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PETER REDDIEN: It's expensive to sequence
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the genome of an individual, but it's
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getting cheaper and cheaper.
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So we could sequence the genome.
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It's about $1,000 to $2,000 per person.
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Which you could do this for the individuals in a pedigree.
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You could also sequence what's called the exome.
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So the exome are just the exons of the genome, which is
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about 1% to 2% of the genome.
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So genes exist in these exons separated by introns,
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and there's lots of repeats and other stuff.
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And you could say, well, let's just
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guess that the mutation is going to be in an exon that's
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causing the trait.
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It doesn't have to be.
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It could be somewhere else.
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And we'll talk about that later.
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But let's just for now say, well,
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let's guess it's in an exon.
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And wouldn't it be nice if we could just
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sequence those things, and that cuts
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by a couple of orders of magnitude
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the size of what you're sequencing.
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And this is a bit cheaper.
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So it's about $500 per person.
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And the way you do it is by taking
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genomic DNA from an individual and making lots
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of little fragments for it.
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So you chop it up into fragments.
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And let's say these dark blue fragments are sequences
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that happen to come from exons.
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Well, you can hybridize those to synthesized
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pieces of DNA, that's these orange ones, that
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correspond to the exons throughout the genome.
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So these would be synthesized.
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And then you can hybridize by base pair complementarity
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the regions of DNA of interest, and then you can sort of
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pull these out, washing away that sequences you don't want,
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and then sequence the library from it.
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These exons will be known from prior efforts
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in annotating the genome.
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So there's lots of ways to annotate a genome.
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You can look for open reading frames present in exons.
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You can look for expressed genes.
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There's experimental ways to find
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the sequence of expressed genes and then map that information
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onto a genome.
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So work in annotating the genome leads to this information.
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All right, so one place in which this is applied,
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either genome or exome sequencing,
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is for rare diseases.
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There are a lot of rare diseases where
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someone has something wrong and it's really hard
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to explain what it is.
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It's not matching some known disease.
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Someone comes into the clinic with this.
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And what do you do?
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Trying to figure out what it is.
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You might not even have-- if it's not a known disease,
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you don't even have this heritability information
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from twin studies.
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So it can be very hard.
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And there's a lot of these types of things.
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And one thing that could be tried
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is to try to sequence the individual.
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And an approach that's often taken
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is to sequence what are called trios
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where you sequence the individual and the individual's
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parents.
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Now what do you do with that information?
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Well, you could look up a database of known variants
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that exist in human populations and you could say, well,
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do these three individuals carry some variant
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within an exon that's not known previously?
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Maybe the parents are heterozygous
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and the individual is homozygous.
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So you try to get some candidate genes this way.
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And an example, a powerful approach,
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is to look for de novo mutations.
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By de novo, I mean the parents don't have it.
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So a mutation that arose in the generation of the gametes
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or early in the development of this individual that
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has this disease.
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So you can identify these de novo mutations
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and identify candidate genes that way.
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Then if you find something, you have some knowledge
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of these genes, you could also go look in other individuals
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and try to find other individuals that
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might have a similar rare trait and see do you ever
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see mutations in that gene in those individuals.
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There are a lot of human Mendelian diseases.
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I list some famous ones here.
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Huntington's disease, inherited forms of risk
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for breast cancer.
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Not all forms of breast cancer display a heritable risk,
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but some do.
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Polycystic kidney disease, Lou Gehrig's disease,
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or ALS, cystic fibrosis, sickle cell anemia, hemophilia,
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and many others.
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So I'm mentioning there's lots of traits and diseases
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that are non-Mendelian, but there are also
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a lot of Mendelian ones.
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Here are some examples of pedigrees with human Mendelian
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traits.
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Polydactyly displays the autosomal dominant pattern
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of inheritance, which you can see in pedigrees.
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Hemophilia displays X-linked recessive inheritance.
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This is an inheritance from the royal family of England
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and through Europe.
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We can see Queen Victoria here passing on an allele
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to the son Leopold, and so on.
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You can go and look up statistics on Mendelian traits
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in humans in the Online Mendelian
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Inheritance in Man database.
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So I looked this up yesterday, where
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they say there are 6,900 something phenotypes for which
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the molecular basis is known.
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That's a lot, and it's been going up rapidly.
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And then depending on how you break down those phenotypes,
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if you just-- if you look at some set of them,
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some Mendelian phenotypes, you can say, how are we
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doing with identifying them.
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So there's 8,500 in this data, Mendelian phenotypes.
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So just focusing on Mendelian phenotypes here.
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And about 67% of those have a known molecular basis.
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So most.
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These numbers are rising.
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Of course, we're identifying new traits and diseases,
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phenotypes, I guess, and then more and more getting
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identified all the time.
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Now there's lots of news stories about this kind of approach,
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using sequencing to try to identify the molecular basis
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of rare traits.
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So you can see some example titles here
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where you take one example here, like this one.
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It was a de novo mutation in this child.
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The parents didn't have it and they found it
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by sequencing the parents and the child.
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Here's an example paper where, if you look at the methods,
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how did they do it, where they found de novo variants
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in some gene causing some neuropathy.
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They say three patients carrying de novo variants
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were identified by a diagnostic trio exome sequencing.
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So now if you see that kind of wording,
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you know what it means.
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Now individuals that are displaying some rare trait
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can participate in studies.
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This is a study the Rare Genomes Project being conducted
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at the Broad Institute here at MIT, in collaboration
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with Mass General Hospital and Brigham and Women's
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where here's the process.
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You submit your DNA, they extract it and process it
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for either exome or genome sequencing,
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depending upon the details of the study.
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And they say in particular, participation
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from both of the patient's parents
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will increase our ability to find a genetic cause,
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and this is the reason why.
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