switch castes, we don't see that effect. They
stay where they are, and the variation that exists is largely due to random
effects: genetic drift, mutation, and so forth. So that corresponds
to the model shown here, in which there is gene flow between castes, primarily
for females, giving this sort of stepwise effect in genetic distance, but
not for males. So it's a nice, essentially, verification or demonstration
that indeed, the history of this population, the history of the social
mating patterns are observable in the genetic variation that we're looking
Now, we can also look at -- and this is some fairly new work that hasn't
yet been published -- mitochondrial DNA, genetic distances between various
caste groups and continental populations. And one of the things we
see here is that all of the castes are most similar to groups of Asian
populations. And that's expected, given the origins of the proto-Dravidian
populations, so that we see much, much smaller distances between Asian
populations and each of the caste groups for the mitochondrial DNA.
When we look at Y chromosome DNA, we again see a somewhat different pattern.
For the upper castes, they actually have slightly greater genetic affinity
(smaller distances) for European populations than for any other population.
The middle castes, a little bit smaller distance between them and Europeans,
and the lower castes instead have the greatest affinity to Asian populations.
Now, if we think back about the history of the population, the most recent
wave, and the one that is the most recent wave of migrants, the one that
instituted the caste system is thought to have come from West Asia, Eurasia,
and those individuals would likely have been more similar to individuals
from Europe. And as those individuals who began the caste system,
they also likely appropriated the highest positions in the system.
So, a very interesting historical insight, again consistent with some historical
hypotheses that the invaders who came in about 3500 years ago, established
the system, and primarily who were male, so we see the Y chromosome versus
mitochondrial difference, we can still see that signature in today's genes.
So now, there have been a number of reactions to the publication of
our first results, showing the difference in mitochondrial and Y chromosome
variation in the caste groups. And I'll just touch on this area,
Professor Naidu will talk more about it. Concerns haven't been addressed,
such as this one here, "Social scientists worry that it won't be long before
concepts like 'My DNA is better than yours' begin to take root," and I
think this is an appropriate concern, and any time we're looking at variation
between populations, [it's] something that we need to be aware of.
But it's also encouraging that in that same publication, the authors interpreted
our results [and?] showing that this study has found that genes reflect
social patterns, but the reverse is certainly not true: that their social
status could not be nestling in their genes. So we were pleased to
see that there was a fairly accurate interpretation of the results, and
certainly one that we have tried to encourage. And finally, in this
publication, they envisioned a scenario where genetics as a study becomes
a partner of social sciences, and I think that 's an encouraging attitude,
certainly one that we want to foster and perpetuate.
So to summarize what we have found so far, I'm encouraged scientifically
at our results, that show that indeed, history leaves a mark on the genome.
And in this case, where we have a historical system, a pattern that we
could test specifically, we saw that our predictions were largely verified.
So that's encouraging for studies in which genetic variation is being used
to deduce population history; it tells us that indeed, population history
leaves a mark on the genome, and one that we can study and interpret.
And the secondary reactions to the study, we have spent, particularly Mike
Bamshad has spent a lot of time talking with journalists from India to
try to be very certain that our results are interpreted accurately.
Professor Naidu has also spent a lot of time doing that. I think
that for those of us who do studies of genetic variation in populations,
that's a very important part of what we do, [an] important part of our
responsibility, to be sure that the results are interpreted accurately.
Thanks very much.