thank you for listening to my talk today
because I know that you’d all rather be
having sex the average healthy person
thinks about sex every day did you know
that one reason that men and women
involved and exist is to have sex and
we’re not the only ones thinking about
it but while you’re lying in bed next to
your partner sweaty and exhausted
wrapped in red satin sheets listening to
Kenny G have you ever pondered why
fundamentally sex is how mums and dads
contribute their genes to their
offspring so for most of the 19,000
genes embedded in our chromosomes we
have two copies one that we inherit from
our mom and one that we inherit from our
dad this is the recipe for life but why
does the recipe call for two helpings of
most genes one reason is that it’s
always good to have a backup if one gene
copy has a mutation the other healthy
copy can compensate and we all have some
intuition for this because it’s common
knowledge that you shouldn’t marry and
have children with your sister or
brother no matter how wonderful they may
be people who are closely related to
share many of the same mutations in
their genes and so if they have kids
together the kids have a higher risk for
having the same mutation in both copies
no healthy
copy and so they have a higher risk for
developing a genetic disorder so one
reason that we have sex is to mix the
genes from different and ideally
unrelated individuals but that’s not the
whole story
in the 1980s scientists learned how to
take all the fun out of making babies at
least for mice when the sperm meets the
egg it forms a zygote that contains the
set of genes you get from mom and the
set of genes you get from dad and the
scientists were working in the lab and
they developed these tiny needles and
they went into the zygote and they
sucked out the genes that came from the
dad and they injected in a second copy
of genes from mum so the embryos
effectively had two mothers no father
involved and they also engineered the
opposite situation where they had
embryos that had two sets of genes from
dad and no mother involved what do you
think happened
they died even though they had the
normal set of gene copies only embryos
that were engineered with a set of gene
copies from mom and a set of gene copies
from dad generated mice that survived
and the experiment revealed that the
genes we get from mom and dad are
somehow different they’re not just
backup copies for each other the
difference turned out to involve a
special kind of gene in our genome
called imprinted genes now imprinted
genes are distinguished by the fact that
moms and dads stick chemical marks to
them in the egg and the sperm and those
chemical marks are inherited by the kids
and they silence the genes in the kid
but mums and dads put those marks on
different genes and so as a consequence
some genes silenced the copy from dad
and Express the copy from mom and the
kids and other genes silenced the copy
from mom but expressed the copy from dad
you may be deeply disturbed by the idea
that your parents sent you secret
messages that are stuck to your genes
but I’m just getting started
the scientists again engineered cells
with genes from two moms and cells with
genes from two dads and they mix them
together with normal cells so that the
embryos would live longer and what they
discovered was amazing the embryos with
cells with two sets of genes from mom
developed small bodies but very large
brains
and the embryos that were engineered
with cells that end that had a set of
genes from only dads had the exact
opposite phenotype they had large bodies
and relatively small brains so you may
not be surprised by this but what it
revealed is that the imprinted genes we
get from mom and dad have very different
effects on offspring brain and body
development so mom and dad moms and dads
send us different messages through these
imprinted genes but while imported genes
are fascinating they’re also rare only
about 1% of the 19,000 genes in our
genome are imprinted and the researchers
in my lab were left with the question
what’s the story with the other 99% of
our genes do they have two copies just
to have a backup is that the whole story
is it time to roll over turn out the
light and go to sleep not yet and this
part of the talk is complicated but you
know it’s not the kamasutra
when the genes in our DNA are expressed
they make a molecule called RNA RNA
makes protein and proteins build our
cells we can measure RNA sometimes when
our genes are activated they make a lot
of RNA and sometimes they make just a
little now imagine that we clone a whole
bunch of nerds
and we dissect out a piece of brain
tissue from each nerd and measure the
activity of the genes in that brain
tissue for given gene and some
individuals each activity level will be
high in others it will be low there will
be just this natural variation across
different individuals because of natural
variation in their physiology and
variation and how we dissected out that
piece of tissue but now we drill down to
the level of the mum and dad’s gene
copies and we expect that the two copies
will go up and down together in their
activity because they’re just backup
copies of one another expressed and
regulated in the exact same way but what
if we discover genes where that’s not
the case and they express the two copies
differently well that would exceed are
not just backup copies of each other
that maybe they’re doing different
things so we did this experiment for
each of the 19,000 genes in the genome
in mice and we found genes that express
mum and dad’s copy the same way they
were highly correlated like this gene as
though they’re acting as backup copies
for each other but we also discovered
hundreds of genes where that was not the
case like this gene a door to B when
mom’s copy increases its activity dad’s
copy decreases its activity they’re
negatively correlated acting
antagonistically to each other clearly
doing different things and the story got
even more interesting when we started to
measure these things at different ages
in the adult brain ten percent of genes
expressed mom and dad’s gene copies
differently but in the developing
newborn brain over eighty five percent
of genes expressed the two copies
differently
it was as though each gene copy had its
own unique role to play in building the
developing brain holy crap
there was no time left for sex we had to
like get into the lab and do some
serious experiments because this could
really change how we think about how our
genes make us who we are over the past
several decades we have developed new
technologies that can routinely sequence
our genomes and analyze our genes and
we’ve learned a whole bunch of
surprising things we’ve learned that all
of us have bonafide disease-causing
mutations in our genome about 400
damaging mutations on average to lethal
mutations but I feel fine and you guys
all look great
so for reasons that we don’t fully
understand some of us get sick and some
of us don’t the other thing that we’ve
learned is that the mutations in our
genes that influence our risk for
disease are typically present in just
one gene copy not both
for example paternal age has emerged as
an important risk factor for a lot of
different disorders like autism and one
reason is that fathers are constantly
generating new sperm and they accumulate
more and more mutations in the genes in
the sperm as they get older and older
about two new mutations per year and
those mutations are inherited by the
kids in their dads gene copies the mom’s
copies should act as a backup but we’ve
just learned that in many cases the mom
and dad copies are expressed differently
so how does this actually play out we
wanted to know and so we engineered mice
with a mutated gene copy and a healthy
gene copy and we looked at how they’re
expressed in the brain cells of the lab
ones we discovered cells that Express
both the healthy copy and the mutated
copy
kind of like we expected so there’s a
backup healthy copy there but we also
discovered cells that were only
expressing the healthy copy which was
very surprising but more alarmingly we
found cells that only expressed the
mutated gene copy the cells that
preferentially expressed mutated gene
copies contribute to our risk for
disease if they do this paints a very
different picture of disease but we
don’t know right now it’s just an idea
and there are a whole bunch of questions
that remain most of what I’ve talked
about we did in lab mice but you may be
wondering what’s happening in you you
may be wondering about how your parents
genes are expressed in you and if you
are a parent then maybe you’re thinking
about how your genes are expressed in
your kids maybe they have really
annoying habits like their father and
now you’re thinking they must express a
lot of his gene copies we also wanted to
know the answer to this and so we
developed a staining method that we
could use in postmortem human brain
tissue to look at the activity of the
two copies we get from mom and dad the
staining method reveals the individual
brain cells in blue and it reveals the
activity of the two copies of a gene in
red we can’t tell which copy is mutated
or healthy yet and we can’t top kill we
can’t tell which one comes from mom and
which one comes from dad but we can see
for each cell whether it’s expressing
both copies equally or differently we
found genes like this one that expresses
both the mom and the dads copy equally
in human brain cells so there’s a back
up copy there but we also discovered
genes like these ones
Huntington which is linked to
Huntington’s disease and a gene called
death one that’s linked to autism they
are clearly expressing there are two
copies differently and we found brain
cells that have only one active gene
copy so like mice we also frequently
express our mom and dad’s gene copies
differently and this means we may not
fully understand why we have sex and
contribute to copies of most genes to
our kids research over the past several
decades has taught us an incredible
amount about how our genes make us who
we are and by gaining a deeper a deeper
understanding of our genes or gaining a
deeper understanding of disease we’re
learning how to make better therapies
better medicines but there are lots of
mysteries that remain we think that
we’ve discovered something fundamentally
new by studying the activity of our
genes at the level of the two copies we
get from mom and dad and we were
surprised to find that there are genes
that we know caused disease and people
that express their two copies
differently we found cells that
frequently Express mom and dad’s copies
differently mutated and healthy gene
copies differently why do these effects
play some special role in shaping the
function of our brain do they shape our
risks for disease we feel like explorers
on the edge of a new frontier and we’re
really excited to find out what we’re
going to learn we may discover that your
parents always have the last word
thank you
[Applause]
because I know that you’d all rather be
having sex the average healthy person
thinks about sex every day did you know
that one reason that men and women
involved and exist is to have sex and
we’re not the only ones thinking about
it but while you’re lying in bed next to
your partner sweaty and exhausted
wrapped in red satin sheets listening to
Kenny G have you ever pondered why
fundamentally sex is how mums and dads
contribute their genes to their
offspring so for most of the 19,000
genes embedded in our chromosomes we
have two copies one that we inherit from
our mom and one that we inherit from our
dad this is the recipe for life but why
does the recipe call for two helpings of
most genes one reason is that it’s
always good to have a backup if one gene
copy has a mutation the other healthy
copy can compensate and we all have some
intuition for this because it’s common
knowledge that you shouldn’t marry and
have children with your sister or
brother no matter how wonderful they may
be people who are closely related to
share many of the same mutations in
their genes and so if they have kids
together the kids have a higher risk for
having the same mutation in both copies
no healthy
copy and so they have a higher risk for
developing a genetic disorder so one
reason that we have sex is to mix the
genes from different and ideally
unrelated individuals but that’s not the
whole story
in the 1980s scientists learned how to
take all the fun out of making babies at
least for mice when the sperm meets the
egg it forms a zygote that contains the
set of genes you get from mom and the
set of genes you get from dad and the
scientists were working in the lab and
they developed these tiny needles and
they went into the zygote and they
sucked out the genes that came from the
dad and they injected in a second copy
of genes from mum so the embryos
effectively had two mothers no father
involved and they also engineered the
opposite situation where they had
embryos that had two sets of genes from
dad and no mother involved what do you
think happened
they died even though they had the
normal set of gene copies only embryos
that were engineered with a set of gene
copies from mom and a set of gene copies
from dad generated mice that survived
and the experiment revealed that the
genes we get from mom and dad are
somehow different they’re not just
backup copies for each other the
difference turned out to involve a
special kind of gene in our genome
called imprinted genes now imprinted
genes are distinguished by the fact that
moms and dads stick chemical marks to
them in the egg and the sperm and those
chemical marks are inherited by the kids
and they silence the genes in the kid
but mums and dads put those marks on
different genes and so as a consequence
some genes silenced the copy from dad
and Express the copy from mom and the
kids and other genes silenced the copy
from mom but expressed the copy from dad
you may be deeply disturbed by the idea
that your parents sent you secret
messages that are stuck to your genes
but I’m just getting started
the scientists again engineered cells
with genes from two moms and cells with
genes from two dads and they mix them
together with normal cells so that the
embryos would live longer and what they
discovered was amazing the embryos with
cells with two sets of genes from mom
developed small bodies but very large
brains
and the embryos that were engineered
with cells that end that had a set of
genes from only dads had the exact
opposite phenotype they had large bodies
and relatively small brains so you may
not be surprised by this but what it
revealed is that the imprinted genes we
get from mom and dad have very different
effects on offspring brain and body
development so mom and dad moms and dads
send us different messages through these
imprinted genes but while imported genes
are fascinating they’re also rare only
about 1% of the 19,000 genes in our
genome are imprinted and the researchers
in my lab were left with the question
what’s the story with the other 99% of
our genes do they have two copies just
to have a backup is that the whole story
is it time to roll over turn out the
light and go to sleep not yet and this
part of the talk is complicated but you
know it’s not the kamasutra
when the genes in our DNA are expressed
they make a molecule called RNA RNA
makes protein and proteins build our
cells we can measure RNA sometimes when
our genes are activated they make a lot
of RNA and sometimes they make just a
little now imagine that we clone a whole
bunch of nerds
and we dissect out a piece of brain
tissue from each nerd and measure the
activity of the genes in that brain
tissue for given gene and some
individuals each activity level will be
high in others it will be low there will
be just this natural variation across
different individuals because of natural
variation in their physiology and
variation and how we dissected out that
piece of tissue but now we drill down to
the level of the mum and dad’s gene
copies and we expect that the two copies
will go up and down together in their
activity because they’re just backup
copies of one another expressed and
regulated in the exact same way but what
if we discover genes where that’s not
the case and they express the two copies
differently well that would exceed are
not just backup copies of each other
that maybe they’re doing different
things so we did this experiment for
each of the 19,000 genes in the genome
in mice and we found genes that express
mum and dad’s copy the same way they
were highly correlated like this gene as
though they’re acting as backup copies
for each other but we also discovered
hundreds of genes where that was not the
case like this gene a door to B when
mom’s copy increases its activity dad’s
copy decreases its activity they’re
negatively correlated acting
antagonistically to each other clearly
doing different things and the story got
even more interesting when we started to
measure these things at different ages
in the adult brain ten percent of genes
expressed mom and dad’s gene copies
differently but in the developing
newborn brain over eighty five percent
of genes expressed the two copies
differently
it was as though each gene copy had its
own unique role to play in building the
developing brain holy crap
there was no time left for sex we had to
like get into the lab and do some
serious experiments because this could
really change how we think about how our
genes make us who we are over the past
several decades we have developed new
technologies that can routinely sequence
our genomes and analyze our genes and
we’ve learned a whole bunch of
surprising things we’ve learned that all
of us have bonafide disease-causing
mutations in our genome about 400
damaging mutations on average to lethal
mutations but I feel fine and you guys
all look great
so for reasons that we don’t fully
understand some of us get sick and some
of us don’t the other thing that we’ve
learned is that the mutations in our
genes that influence our risk for
disease are typically present in just
one gene copy not both
for example paternal age has emerged as
an important risk factor for a lot of
different disorders like autism and one
reason is that fathers are constantly
generating new sperm and they accumulate
more and more mutations in the genes in
the sperm as they get older and older
about two new mutations per year and
those mutations are inherited by the
kids in their dads gene copies the mom’s
copies should act as a backup but we’ve
just learned that in many cases the mom
and dad copies are expressed differently
so how does this actually play out we
wanted to know and so we engineered mice
with a mutated gene copy and a healthy
gene copy and we looked at how they’re
expressed in the brain cells of the lab
ones we discovered cells that Express
both the healthy copy and the mutated
copy
kind of like we expected so there’s a
backup healthy copy there but we also
discovered cells that were only
expressing the healthy copy which was
very surprising but more alarmingly we
found cells that only expressed the
mutated gene copy the cells that
preferentially expressed mutated gene
copies contribute to our risk for
disease if they do this paints a very
different picture of disease but we
don’t know right now it’s just an idea
and there are a whole bunch of questions
that remain most of what I’ve talked
about we did in lab mice but you may be
wondering what’s happening in you you
may be wondering about how your parents
genes are expressed in you and if you
are a parent then maybe you’re thinking
about how your genes are expressed in
your kids maybe they have really
annoying habits like their father and
now you’re thinking they must express a
lot of his gene copies we also wanted to
know the answer to this and so we
developed a staining method that we
could use in postmortem human brain
tissue to look at the activity of the
two copies we get from mom and dad the
staining method reveals the individual
brain cells in blue and it reveals the
activity of the two copies of a gene in
red we can’t tell which copy is mutated
or healthy yet and we can’t top kill we
can’t tell which one comes from mom and
which one comes from dad but we can see
for each cell whether it’s expressing
both copies equally or differently we
found genes like this one that expresses
both the mom and the dads copy equally
in human brain cells so there’s a back
up copy there but we also discovered
genes like these ones
Huntington which is linked to
Huntington’s disease and a gene called
death one that’s linked to autism they
are clearly expressing there are two
copies differently and we found brain
cells that have only one active gene
copy so like mice we also frequently
express our mom and dad’s gene copies
differently and this means we may not
fully understand why we have sex and
contribute to copies of most genes to
our kids research over the past several
decades has taught us an incredible
amount about how our genes make us who
we are and by gaining a deeper a deeper
understanding of our genes or gaining a
deeper understanding of disease we’re
learning how to make better therapies
better medicines but there are lots of
mysteries that remain we think that
we’ve discovered something fundamentally
new by studying the activity of our
genes at the level of the two copies we
get from mom and dad and we were
surprised to find that there are genes
that we know caused disease and people
that express their two copies
differently we found cells that
frequently Express mom and dad’s copies
differently mutated and healthy gene
copies differently why do these effects
play some special role in shaping the
function of our brain do they shape our
risks for disease we feel like explorers
on the edge of a new frontier and we’re
really excited to find out what we’re
going to learn we may discover that your
parents always have the last word
thank you
[Applause]
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