Structural Variation in Genomes

Tobias Marschall

Structural Variation in Genomes

Each of our body cells harbors a copy of our genome, the set of all genetic material. The genome is organized in chromosomes: we inherit 23 chromosomes from our mother and father, respectively. A chromosome consists of a long DNA molecule, stabilized and spatially structured by special proteins. The DNA encodes genetic information as a sequence of its constituting bases adenine (A), cytosine (C), guanine (G), and thymine (T). In this sense, a chromosome can be viewed as a sequence of the letters A, C, G, and T. Likewise, we can represent a genome as a set of such sequences (one for each chromosome). The research fi eld of genomics asks the question, among others, of how our genome infl uences our traits. Many different traits can be of interest, such as body height, the risk of contracting a certain disease, or the tolerance to a drug, for instance. The genomes of two persons can differ in a multitude of ways, as illustrated in fi gure 1. Traditionally, many genetic studies focused on point mutations (SNPs). That is, one restricts oneself to differences in single letters. In recent years, however, increasing attention has also been given to larger differences, the so-called structural variants, such as deletions or duplications of whole DNA segments. Such variants occur frequently in humans and, hence, studying them is indispensable for capturing the full spectrum of human genetic diversity. This is enabled by new sequencing technologies in combination with novel algorithmic methods, which we develop actively. High-throughput methods for genome sequencing allow for reading millions of short DNA fragments in parallel. That means, these devices do not return the sequence of a whole chromosome; instead, they output the sequences of short fragments, called reads. The analysis of the resulting data is thus comparable to solving a jigsaw puzzle: from the reads, we want to reconstruct the sequenced genome. Here, we particularly focus on detecting structural differences.