From Disease to Genes and Back

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.

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 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.

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.