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Centromere Scission Drives Chromosome Shuffling and Reproductive Isolation

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Centromere Scission Drives Chromosome Shuffling and Reproductive Isolation Centromere scission drives chromosome shuffling and reproductive isolation Vikas Yadava, Sheng Suna, Marco A. Coelhoa, and Joseph Heitmana,1 aDepartment of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710 Edited by Steven Henikoff, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved February 24, 2020 (received for review October 25, 2019) A fundamental characteristic of eukaryotic organisms is the genera- which are then fused in an error-prone mechanism known as tion of genetic variation via sexual reproduction. Conversely, signif- nonhomologous end joining (NHEJ) (9). The two sites can be icant large-scale genome structure variations could hamper sexual present on either the same chromosome or different chromo- reproduction, causing reproductive isolation and promoting specia- somes. Repair of two DSBs present on the same chromosome tion. The underlying processes behind large-scale genome rear- can result in the deletion of the intervening sequence or inver- rangements are not well understood and include chromosome sion if the sequence is rejoined in reverse orientation (7). On the translocations involving centromeres. Recent genomic studies in other hand, the fusion of DSBs from two different chromosomes the Cryptococcus species complex revealed that chromosome trans- can result in chromosomal translocation. In some instances, locations generated via centromere recombination have reshaped other repair pathways like microhomology-mediated end joining the genomes of different species. In this study, multiple DNA or alternative end joining (alt-EJ) also participate in the repair of double-strand breaks (DSBs) were generated via the CRISPR/Cas9 DSB ends (9, 10). system at centromere-specific retrotransposons in the human fungal The occurrence of multiple DSBs in mitotically growing cells Cryptococcus neoformans pathogen . The resulting DSBs were at the same time is rare but occurs at a relatively higher fre- repaired in a complex manner, leading to the formation of multiple quency in cancer cells. Such events could occur in a genome due interchromosomal rearrangements and new telomeres, similar to to replication defects or exogenous factors such as ionizing ra- chromothripsis-like events. The newly generated strains harboring diation or chemotherapeutic agents (11). Multiple DSBs also chromosome translocations exhibited normal vegetative growth occur naturally during processes like V(D)J recombination (12). but failed to undergo successful sexual reproduction with the pa- The occurrence of multiple DSBs can also be induced in the GENETICS rental wild-type strain. One of these strains failed to produce any micronuclei of cancer cells (13). Micronuclei are small nuclei spores, while another produced ∼3% viable progeny. The germi- harboring one or a few chromosomes and are generated as a nated progeny exhibited aneuploidy for multiple chromosomes result of a mitotic failure. These small nuclei act as hot spots of and showed improved fertility with both parents. All chromosome translocation events were accompanied without any detectable chromosome fragmentation, where multiple DSB sites are al- change in gene sequences and thus suggest that chromosomal most simultaneously generated and subsequently rejoined in a translocations alone may play an underappreciated role in the onset random order, a process known as chromothripsis. Previous of reproductive isolation and speciation. Significance Cryptococcus neoformans | DSB repair | chromosome translocation | karyotype evolution | retrotransposons The centromere is an essential chromosomal element that en- ables faithful segregation of chromosomes during cell division. hromosomes are prone to undergo several rearrangement In many species, centromeres are enriched in transposons and Cevents, including fusion, fission, deletion, and segmental repetitive elements, and centromeres have been proposed to duplication. In some cases, one chromosome segment is ex- play roles in shaping genomic architecture. In this study, we changed with another to generate chromosomal translocations. induced double-strand breaks (DSBs) at centromeric retro- Such exchanges between homologs are regularly observed dur- transposons to generate multiple centromere-mediated chro- ing meiosis when homologous chromosomes exchange arms mosomal translocations shuffling the genome karyotype. DSB via meiotic recombination (1). Chromosome rearrangements repair involved both homologous and nonhomologous re- can also occur during mitosis, but in a less well-regulated man- combination and led to chimeric centromeres. Genome shuffled ner, and sometimes as a result of disease conditions like cancer strains exhibited severe defects in sexual reproduction with (2, 3). Additionally, rearrangements can also occur within a the parental genotype and produced no or few (3%) viable single chromosome. As a result, chromosome rearrangements aneuploid F1 progeny. Overall, our findings provide experi- during mitosis can cause mutations, gene disruption, copy mental evidence supporting models in which centromere- number variations, as well as alter the expression of genes near mediated chromosomal rearrangements reshape eukaryotic the breakpoints (4). Cancer cells show a high level of chromo- genomes and may contribute to incipient species boundaries. some rearrangements compared to healthy cells, and this con- Author contributions: V.Y. and J.H. designed research; V.Y. and S.S. performed research; tributes to critical pathological conditions observed in these cells, V.Y. and M.A.C. contributed new reagents/analytic tools; V.Y., S.S., M.A.C., and J.H. ana- such as activation of oncogenes (5, 6). lyzed data; V.Y. and M.A.C. wrote the paper; and J.H. supervised the work. Chromosomal translocations are initiated by double-strand The authors declare no competing interest. breaks (DSBs) in DNA (7). Rearrangements involving a single This article is a PNAS Direct Submission. DSB are mainly repaired by the invasion of the broken DNA Published under the PNAS license. molecule into a homologous DNA molecule, in a process termed Data deposition: The sequence data generated in this study have been deposited in homologous recombination (HR) (6, 8). This invasion can lead National Center for Biotechnology Information BioProject database, https://www.ncbi.nlm. to the exchange of DNA between the two molecules of DNA, nih.gov/bioproject/ (accession no. PRJNA577944). leading to reciprocal crossover or gene conversion (2). These 1To whom correspondence may be addressed. Email: [email protected]. types of rearrangements occur during meiosis and are regulated This article contains supporting information online at https://www.pnas.org/lookup/suppl/ to give rise to an error-free repaired sequence. Other types of doi:10.1073/pnas.1918659117/-/DCSupplemental. chromosomal translocation involve two or more DNA DSB sites, First published March 19, 2020. www.pnas.org/cgi/doi/10.1073/pnas.1918659117 PNAS | April 7, 2020 | vol. 117 | no. 14 | 7917–7928 Downloaded by guest on September 26, 2021 reports have suggested that the occurrence of multiple DSBs In this study, we exploited the genomic features of C. alters HR pathways leading to NHEJ- or alt-EJ–mediated repair neoformans to study the impact of chromosome translocations (14, 15). Because both NHEJ and alt-EJ are error-prone, they on reproductive isolation. First, retrotransposons present in lead to a significant increase in mutation at the repair junctions centromeres were targeted with CRISPR (27), generating mul- and also randomly join broken fragments. tiple DSBs simultaneously. Next, the presence of chromosome Apart from generating mutations and gene disruptions, chro- rearrangements was screened by pulsed-field gel electrophoresis mosome translocations can also result in reproductive isolation (PFGE), and isolates with multiple chromosomal translocations during meiosis and facilitate speciation (16). The presence of were identified. The genomes of these strains were assembled multiple rearrangements between the two homologous chromo- based on long-read nanopore sequencing to characterize the somes from the parents leads to failures in chromosome pairing chromosome rearrangements. Although the strains with new during meiosis or crossovers that result in loss of essential genes karyotypes did not exhibit growth defects compared to the wild (17). Meiosis that is defective in this way will result in the pro- type, the chromosomal rearrangements had a profound effect on duction of progeny with abnormal genome content. In fungi, the sexual reproduction. These findings demonstrate that C. neo- parental nuclei fuse and undergo meiosis before sporulation that formans can tolerate multiple chromosomal translocations, but gives rise to progeny. Thus, defects in meiosis lead to the pro- that such large-scale changes can cause reproductive isolation duction of spores with abnormal or incomplete genetic compo- and promote incipient speciation. sitions rendering them inviable. Cryptococcus neoformans is a basidiomycete fungus that largely infects immunocompromised Results humans causing cryptococcal meningoencephalitis (18–20). Simultaneous Breaks at Multiple Centromeres Lead to Chromosome C. neoformans harbors a 19-Mb genome with 14 chromosomes Shuffling. Centromeres in C. neoformans were previously identi- (21). While most of the genome is devoid of repeat regions, fied and shown to possess multiple retrotransposons named centromeres in C. neoformans are rich in a
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