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Accurate Tracking of the Mutational Landscape of Diploid Hybrid Genomes

Authors
  • Tattini, Lorenzo1
  • Tellini, Nicolò1
  • Mozzachiodi, Simone1
  • D’Angiolo, Melania1
  • Loeillet, Sophie2
  • Nicolas, Alain2
  • Liti, Gianni1
  • 1 CNRS UMR7284, INSERM, IRCAN, Université Côte d’Azur, Nice, France
  • 2 CNRS UMR3244, Institut Curie, PSL Research University, Paris, France
Type
Published Article
Journal
Molecular Biology and Evolution
Publisher
Oxford University Press
Publication Date
Aug 09, 2019
Volume
36
Issue
12
Pages
2861–2877
Identifiers
DOI: 10.1093/molbev/msz177
PMID: 31397846
PMCID: PMC6878955
Source
PubMed Central
Keywords
License
Unknown

Abstract

Mutations, recombinations, and genome duplications may promote genetic diversity and trigger evolutionary processes. However, quantifying these events in diploid hybrid genomes is challenging. Here, we present an integrated experimental and computational workflow to accurately track the mutational landscape of yeast diploid hybrids (MuLoYDH) in terms of single-nucleotide variants, small insertions/deletions, copy-number variants, aneuploidies, and loss-of-heterozygosity. Pairs of haploid Saccharomyces parents were combined to generate ancestor hybrids with phased genomes and varying levels of heterozygosity. These diploids were evolved under different laboratory protocols, in particular mutation accumulation experiments. Variant simulations enabled the efficient integration of competitive and standard mapping of short reads, depending on local levels of heterozygosity. Experimental validations proved the high accuracy and resolution of our computational approach. Finally, applying MuLoYDH to four different diploids revealed striking genetic background effects. Homozygous Saccharomyces cerevisiae showed a ∼4-fold higher mutation rate compared with its closely related species S. paradoxus . Intraspecies hybrids unveiled that a substantial fraction of the genome (∼250 bp per generation) was shaped by loss-of-heterozygosity, a process strongly inhibited in interspecies hybrids by high levels of sequence divergence between homologous chromosomes. In contrast, interspecies hybrids exhibited higher single-nucleotide mutation rates compared with intraspecies hybrids. MuLoYDH provided an unprecedented quantitative insight into the evolutionary processes that mold diploid yeast genomes and can be generalized to other genetic systems.

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