Aborting meiosis allows recombination in sterile diploid yeast hybrids.

Hybrids between diverged lineages contain novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explore to what extent an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 Saccharomyces cerevisiae and S. paradoxus diploid hybrids with different genomic structures and levels of sterility. Genome analyses of 275 clones reveal that RTG promotes recombination and generates extensive regions of loss-of-heterozygosity in sterile hybrids with either a defective meiosis or a heavily rearranged karyotype, whereas RTG recombination is reduced by high sequence divergence between parental subgenomes. The RTG recombination preferentially arises in regions with low local heterozygosity and near meiotic recombination hotspots. The loss-of-heterozygosity has a profound impact on sexual and asexual fitness, and enables genetic mapping of phenotypic differences in sterile lineages where linkage analysis would fail. We propose that RTG gives sterile yeast hybrids access to a natural route for genome recombination and adaptation.

A yeast living ancestor reveals the origin of genomic introgressions.

Genome introgressions drive evolution across the animal1, plant2 and fungal3 kingdoms. Introgressions initiate from archaic admixtures followed by repeated backcrossing to one parental species. However, how introgressions arise in reproductively isolated species, such as yeast4, has remained unclear. Here we identify a clonal descendant of the ancestral yeast hybrid that founded the extant Saccharomyces cerevisiae Alpechin lineage5, which carries abundant Saccharomyces paradoxus introgressions. We show that this clonal descendant, hereafter defined as a 'living ancestor', retained the ancestral genome structure of the first-generation hybrid with contiguous S. cerevisiae and S. paradoxus subgenomes. The ancestral first-generation hybrid underwent catastrophic genomic instability through more than a hundred mitotic recombination events, mainly manifesting as homozygous genome blocks generated by loss of heterozygosity. These homozygous sequence blocks rescue hybrid fertility by restoring meiotic recombination and are the direct origins of the introgressions present in the Alpechin lineage. We suggest a plausible route for introgression evolution through the reconstruction of extinct stages and propose that genome instability allows hybrids to overcome reproductive isolation and enables introgressions to emerge.

Genome evolution across 1,011 Saccharomyces cerevisiae isolates.

Large-scale population genomic surveys are essential to explore the phenotypic diversity of natural populations. Here we report the whole-genome sequencing and phenotyping of 1,011 Saccharomyces cerevisiae isolates, which together provide an accurate evolutionary picture of the genomic variants that shape the species-wide phenotypic landscape of this yeast. Genomic analyses support a single 'out-of-China' origin for this species, followed by several independent domestication events. Although domesticated isolates exhibit high variation in ploidy, aneuploidy and genome content, genome evolution in wild isolates is mainly driven by the accumulation of single nucleotide polymorphisms. A common feature is the extensive loss of heterozygosity, which represents an essential source of inter-individual variation in this mainly asexual species. Most of the single nucleotide polymorphisms, including experimentally identified functional polymorphisms, are present at very low frequencies. The largest numbers of variants identified by genome-wide association are copy-number changes, which have a greater phenotypic effect than do single nucleotide polymorphisms. This resource will guide future population genomics and genotype-phenotype studies in this classic model system.

Polymorphism in the alpha cardiac muscle actin 1 gene is associated to susceptibility to chronic inflammatory cardiomyopathy.

AIMS: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America, and may lead to a life-threatening inflammatory dilated, chronic Chagas cardiomyopathy (CCC). One third of T. cruzi-infected individuals progress to CCC while the others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Since mutations in multiple sarcomeric genes, including alpha-cardiac actin (ACTC1) have been involved in hereditary dilated cardiomyopathy, we investigated the involvement of the ACTC1 gene in CCC pathogenesis. METHODS AND RESULTS: We conducted a proteomic and genetic study on a Brazilian study population. The genetic study was done on a main cohort including 118 seropositive asymptomatic subjects and 315 cases and the replication was done on 36 asymptomatic and 102 CCC cases. ACTC1 protein and mRNA levels were lower in myocardial tissue from patients with end-stage CCC than those found in hearts from organ donors. Genotyping a case-control cohort of CCC and ASY subjects for all informative single nucleotide polymorphism (SNP) in the ACTC1 gene identified rs640249 SNP, located at the 5' region, as associated to CCC. Associations are borderline after correction for multiple testing. Correlation and haplotype analysis led to the identification of a susceptibility haplotype. Functional assays have shown that the rs640249A/C polymorphism affects the binding of transcriptional factors in the promoter regions of the ACTC1 gene. Confirmation of the detected association on a larger independent replication cohort will be useful. CONCLUSIONS: Genetic variations at the ACTC1 gene may contribute to progression to chronic Chagas Cardiomyopathy among T. cruzi-infected patients, possibly by modulating transcription factor binding to ACTC1 promoter regions.

Polymorphism in the alpha cardiac muscle actin 1 geneIs associated to susceptibility to chronic inflammatory cardiomyopathy

Aims: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America, and may lead to alife-threatening inflammatory dilated, chronic Chagas cardiomyopathy (CCC). One third of T. cruzi-infectedindividuals progress to CCC while the others remain asymptomatic (ASY). A possible genetic component to diseaseprogression was suggested by familial aggregation of cases and the association of markers of innate and adaptiveimmunity genes with CCC development. Since mutations in multiple sarcomeric genes, including alpha-cardiac actin(ACTC1) have been involved in hereditary dilated cardiomyopathy, we investigated the involvement of the ACTC1gene in CCC pathogenesis.Methods and Results: We conducted a proteomic and genetic study on a Brazilian study population. The geneticstudy was done on a main cohort including 118 seropositive asymptomatic subjects and 315 cases and thereplication was done on 36 asymptomatic and 102 CCC cases. ACTC1 protein and mRNA levels were lower inmyocardial tissue from patients with end-stage CCC than those found in hearts from organ donors. Genotyping acase-control cohort of CCC and ASY subjects for all informative single nucleotide polymorphism (SNP) in the ACTC1gene identified rs640249 SNP, located at the 5’ region, as associated to CCC. Associations are borderline aftercorrection for multiple testing. Correlation and haplotype analysis led to the identification of a susceptibility haplotype.Functional assays have shown that the rs640249A/C polymorphism affects the binding of transcriptional factors in thepromoter regions of the ACTC1 gene. Confirmation of the detected association on a larger independent replicationcohort will be useful.Conclusions: Genetic variations at the ACTC1 gene may contribute to progression to chronic ChagasCardiomyopathy among T. cruzi-infected patients, possibly by modulating transcription factor binding to ACTC1promoter regions.