G C A T T A C G G C A T genes Review The Role of Structural Variation in Adaptation and Evolution of Yeast and Other Fungi Anton Gorkovskiy 1,2 and Kevin J. Verstrepen 1,2,* 1 Laboratory for Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Gaston Geenslaan 1, 3001 Leuven, Belgium; [email protected] 2 Laboratory for Systems Biology, VIB—KU Leuven Center for Microbiology, Bio-Incubator, Gaston Geenslaan 1, 3001 Leuven, Belgium * Correspondence: [email protected]; Tel.: +32-(0)16-75-1393 Abstract: Mutations in DNA can be limited to one or a few nucleotides, or encompass larger deletions, insertions, duplications, inversions and translocations that span long stretches of DNA or even full chromosomes. These so-called structural variations (SVs) can alter the gene copy number, modify open reading frames, change regulatory sequences or chromatin structure and thus result in major phenotypic changes. As some of the best-known examples of SV are linked to severe genetic disorders, this type of mutation has traditionally been regarded as negative and of little importance for adaptive evolution. However, the advent of genomic technologies uncovered the ubiquity of SVs even in healthy organisms. Moreover, experimental evolution studies suggest that SV is an important driver of evolution and adaptation to new environments. Here, we provide an overview of the causes and consequences of SV and their role in adaptation, with specific emphasis on fungi since these have proven to be excellent models to study SV. Citation: Gorkovskiy, A.; Verstrepen, Keywords: structural variation; fungi; adaptation K.J. The Role of Structural Variation in Adaptation and Evolution of Yeast and Other Fungi. Genes 2021, 12, 699. https://doi.org/10.3390/ 1. Introduction genes12050699 Structural variation (SV) groups different forms of mutations that involve longer stretches of DNA, including deletions, insertions, duplications, inversions, translocations, Academic Editor: Manuel or even full chromosome fusion, fission or loss (Figure1). Structural variants can be A. Garrido-Ramos balanced and show no specific loss or gain of DNA information, such as inversions of a genetic fragment or translocations of a stretch of DNA within or between chromosomes, or Received: 14 April 2021 they can be unbalanced, where a part of the genome is lost (deletions), acquired (insertions) Accepted: 4 May 2021 Published: 8 May 2021 or duplicated (duplications), which is termed copy number variation (CNV). Structural variation may occur both in coding and noncoding regions of the genome, Publisher’s Note: MDPI stays neutral including in highly repetitive elements, such as transposons. SV events can lead to ma- with regard to jurisdictional claims in jor phenotypic changes via diverse mechanisms including modification of open reading published maps and institutional affil- frames, changes in gene expression due to copy number variation, alteration of regulatory iations. sequences (via gain or loss of functional genomic elements) or chromatin structure, or even formation of novel genes [1–5]. Moreover, some forms of SV, such as large inversions and chromosomal fusions, cause a reduction in recombination rates between homologous chromosome pairs. In turn, the reduced recombination may facilitate the cosegregation of multiple adaptive polymorphisms as if they were controlled by a single genetic locus Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. (linkage disequilibrium and supergene formation) [6–11]. This article is an open access article In humans, single nucleotide variants (SNVs) are the most common type of variation, distributed under the terms and but SV accounts for a higher number of variable nucleotides between genomes, with conditions of the Creative Commons roughly 0.5% of the human genome being involved in structural variation [12,13]. Strikingly, Attribution (CC BY) license (https:// third-generation (long-read) genome sequencing of a clonal population of seven closely creativecommons.org/licenses/by/ related Schizosaccharomyces pombe strains that diverged ∼50–65 years ago revealed that 4.0/). they have an average pairwise difference of 19 SNVs and four nonoverlapping larger Genes 2021, 12, 699. https://doi.org/10.3390/genes12050699 https://www.mdpi.com/journal/genes Genes 2021, 12, x FOR PEER REVIEW 2 of 27 Genes 2021, 12, 699 2 of 26 that they have an average pairwise difference of 19 SNVs and four nonoverlapping larger duplicationsduplications [[14]14].. Moreover, Moreover, SVs SVs are are three three times times more more likely likely to tobe beassociated associated with with a ge- a genome-widenome-wide association association signal signal and and 50 50 times times more more likely likely t too be associatedassociated withwith expressedexpressed quantitativequantitative trait trait loci loci than than single single nucleotide nucleotide variants, variants, further further hinting hinting at theirat their importance importance as driversas drivers of phenotypic of phenotypic variation variation [13 ,15[13,15]]. Importantly,. Importantly, despite despite the significantthe significant contribution contribu- oftion SV of events SV events (especially (especially of CNVs) of CNVs) to quantitative to quantitative traits, they traits, are they frequently are frequently overlooked over- in studieslooked employingin studies employing short-read short sequencing-read sequencing technologies technologies [14]. [14]. Figure 1. Types of structural variation. Figure 1. Types of structural variation. TheThe phenotypicphenotypic consequencesconsequences ofof SVsSVs havehave traditionallytraditionally beenbeen assumedassumed toto bebe almost almost exclusivelyexclusively negative. negative This. This is is perhaps perhaps partly partly due due to theto the association association of SVs of SVs with with many many human hu- diseases,man diseases, especially especially autoimmune, autoimmune, metabolic, metabolic, and cognitive and cognitive disorders disorders [16–20]. [16 However,–20]. How- the emergenceever, the emergence of advanced of genotype-to-phenotypeadvanced genotype-to-phenotype mapping technologies, mapping technologies, as well as studies as well focusingas studies on focusing experimental on experimental evolution have evolution led to a growinghave led body to a ofgrowing evidence body suggesting of evidence that manysuggesting SVs are that neutral many or SVs even are adaptive, neutral or both even in adaptive, humans [ 12both,15 ,21in ]humans and other [12,15,21] organisms, and includingother organisms, microbes including [11,22–31 microbes]. SVs are [11,22 therefore–31] increasingly. SVs are therefore considered increasingly to be an considered important evolutionaryto be an importan driver,t evolutionary and some studies driver, suggest and some that studies SV may suggest be especially that SV important may be espe- for quickcially adaptation.important for quick adaptation. InIn thisthis paper,paper, we we summarize summarize recent recent advances advances in in the the detection detection and and analysis analysis of of SV SV and and thethe emergingemerging insightinsight intointo theirtheir adaptiveadaptive rolerole withwith thethe focusfocus onon yeastsyeasts andand otherother fungi,fungi, whichwhich have have served served as as prime prime models models for for many many studies studies focusing focusing on on SV. SV. 2.2. MechanismsMechanisms ofof SVSV FormationFormation SVSV involvinginvolving complete complete chromosomes chromosomes is is often often caused caused by by defective defective chromosome chromosome segre- seg- gation.regation. Chromosomes Chromosomes must must be meticulouslybe meticulously replicated replicated and and equally equally segregated segregated at each at each cell division.cell division. Distortion Distortion of either of either one of one these of these processes processes can lead can to lead SV formation.to SV formation. In particular, In par- failureticular, of failure any of of the any critical of the chromosome critical chromosome segregation segregation steps, including steps, including chromatid chromatid cohesion, spindlecohesion, pole spindle body pole (functional body (functional equivalent equivalen of the mammaliant of the mammalian centrosome) centrosome) formation for- at oppositemation at cell opposite poles, kinetochore–microtubulecell poles, kinetochore–microtubule attachment, attachment, and quality controland quality at the control spindle at assemblythe spindle checkpoint assembly cancheckpoint result in can aneuploidy result in aneuploidy (i.e., loss or (i.e. gain, loss of wholeor gain chromosomes) of whole chro- (Figuremosomes)2A) [(Figure32]. 2A) [32]. An SV that does not involve full chromosomes often results from compromised DNA An SV that does not involve full chromosomes often results from compromised DNA replication, where processive forks collide with the replication fork barriers replication, where processive forks collide with the replication fork barriers (Figure 2B) (Figure2B) [ 33–35]. These barriers typically include (1) specific DNA secondary structures [33–35]. These barriers typically include (1) specific DNA secondary structures such as such as G-quadruplex (G4) motifs [36–38], which are enriched in the telomeres, ribosomal G-quadruplex (G4) motifs [36–38], which are enriched in the telomeres, ribosomal DNA DNA (rDNA) and promoter regions in S. cerevisiae, Schizosaccharomyces pombe, and human (rDNA) and promoter