Sulev Koks

Hereditary diseases, or genetic diseases, are generally considered to be caused only by single-nucleotide mutations. Typically, the assumption is that a single mutation is solely responsible for the clinical syndrome. This perspective is common, as geneticists search for one specific nucleotide mutation or variant that can account for the clinical phenotype. However, this approach has led to an oversimplified understanding of the genetic pathology or causes of these diseases, resulting in a diagnostic gap for many hereditary conditions. Consequently, we encounter patients with apparent hereditary issues yet lack a meaningful genetic explanation. This has led to reduced diagnostic yield and is one of the main challenges for genetic counsellors. Moreover, GWAS studies have shown limited success in fully elucidating the inheritance of most of the complex traits studied, typically reaching the explained heritability of not more than 30%. These limitations have given rise to the term “missing heritability”, which signifies our inability to clarify genetic inheritance using mainstream methods. This chapter presents a potential solution to the missing heritability problem. It demonstrates that much of the heritability remains unaccounted for due to its complexity, arising from transposable or repetitive elements in the human genome. The genetic basis for heritable conditions is intricate and necessitates a sophisticated approach to reveal the parts of missing heritability.

Carcinogenesis is based on acquiring the mutations that will trigger and maintain the malignant cellular growth. According to the widely accepted concept, these mutations are single-nucleotide variants, and environmental factors mainly generate them. In this chapter, we describe an alternative understanding based on the human genome’s internal capacity to generate structural variants within the “dark matter” of the human genome. The “dark matter” of the genome contains transposable elements (TEs) that can transpose and generate mutations in the genomes. These de novo variants affect the functioning of the genome and are the leading cause of the aberrant transcription that is the basis of many, if not most, of the complex diseases. In this chapter, I focus on the impact of TEs on cancer development.

Transposable elements (TEs) form a large proportion of many eukaryotic genomes and we are beginning to develop an understanding of their function. TEs are a large and diverse family of elements forming part of the repetitive genome or genomic dark matter that has not been addressed in detail in the majority of genetic studies. These repetitive and large elements are impossible to call from SNP-based genotyping data, and this is the main factor limiting research in this field thus far. However, the increasing availability of whole genome sequencing data provides the necessary data structure and quality needed for correct calling of TEs. Here we focus on the calling of variation of the composite element SINE-VNTR-Alu (SVA) which is the youngest TE family present in the human genome. Utilizing high-coverage whole genome sequencing data, we address the presence/absence and size variation of these elements. These data can be combined with whole transcriptome data to provide potential functional importance of SVAs in the regulation of the transcriptome and the pathophysiology of diseases. We recently applied this technology to analyze the effect of SVAs on the longitudinal course of Parkinson’s disease in the Parkinson’s Progression Markers Initiative cohort. This chapter briefly describes the background of transposable elements with the emphasis on SVAs and the available methods to study SVAs in genetic analysis of complex diseases.

This article gives an overview about the aging in rodents and how rodents can be used for aging modelling. The article starts with more general consideration about the modelling and some basic background. It is followed by the review of the most common progeroid syndromes along with the molecular mechanisms of aging. Then the effect of caloric restriction is described in deeper details. And finally, the role of transposable elements and the role of their activation during aging is described. Therefore, present article covers broadly the modelling of aging in the rodents with some more detailed overviews for the mechanisms explaining the potential interventions to modify the aging and aging related problems.

The present chapter is trying to give an overview of how data from current genomic research could unveil the role of hidden parts of our genome in our health. This hidden part was called “junk DNA” in the past, and even today, its role has been quite underestimated. In the recent past, our tools were too general or broad to give enough evidence about the activity of this part of our genome. We just called it “junk DNA,” but accumulating data suggest that this hidden part of our genome orchestrates several important processes necessary for normal physiology. If regulation of these processes fails, diseases emerge, and given our blindness for the unconventional approaches, we consider these diseases as “idiopathic” or “cryptic,” and we blame the bluntness of our tools (“missing heritability”). Fortunately, modern genomic techniques started to uncover the activity of so-called human endogenous retroviruses (HERVs), which form at least 8% of our genomes. This 8% is far more than all the coding sequences that are explored in most of our biomedical studies. Without proper and thorough understanding of the function of this part of our genome, it is hopeless to explore the genetics of human diseases. Most Genome Wide Association Studies (GWAS) studies end up with variations in the genomic regions considered to be “gene-deserts,” because no coding sequences, hence no meaningful translation events, occur in these regions. The number of studies on the role of HERVs in relation to physiological regulation and diseases is increasing. Results of these studies indicate that HERVs have substantial impact on the regulation of genome function. This chapter focuses on the findings on the role of HERVs in development of neuropsychiatric diseases.