From Linkage to Association Gene-Mapping

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Из курса от партнера Novosibirsk State University

From Disease to Genes and Back

38 оценки

Novosibirsk State University

From Disease to Genes and Back

38 оценки

Human genetics explores the genetically determined similarities and differences between human beings. This scientific discipline encompasses a variety of related fields such as molecular genetics, genomics, population genetics and medical genetics. Study of human genetics can help to find answers to questions regarding the inheritance and development of different human phenotypes. The field of medical genetics is quickly growing and dynamically developing thanks to the new technologies such as the next-generation sequencing. Most human diseases have a genetic component. This genetic component varies by disease. Some rare diseases appear to be completely determined by the genome, whereas more common diseases arise from a complex interplay of many genes, the environment and chance. The understanding of how our genomes contribute to disease susceptibility offers the prospect of large gains: it may guide disease diagnostics and prognostics and help in developing new therapies. The overall goal of this course is to describe how the researchers find genes responsible for different diseases and how this information is used to better understand and fight these diseases. You will learn about current approaches for finding single genetic variants underlying monogenic (Mendelian) diseases and sets of variants responsible for more complex, multifactorial ones. Furthermore, you will learn how the identification of these genetic variants makes it possible to understand how the affected biological pathways lead to disease development. During the final week of the course, we will talk more about clinical applications of the genetic findings. Upon completing the course, you will be able to: - give examples of monogenic and complex disorders - recognise patterns of Mendelian inheritance of monogenic diseases; - understand and describe principles and methods of gene mapping ; - describe the main steps and principles of genome-wide association studies (GWAS); - give examples of modern technologies that are currently used to find variants underlying human diseases; - discuss the approaches to finding causative variants underlying complex disorders; - discuss the possibilities and areas of application of genetic findings.

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Complex disorders

In contrast to Mendelian disorders that are controlled by a mutation in one gene, the multifactorial disorders are more complex, thus the name. These disorders are affected by an interplay of many genetic and environmental factors and also by a chance. Most of the human disorders, including prevalent types of diabetes, cardiovascular diseases, different cancers, are of such type. Although these disorders often cluster in families, they do not segregate in ways that are consistent with simple Mendelian inheritance. The methods used to find variants responsible for Mendelian disorders are not applicable for complex ones. Genome-wide association studies, or “GWAS” is a current method of choice to pinpoint the genetic variation predisposing to complex disorders. Yurii Aulchenko together with Lennart Karssen will tell you about this method and discuss its advantages and limitations.

From Linkage to Association Gene-Mapping6:23

Познакомьтесь с преподавателями

Marianna Bevova
PhD, Director of GIGA Doctoral School
University of Liège (GIGA)
Michel Georges
PhD, Professor, GIGA Research Director
University of Liège
Gert Matthijs
PhD, Professor
Center for Human Genetics, University of Leuven
Lennart Karssen
PhD, Owner and Chief Computational Scientist
PolyOmica
Natalia Aulchenko
M.Sc., Project manager
Theoretical and Applied Functional Genomics Laboratory
Yakov Tsepilov
PhD, Senior Researcher
Theoretical and Applied Functional Genomics Laboratory
Sodbo Sharapov
M.Sc, Junior Researcher
Theoretical and Applied Functional Genomics Laboratory
Alexander Tashkeev
Skolkovo Institute of Science and Technology (Skoltech), Junior Researcher
Laboratory of Computational and Structural Transcriptomics
Yurii Aulchenko
PhD, Professor, Head of Theoretical and Applied Functional Genomics Laboratory
Theoretical and Applied Functional Genomics Laboratory

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Before we will go into genome wide association studies, or GWAS for short,

let us consider a fate of individual mutant allele.

So to start with, any mutation in human population occurs in a single copy

on a single specific ancestral chromosome.

Because of drift,

because of random genetic events, this mutation may spread in the population.

However, it's not only the mutation, but

also genetic context around this mutation which spreads.

And originally, in the first few generations, there are rather big

stretches of DNA which co-segregate together with the mutation, while in

the number of generation recombination is breaking down the structure.

And the region shared by mutations identical by descent becomes shorter and shorter.

Here on the picture, I have depicted this

fact by painting the regions around the mutation with red.

Of course, in reality, we are not really painting the chromosomes in red.

However, we can trace the inheritance

of specific stretches of DNA using genetic markers.

Something about which Michelle was talking in some of the previous lectures.

Let's now think what happens if this mutation leads to a Mendelian disease.

So with few exceptions, Mendelian disease are rare and

the alleles which lead to this disease have very high penetrance.

At the same time, there is as a rule, absence or very low rate of phenocopies.

That is, if we see the mutation, almost for certain it will lead to the disease.

While if it's a disease, most likely we will see a mutation in specific gene.

This means that we can study this disease via collecting material

through ascertainment through proband.

So we can go to a population and sample just one case with a disease.

However, given this disease is controlled by rare mutation with high penetrance,

this means that it's very likely that the relatives of this person

are going to also be carriers of this mutation.

And through proband we are going to ascertain a whole pedigree,

where the number of cases is going to be enriched compared

to the populational very rare rate.

So what this means, that we can study this disease in relatively small families.

Well first of all, close relatives are going to share very big stretches of DNA.

If you take any specific chromosomes in the example presented on the screen,

there are going to be only few recombination events.

This means that only few hundreds of markers is enough

to paint our chromosomes and to define the combination events and

consequently to map the disease locus in this pedigree.

Although the resolution of this method will be relatively low, we can go and

ascertain different families.

And through overlapping the signals for linkage in these families

families we are going to fine map the region where the affected local lies.

So the technology was already developed to do several hundreds of markers in 80s.

And this defined very large progress in the mapping of loci

of Mendelian diseases during last decades.

However, now let's turn to complex traits or polygenic traits.

And here the model of control is different.

So we've been talking about mutation which is almost necessary and

sufficient for the disease.

When we talk about polygenic disease, any particular mutation

is neither necessary nor sufficient to determine disease.

We are talking about disease or complex phenotypes, quantitative traits, for example

example, which are defined by joint effect of multiple genetic and

environmental factors and their interplay.

So, if we can see each of these genetic variants, we will find that they have

a potentially very low, or maybe moderate effect on the phenotype.

So what does it mean?

This means, first of all, that if you're going to try to extend the design,

which we've been using to study monogenic disease,

into complex traits, we are going to fail miserably.

Because if you try to ascertain a pedigree via proband with the disease,

you're going to find that your proband is most likely because of one reason,

while the diseased in this family are going to be because of some other reason.

So this gives you effectively no power to study complex disease via linkage.

But what we can do?

So the key is of course the power, so you need very big sample sizes.

However, the problem will be that if you sample very big

samples they're going to be connected together in a huge pedigree.

And this means that the region surrounding any particular mutation or

a variant affecting your trait or disease of interest is going to be very small.

This means, you need a huge number of markers to study this complex traits.

By the end of 90s, it was theoretically figured out how many markers

you would need to study disease and complex traits in huge pedigrees or

huge populational base samples.

And it appears that the number is about few hundreds of thousands.

However, in the end of 90s, the technology didn't allow for

a genotyping of hundreds of thousands markers and

the genetics of complex human disease had to wait until new technologies appeared.

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