From Disease to Genes and Back

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.

• Introduction. Human genome
• This week you will learn about human genome organisation. This week is very important as all this knowledge will form a basis for all of the subsequent weeks of the course. Michel Georges will tell you about the structural organisation of the human genome, the mechanisms contributing to the genome variability, the main types of genetic variation (SNPs, CNVs, aneuploidy, etc.), and differences between alleles and genotypes. You will also learn the techniques used to detect different types of variations in human genome and you will find out how we can follow the inheritance of genetic material through generations.
• 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.
• 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.
• 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 variant to function. Application of the genomic findings
• During the last two weeks, we have been discussing the approaches to finding variants and genomic regions underlying the development of human disorders or predisposition to them. The question is – what are the next steps that should be taken in order to prove the causality of the identified variants? Moreover, we are eager to understand if these findings can be translated into the clinics. Can these variants provide predictive or prognostic information and do they have any important pharmacological implications? Will the answers be the same for variants underlying Mendelian and complex disorders? Gert Matthijs, Yurii Aulchenko and Michel Georges will tell you more this week.
• Final reflection
• This is it. The last week of our course. You have learned a lot during the past five weeks. The final week of the course is the reflection week. We have prepared for you the interviews with Michel Georges, Gert Matthijs and Yurii Aulchenko. These interviews reflect their personal opinions about some of the current and future challenges of human genetics. Additionally, you can put everything you have learned during the course into practice by writing an essay on one of the proposed topics.