Learn how advances in biomedicine hold the potential to revolutionize drug development, drug treatments, and disease prevention: where are we now, and what does the future hold? This course will present short primers in genetics and mechanisms underlying variability in drug responses. A series of case studies will be used to illustrate principles of how genetics are being brought to bear on refining diagnoses and on personalizing treatment in rare and common diseases. The ethical and operational issues around how to implement large scale genomic sequencing in clinical practice will be addressed. After completing this course, learners will understand 1. The ways in which genetic variants can contribute to human disease susceptibility 2. How to choose among drug therapies based on genetic factors 3. That the functional consequences of the vast majority of genetic variants discovered by modern sequencing are unknown. This course is targeted primarily at physicians 5+ years out of training. Other healthcare providers, medical/health sciences students, and members of the public may also be interested. Course launches January 15, 2016. * The information presented in “Case Studies in Personalized Medicine” is offered for educational and informational purposes only, and should not be construed as personal medical advice. If you have questions or concerns about a medical matter, please consult your doctor or other professional healthcare provider.
Finding Disease-Associated Genes: Linkage
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En provenance du cours de Vanderbilt University
Case Studies in Personalized Medicine
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UNIT 2: STUDYING GENETIC VARIATION
Module 3 focuses on how we study genetic variation. We'll start by looking at families and populations. Topics that will be introduced include family history and inheritance patterns, ancestry, and linkage. Then in Module 4 we shift our focus to studying the contemporary techniques and technologies used to study genetic variation, including genome-wide association and sequencing.
Rencontrer les enseignants
Dan Roden, M.D.Professor of Medicine and Pharmacology
Assistant Vice Chancellor for Personalized Medicine
[MUSIC]
In this module I'm going to talk a little bit about how we approach finding
diseased genes in families that have unusual diseases like
the familial forms that I've talked about before.
So here is a family, I think I showed this particular family tree before and
this family has a pattern of inheritance that goes across generations.
Each affected individual is shown in red, and
you can see that the pattern is that women transmit to men, men transmit to women.
And there's approximately equal numbers of men and women affected that in each
generation an affected person transmits to approximately 50% of their offspring.
So this is a family tree that I did show before and
I wanted to highlight the idea that in generations three
there's nobody marked as having the phenotype that we're interested in.
And the reason for
that is many of these diseases will have what's called variable penetrants.
So there has to be somebody in that family, and it has to be this person,
in fact that's shown in red now who is an obligate mutation carrier.
That doesn't mean they have the disease.
But we know that if the grandfather has it, and it is genetic, and
it's transmitted in an autosomal dominant fashion,
which is what this pattern looks like.
Then that person in generation three,
the mother of the two affected children in generation four must be a carrier.
So an important step in starting to resolve these particular
patterns is to make sure that we understand the phenotype and understand
the family relationships because otherwise it's a garbage in, garbage out problem.
And if we analyze on the wrong assumptions well, we'll get to the wrong place.
So the question that an investigator would have
when they're faced with large kindred like that.
Where they're reasonably certain that it's a genetic disease,
is where in the genome is the variant or perhaps the set of variants but
hopefully the single variant causes the disease, how do you find that?
Well it turns out there are places in the genome that are variable, and
they're variable in a random relatively random way across individuals and
those places in the genome allow us to do what's called mapping.
So one kind of variant that's very,
very common is a single nucleotide polymorphism or a snip.
Another kind of variant that I haven't talked about much before is what's called
a repeat variant.
So here is, here are two separate genetic sequences and
one person has four TA repeats and the other one has two TA repeats.
That's called a dinucleotide repeat because it's a pattern of two.
And here is a person who has four Trinucleotide repeats TAC,
TAC, TAC, TAC, and the other one is only TACTAC.
So, that's two copies or four copies.
And there are ways that are pretty simple To distinguish between people with
two copies or four copies of these repeats or ten copies or 17 copies.
Most of these repeats will not be in the coding region, and in fact, if
a dinucleotide or a trinucleotide repeat were in the coding region, it would almost
certainly disrupt the amino acid sequence and have profound functional changes.
So here is a small family.
And these are representations of a chromosomal sequence
in the mother and the father in this family.
So the chromosomal sequence in the mother is shown in pink and green and
in the father in pink.
And then there's a little block at the top that's yellow and
a little block in the middle that is blue.
Those blocks represent individual haplotype blocks that have
arisen over time, and make different sequences in mom and dad.
Each one of those are mappable using dinucleotide or trinucleotide repeat
patterns across the genome that allow people to distinguish those alleles.
Now what happens here is that one daughter,
it has a pattern that is actually interesting, it's not like mom or dad.
It's sort of the top half is like mom, and the bottom half is like dad.
The one son inherits that particular region
of this particular chromosome from dad.
The infected son inherits it from Dad, and
the uninfected son inherits the maternal chromosome.
So when you look at this pattern and
you start to think about which patterns track across generations.
You think, well maybe it's something in that blue region that confers disease.
Everybody who has the blue region has the disease.
Everybody who has not the blue region does not have the disease.
That's why the phenotyping is so important, deciding who is a carrier and
who is not.
And then having large, large multigeneration families because that
allows more recombination events to take place and more genetic mapping to occur.
And how do you find that blue region?
Uses the dinucleotide or trinucleotide repeats currently it uses snips and
as I'll talk about in a couple of modules, there are much newer ways that have
actually superseded these kinds of approaches which many people would
regard as relatively primitive, but of huge historical importance.
So, the way in which the statistics are done in these kinds of families
is there's logarithm of the odds ratio score, the lod score.
And a lod score greater than three, And there's a way of defining that statistic.
Suggest that you have landed in the right region for
this particular genetic variant.
Now it doesn't tell you what the genetic variant is,
the region might be huge, it might encompass dozens and dozens of genes, and
the challenge to the investigator is to either get the region smaller by acquiring
More recombination events, in other words, more generations.
Or by tediously tracking through the particular region
of linkage to find the gene that actually causes the disease.
A Lod score less than two suggests that the region that you've been looking
does not have the disease locus contained.
And in between, you just need to do more.
So I'm going to show you one example Of how this technology was used to crack
a common, a relatively common disease that's inherited in an autosomal fashion,
what's so called Mendelian disease.
This is a very, very large kindred.
You can see With affected individuals shown in dark,
many of the individuals are dead because it's a large family.
And the disease might kill them early, but in fact, age will kill many of them.
So you have to have phenotypes.
You have to have DNA on large, large numbers of patients, and do mapping.
This particular phenotype happens to be a family,
a French Canadian family in fact with a disease called hypertrophic
cardiomyopathy that results in a thickened ventricle.
This exercise in mapping initially would cover perhaps
several hundred dinucleotide repeat regions across the genome.
Mapping those would identify a region of the genome
in which the disease gene would occur.
So you can imagine with mapping 400 markers,
you would arrive at a very very large chunk of the genome.
In which the disease gene occur.
So that was what was done.
First this a small region of chromosome 14 in that particular family.
And you can see there's a Lod score that is very,
very high in this particular region of linkage.
So, with that particular marker, it's likely that the disease
chain the actual mutation that causes the disease is located in that region.
But that region spans hundreds of thousands of base pairs.
So with advancing technologies and the ability to define those regions in more
detail, and to define the genes in those regions.
Came the ability to actually isolate the specific gene and the specific mutation
that causes the disease in that family and the way to do
that is to have a large family with a high Lod score and some physiologic rationale.
This is a map of the disease genes called the beta-myosin heavy chain gene.
It's a gene that's expressed in the heart as an important
part of the contractile apparatus.
This gene was identified as a disease gene in the disease hypertrophic cardiomyopathy
in 19 89.
To this day it's not very clear how a mutation is beta
myacin heavy chain results in the phenotype of hypertrophic cardiomyopathy.
Nevertheless, the discovery has been a huge boon to clinicians because we can now
use genetic testing to identify mutation carriers and non-mutation carriers.
This is a cartoon from the very first publication that identified the mutation
in this particularly family, but we now know that there are literally hundreds
of mutations in this particular gene that cause the disease in other families.
And there are literally dozens of genes in which mutations can
cause the disease not just in betamyosin heavy chain, but in other genes.
And the interesting thing about those genes is that they all
encode proteins that interact in some way with the beta myosin heavy chain gene
to effect the way the heart contracts.
So it's a great story of going from a family,
doing traditional linkage, finding the region, finding the gene and then using
that information to uncover the cause of the disease in many many other families.
And start to understand the underlying path of physiology,
start to develop genetic testing, which we talk about more in the case studies.
And I emphasize again, the reason that that was successful is that it starts
with this very very large Family.
Very small families, individuals with hypertrophic
cardiomyopathy are just simply not informative using this linkage approach.
But what the good news is is that with newer sequencing technologies which I'll
talk about in a couple of modules.
We can actually crack cases of patients who have unusual phenotypes and
don't have much of a family history and we'll talk about that later.
[MUSIC]
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