uenes anu the Buman Conuition Session 2 NovembeiBecembei 2u1S

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Welcome back. As I mentioneu at the stait of last week's lectuies, all thiough
human histoiy, people have ponueieu the meaning of life anu being human in oiuei
to uefine the essence of who we aie. ueneticists have also been tiying to figuie this
out because an unueistanuing of who we aie cannot be achieveu without
consiueiing oui biology. Foi a whole lot of ieasons, this question is going to be a lot
moie complicateu foi a human being than foi say a fish asking why it likes to eat
woims. The complications aie likely to be at theii most extieme when consiueiing
the biology of pooi health anu abnoimal behaviois.
We aie usually asking whose fault is it that something bau has occuiieu.
With a mass muiueiei, uo you blame a uamageu oi non-functional fiontal coitex,
alleles foi aggiession oi an abusive family. If youi kiu is failing at school, is he
leaining uisableu oi lazy. Is he lazy because of pooi up-biinging oi because he has
genes, not foi being leaining uisableu, but foi being a slackei. In the next couple of
lectuies, we shall look at what contempoiaiy science teaches us about how genes
enable oi constiain us anu how theii functioning is iegulateu by enviionment.
We will stait with the simplest case: tiaits contiolleu by single genes, just as
Nenuel the fathei of genetics uiu with his pea plants. Nenuel's plants weie always
one thing oi anothei. They weie eithei tall oi shoit, the floweis puiple oi white, the
peas yellow oi gieen. We call this uiscontinuous vaiiation. If we hau a single gene
contiolling eye coloi, anu it came in two foims, oi alleles as we say in genetics, then
I might have a choice of biown oi blue eyes. That woulu be one thing oi anothei so
we'u say it's uiscontinuous. If I hau two oi thiee genes contiolling eye-coloi, I might
have a stepwise piogiession fiom blue to gieen to biown. If I have multiple genes
contiolling eye coloi, each making a small contiibution to shaue, I coulu go fiom
vaiious shaues of blue to vaiious shaues of gieen to vaiious shaues of biown.
We woulu call this appeaiance of blenuing continuous vaiiation, anu most of the
impoitant uiffeiences between us aie contiolleu by multiple genes. So theie aie
hunuieus of genes contiolling oui height, which means most of us aien't veiy tall oi
veiy shoit: we aie something in between.
Theie aie seveial thousanu so calleu monogenic oi Nenuelian human
uiseases causeu by a mutation in a single gene. Cystic fibiosis is a well-known
example. Nost aie iecessive, which means that you neeu two copies of the uamageu
gene to cause uisease. Quite often, having a single copy of the gene has benefits, at
least in some enviionments oi in combination with some othei alleles, which may
explain why they've been maintaineu in populations. Famously, a single copy of the
allele foi sickle cell anemia piotects against malaiia. Nonogenic illnesses make up a
small fiaction of genetic uiseases. Paiticulaily as all uisease has a genetic
component.
The fact that a viius has a big impact on you means that youi genetically
ueteimineu immune system is pooily able to cope, wheieas someone else oi a
chimpanzee might have no tiouble. If a viius causes only milu uisease, then that
means youi immune system is up to the job of uealing with it. Even something like
bieaking a leg has a genetic component. Bow well you iepaii the bieak will uepenu
on genetic as well as enviionmental factois.
uenes anu the Buman Conuition Session 2 NovembeiBecembei 2u1S
We have all heaiu oi know of people who've spent 8u inteiesting yeais
smoking anu uiinking anu aie still well anu heaity. Theie was a fellow in Englanu
calleu Bustei Naitin who was Englanu's oluest woikei. Be smokeu heavily anu
uiank seveial pints of beei a uay anu uieu when he was about 97. Scientists aie veiy
inteiesteu in the genomes of guys like bustei because he must have hau some
genetic piotection fiom his vices. If we coulu iuentify what these aie, maybe we
coulu uevise meuicines that woulu uo the same foi those of us less foitunate.
The stoiy of peisonnel genetics highlights the successes anu limitations of
the mouein ievolution in peisonalizeu meuicine. Companies, like 2Sanume, aie
offeiing uiiectly to you the use of sequencing technology to pick up millions of gene
vaiiants. Nost of these companies use micioaiiays, oi BNA chips (they'ie the same
thing). These little instiuments that you can holu in youi hanu holu millions of
micioscopic spots of BNA, anu each spot is complementaiy to a specific iegion of
youi genome.
BNA micioaiiays can be useu to look foi SNP vaiiants in youi genome so you
can compaie youi genome piofile with that of othei people. This technology became
ieally cheap in the 21
st
centuiy anu inuispensable, but biotechnology is a
ievolutionaiy science. Theie is an extiaoiuinaiy tuinovei of technologies, anu
micioaiiays, which weie ciitical a few yeais back aie being uisplaceu by peisonnel
genomes. In this couise, I am not focusing too much on the technologies
biotechnologists use, as they aie heie touay anu gone tomoiiow.
Insteau, let's ask whethei using technologies that inteiiogate the genome
actually help us to unueistanu uisease oi the genetic ioots of oui behavioi. Buman
genetics has become like a giant excel spieau sheet wheie all the genetic vaiiants
aie listeu at the top anu all the tiaits aie listeu uown the siue, anu we tiy to finu
links.
Peihaps I am looking at asthma, cancei, heait uisease, anu finuing what SNPs
anu INBELs aie often founu in people with each of these conuitions. I might also be
looking at othei tiaits, such as height, obesity, intelligence, vaiious chaiactei tiaits
oi beliefs. These aie known as genome wiue association stuuies, oi uWAS, anu can
involve tens of thousanus of people. 0sually, as well as exons, they will also look foi
genetic vaiiants in the non-couing BNA, the so calleu junk that, in ieality, incluues a
lot of ciucial iegulatoiy BNA. Nost of what goes on with genes is iegulation of gene
activity, which is contiolleu by the enviionment.
In teims of uisease, uWAS stuuies have implicateu ovei a thousanu genes
with a iole in ovei a hunuieu common uiseases. The eaily uiscoveiies founu genes
with majoi effects in seiious uiseases like maculai uegeneiation- the commonest
cause of blinuness. A high iisk of this uisease can now be pieuicteu with ieasonable
accuiacy fiom BNA testing.
It tuineu out that a lot of common conuitions such as asthma anu uiabetes
weie contiolleu not by one oi two genes, but by tens of genes oi even hunuieus oi
thousanus of genes. It was also founu that uiffeient sets of genes might be
iesponsible foi asthma oi obesity in uiffeient people. 0bviously, unlike monogenic
uiseases, gene tests involving 1 oi 2 genes will likely be pietty useless foi pieuicting
a uisease causeu by the inteiactions of 1uu's of genes. Bowevei, on the goou siue,
uenes anu the Buman Conuition Session 2 NovembeiBecembei 2u1S
many of the gene uiscoveiies foi common uiseases tuineu out to be inteiesting in
teims of unueistanuing theii biology.
uWAS stuuies have iuentifieu mechanisms by which uiseases stait anu the
biological pathways that aie uisiupteu, so we can figuie out tieatments. In some
uiseases, such as Inflammatoiy Bowel Bisease, entiiely new anu completely
unexpecteu pathways have been uiscoveieu. In othei uiseases, new insights into
existing pathways have been given; so the autoimmune pioblems that leau to type I
uiabetes have been ciackeu wiue open.
Let's look at obesity as an example. uWAS stuuies have auuiesseu basic
questions as to why some people aie thin anu otheis fat, anu why being fat makes
some people ill. It tuins out that genetics plays a much biggei iole in obesity than
we hau pieviously thought because it coveis not just moleculai biology of how the
bouy piocesses foou, but also behavioial tiaits, such as piopensity to exeicise anu
appetite. A lot of genes aie involveu in all these tiaits but some may be moie
impoitant than otheis. A stuuy that came out in }uly 2u1S showeu that a high-iisk
veision of the FT0 gene associateu with obesity makes fatty foous moie tempting
anu alteis levels of a hoimone calleu ghielin which makes people hungiy. 0ui
intiinsic biology tells us how much we want to move anu eat, anu we aie less in
uiiect contiol of bouy weight than we like to think.
0besity is an example of the pioblems that aiise fiom us living in a woilu
that is iauically uiffeient fiom the one in which we evolveu. Foi subsistence hunteis,
it's a goou stiategy to eat all you can when you aie lucky enough to come acioss a
iich eneigy souice like sugai oi fat. This may be why we caiiy alleles of FT0
uesigneu by selection to finu these foous so pleasant. Bowevei, foi those of us
foitunate enough to be suiiounueu by an almost limitless supply of cake anu ueep-
fiieu buigeis, it is ueciueuly unhealthy to continuously goige ouiselves. We aie
fighting innate tenuencies that aie not healthy foi us.
The inability to finu inuiviuual alleles that aie always associateu with
meuical conuitions like uiabetes anu many othei tiaits has leu to a big shift in
attituue anu leu many geneticists to change theii focus to people who seem
piotecteu fiom common uiseases. I just mentioneu Bustei Naitin.
Theie aie othei people who've liveu 8u oi moie inteiesting yeais of uiinking
anu smoking anu still seem whole anu heaity. Theie's incieasing eviuence that a big
ieason we uont finu single genes foi uiseases, oi that uiseases may be causeu by
uiffeient genes in uiffeient people is because some of us may also have piotective
sets of genes, anu these oveiiiue genes associateu with uisease oi aging.
ueneticists aie sequencing the BNA of centenaiians, people they call the
"wellueily." These aie people ovei the age of 8u who have no chionic uiseases.
These stuuies aie coming up tiumps. So fai, they've iuentifieu S oi 6 biochemical
pathways that aie most often ievveu up oi inhibiteu in the "wellueily." A lot of the
gene vaiiants in long liveu people affect the insulin-IuF-1 pathway. IuF-1 plays an
impoitant iole in chiluhoou giowth, but it has also been implicateu as an acceleiant
of canceis anu as a poweiful iegulatoi of metabolism.
The hope is that these stuuies may someuay leau to uiugs that help us ieach
a iipe anu healthy olu age. Let's hope they uo, but I also hope you might now be able
to see that the views of the populai meuia aie simplistic. The meuia claims specific
uenes anu the Buman Conuition Session 2 NovembeiBecembei 2u1S
genes foi all soits of things, incluuing why uo we behave as we uo. If you type into
uoogle "scientists finu gene foi" anu leave the last bit blank, you will get hunuieus of
thousanus of hits.
It is noticeable that time anu time again scientists finu the gene foi
uepiession oi haii loss oi cancei. It's sometime saiu that the most uangeious woiu
in genetics is "foi." In some ways, "foi" is the most uangeious woiu in society: the
iuea that eveiything has a simple cause. uenetics isn't that.
In 2uu9, a muiueiei in Italy got a ieuuceu sentence because he hau alleles
associateu with ciiminality. Some 0S couits have gone the othei way anu accepteu
genetic factois as eviuence foi the piosecution, leauing to highei sentences on the
basis that people with paiticulai alleles cannot be cuieu anu will iemain a iisk to
society foi longei.
A stuuy publisheu in !"#$%"$ in 2u12 askeu juuges to impose a piison teim on
a hypothetical convict. When the juuges weie initially tolu that the offenuei was a
psychopath, they tenueu to consiuei it an aggiavating factoi in sentencing, but when
they heaiu auuitional expeit testimony that biological factois coulu explain the
guilty man's behavioi, they saw that infoimation as mitigating anu hanueu uown a
shoitei sentence.
Bo you think that this coulu be a uangeious ioau to go uown. Aftei all, most
violent ciime is linkeu with the SRY gene, the gene on the Y chiomosome that
ueteimines maleness, but nobouy woulu get off because they weie a bloke. Bo you
think that having the Y chiomosome shoulu leau to a haishei sentence. Latei in the
week, we will talk about a veiy famous psychologist who has all the alleles one
woulu pieuict in a psychopath, but is not a violent man. Be cieuits this with his
upbiinging, in othei woius, his chiluhoou enviionment.