Novosibirsk State University

From Disease to Genes and Back

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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.

From the lesson

Populational genetics

During this week, Yurii Aulchenko will teach you the basics of population and quantitative genetics. Population genetics is a branch of genetics that deals with genetic variation among individuals in a population. "Nothing in Biology Makes Sense Except in the Light of Evolution" is a quotation from a 1973 essay by the evolutionary biologist Theodosius Dobzhansky. The fundamental importance of population genetics lies in the insights it provides into the mechanisms of evolution, thus allowing geneticists to better understand the drivers behind the organization and functioning of human genomes. You will learn about such phenomena as population structure, selection and genetic drift. You will also learn about quantitative genetics, which studies how the genes and environment control variations in complex phenotypes.

Introduction to Populational Genetics6:10

Meet the Instructors

Marianna Bevova
PhD, Director of GIGA Doctoral School
University of Liège (GIGA)
Yurii Aulchenko
PhD, Professor, Head of Theoretical and Applied Functional Genomics Laboratory
Theoretical and Applied Functional Genomics Laboratory
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

In the next few lectures,

we are going to discuss the genetics of populations or populational genetics.

Populational genetics is dealing with changes which happens in

populations under the influence of evolutionary factors.

Populational genetics is actually one of

the most mathematical fields of biology and genetics,

and therefore,

it makes sense to also redefine the subject of populational genetics

in a little bit more mathematical terms.

Then we can define this subject as studying the question that,

given a set of initial conditions,

a set of certain parameters,

what we expect about allelic frequencies dynamics in space and time.

Before this definition becomes any operational,

we first need to define what are these evolutionary factors

which I have mentioned,

and we also will need to define what is genetic population.

So, if we think of evolutionary factors,

the first thing which comes to mind is mutation.

A mutation is a process of random change in DNA sequence,

and this mutation may be inherited by future generations.

So, in that mutation process,

provides the material for genetic diversity.

Then we need to define selection,

and we define it as a process of differential reproduction.

And differential here means that it is genotype-dependent.

So selection is acting upon on the material which is provided by the mutation process.

Next, a very important set of factors which need to be considered,

are factors which are putting constraints and certain structure on potential gene flow.

So, these are such factors as migration,

isolation, or presence of specific breeding structures.

And finally last but not the least,

we need not forget that natural populations have finite size, therefore,

in these populations, random events are also playing

important role in the dynamics of allele and genotypic frequencies.

So, we need to also keep in mind the presence of genetic drift.

Now, let us define what is a genetic population.

Here, we are interested in what is going to happen with these populations,

so this means we are going to use prospective definition,

and our definition is going to be also relative.

You will understand what I mean by these just in few minutes.

So, we will call two individuals,

say A and B,

to be belonging to the same genetic population if there is

some non-zero chance for these two individuals to have a common offspring.

And here by having common offspring,

I don't mean that they should have common offspring immediately,

but this is to denote a possibility that these two individuals

may have a common offspring in potentially number of generations.

However, we cannot stop here,

because this definition is now coming too close to the definition of species,

and we are interested in genetic populations which exist within the species.

So, we miss something important in our definition.

So, we are going to extend it as follows.

We will tell that two individuals, A and B,

belong to the same genetic population if they

have non-zero chance to have an offspring in common,

and this chance is much higher than the chance for

this individual to have an offspring in common with some third individual C,

which we will say is belonging to a different genetic population.

To give a little bit more of practical flavor to this definition,

I'm going to consider relatively simple example,

an example of a population of

individuals which live on the islands scattered across the sea.

So, let's consider to start with two islands which are separated by the sea.

And then, of course, if we consider a group of individuals which live within the island,

and we assume that the major factor which isolates

the populations and which sets the boundary on the gene flow is isolation by distance,

then, naturally, we can assume that within the island,

the chance for two individuals to have common offspring is much

higher than the chance for two individuals coming from different islands.

So, in this context, we can speak about genetic population

of island A and separate genetic population of island B.

However, our definition is relative.

So, if we introduce another island, say C,

which is more remote than islands A and B,

then we can think of genetic populations,

joined genetic populations of islands A and B are relative to

the population of island C. We can even take this one step further,

because A, B, and C,

despite the fact that they may be quite isolated by the scene between,

still may have some gene flow between them,

and the possibility for individuals from

these three islands to have a progeny in common may still be much higher

than chances of these individuals to have common progeny

with individuals from some way remote continental population.