Introduction to Monogenic Disorders

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Из курса от партнера Novosibirsk State University

From Disease to Genes and Back

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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.

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Mendelian disorders

Mendelian or monogenic disorders are the kind of genetic disorders in humans that arise from a mutation in a single gene. These disorders run in families and can be autosomal or sex-linked depending whether the affected gene is located on autosomes or sex chromosomes, and they can also be dominant or recessive depending if one or two alleles are necessary to develop the disorder. The name “Mendelian” is used because these diseases follow simple monogenic patterns of inheritance, similar to these first studied by Gregor Mendel in pea plants. There are an estimated 8000 rare Mendelian diseases. Although each of them are very rare, collectively they affect millions of individuals world-wide. How can we find the variants and genes that are responsible for the development of these diseases? You will learn about “linkage analysis” – a technique that has been previously used for this purpose. You will also learn about Next-generation sequencing (NGS) technologies that have revolutionized the studies of Mendelian diseases in recent years.

Introduction to Monogenic Disorders7:42

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

Genetic disorders can be

divided in two main groups.

Mendelian disorders, and then the complex disorders.

So Mendelian disorders are monogenic one,

disorders with a very strong genetic component.

It's up to 100%.

And for most of these disorders,

one or two alleles is sufficient and enough to develop the disease.

Complex disorders or in other word is multifactorial,

is an interplay between genes,

and then several genes,

not one, and also the environmental factors.

So the genetic influence is way weaker compared to the Mendelian disorders.

And also, the variants in the genes are not

sufficient and not enough to develop the complex disorders.

So this week, we're talking about the Mendelian disorders.

And next week, we will hear from Yuri and Leonard about the complex ones.

So named Mendelian disorders,

came from the type of inheritance in humans.

In 1902, British physician,

Archibald Garrod, published his observation on alkaptonuria.

He made a link between Mendelian type of inheritance and specific medical condition.

So he deduced that the alkaptonuria was inherited in a recessive manner.

Mendelian disorders such as,

for example, cystic fibrosis, sickle-cell anemia,

Duchenne muscular dystrophy, Huntington's disease,

each of them are quite rare in a population.

However, if we take as a cumulative amount of them,

they account in approximately 0.4 percent of all life birth.

And if we add to that also congenital abnormalities,

it will result in approximately eight percent of the cases of the live birth,

which have a genetic disorders recognizable by early adulthood.

It's results in up to 8 million children every year,

born with a genetic condition. It's of course,

cause economical burden, social burden,

a personal burden for the families.

And what we would like to do is to find the genes underlying these disorders

in order to try to improve the diagnostic treatment of these conditions.

Before we go further with the story,

let me remind you of some terms.

It's a genotype, allele,

haplotype, and then the phenotype.

So let's assume we have two loci,

A and B, which are laying on a certain chromosome.

And the genotype for this loci for A will be A_1 and A_2,

and for the B will be B_1, and then B_2.

So A_1 and B_1 is laying on

one homologous chromosome and we call these two alleles haplotype.

And then B_2, and then A_2 are laying on another chromosome and this is also haplotype.

So their allelic combination, A_1, B_1,

and then A_2, and then B_2, called the haplotype.

And haplotype information is also known as a phase.

So the results of genotype may be a phenotype.

The phenotype of traits may be binary,

so the presence or absence or quantitative.

Most of the Mendelian disorders are example of the binary traits,

like presence or absence of a certain disease,

like cystic fibrosis, for example.

Mendelian disorders do run in families and most of

the time have a predictable and recognizable inheritance pattern.

If we talk about Mendelian disorders,

we may talk about the type of inheritance like

autosomal dominant and recessive, and then sex-linked.

So what does it mean? Autosomal dominant,

meaning that the loci and the variant which

is causing the disease is laying on autosomes,

and one allele is sufficient and enough to develop the disease.

We talk about recessive type of inheritance,

autosomal recessive type of inheritance,

when two alleles, which are laying on one of

the autosomes is sufficient and enough to develop the disease.

If the causative alleles are laying on X or Y chromosome,

we talk about sex-linked type of inheritance.

And pedigree analysis of especially large families with

many affected individuals are very helpful

to understand and to recognize inheritance pattern.

As an example of different inheritance patterns, for example,

cystic fibrosis, is inherited in autosomal recessive manner.

Myotonic dystrophy type one is autosomal dominant.

And the examples of the sex-linked type of inheritance is, for example,

hemophilia A and muscular dystrophy Duchenne,

which are inherited in X-linked recessive type.

And Rett syndrome is an example of X-linked dominant.

So to recognize Mendelian disorders and to assume the genetic influence,

we may, by studying the families.

Usually, it's increased frequency of the phenotype,

disease in this case, in the close relatives.

Also, it's increased frequency of the disease in a certain population.

And also, to study the genetic influence,

we may use a concordance between the monozygotic and the dizygotic twins.

There is a database which called OMIM,

Online Mendelian Inheritance in Men.

It's online database which has been established in 1997 by

Victor McKusick and that is focused on inherited genetic conditions in humans.

So currently, it's more than seven and a half thousand conditions which are listed there,

and this number is not static.

So approximately, 300 entities are added every year,

and there is an opinion that this amount is actually underestimated.

So in reality, there is much more Mendelian conditions which we don't know yet.

So if we look at this database,

more than 3,000 genes has been identified,

underlying more than 4,000 Mendelian diseases.

The question is, how these genes has been found and

how we will and may identify the new genes?

So we will spend the next four videos talking about approaches

which are used and currently in use to study the Mendelian conditions.

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