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Results for “Aneuploidy”

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DOE OSTI2024

Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model

Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will be maintained only if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications in Saccharomyces cerevisiae and applied comparative modeling and molecular validation to understand aneuploidy toxicity. We show that 74%–94% of the variance in aneuploid strains’ growth rates is explained by the cumulative cost of genes on each chromosome, measured for single-gene duplications using a genomic library, along with the deleterious contribution of small nucleolar RNAs (snoRNAs) and beneficial effects of tRNAs. Machine learning to identify properties of detrimental gene duplicates provided no support for the balance hypothesis of aneuploidy toxicity and instead identified gene length as the best predictor of toxicity. Our results present a generalized framework for the cost of aneuploidy with implications for disease biology and evolution.

genic load↗

DOE OSTI2025

Development and characterization of a wild emmer wheat backcross introgression population for hard winter wheat improvement

Abstract Wild emmer wheat (Triticum turgidumsubsp.dicoccoides) is the tetraploid progenitor of hexaploid bread wheat (Triticum aestivumL.) and is known to be a valuable source of genetic variation for wheat improvement. However, direct evaluation of wild emmer diversity for agronomic potential has limited value unless performed in the backgrounds of adapted cultivars. Here, we present a genetic characterization of a population of 1601 backcross recombinant inbred lines, with an average genome composition of 75% bread wheat and 25% wild emmer. Low‐coverage whole‐genome sequencing allowed introgressions and aneuploidies to be identified at a relatively low cost per sample. We identified a relatively large proportion of small introgressions (median length 38 Mb), and we found introgressions to be distributed across all chromosomes. Approximately 44% of genotyped progeny carried at least one aneuploidy, with monosomies being by far the most common. This population, which we have denoted as the Great Plains Wild Emmer/Hard Winter Wheat introgression population (GPWEW‐IP), is, to our knowledge, the first introgression population developed through the direct hybridization of wild emmer wheat and US‐adapted hard winter wheat. We believe that this population represents a valuable resource for wheat breeders and will accelerate the discovery and integration of useful variation from wild emmer wheat.

Genetics & Heredity↗

DOE OSTI2025

Chromosome duplication causes premature aging via defects in ribosome quality control

Down syndrome, caused by an extra copy of Chromosome 21, causes lifelong problems. One of the most common phenotypes among people with Down syndrome is premature aging, including early tissue decline, neurodegeneration, and shortened life span. Yet the reasons for premature systemic aging are a mystery and difficult to study in humans. Here we show that chromosome amplification in wild yeast also produces premature aging and shortens life span. Chromosome duplication disrupts nutrient-induced cell-cycle arrest, entry into quiescence, and cellular health during chronological aging, across genetic background and independent of which chromosome is amplified. Using a genomic screen, we discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). We show that aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates compared to euploid cells. Although they maintain proteasome activity, aneuploids also show signs of ubiquitin dysregulation and sequestration into foci. Remarkably, inducing ribosome stalling in euploids produces similar aging phenotypes, while up-regulating limiting RQC subunits or poly-ubiquitin alleviates many of the aneuploid defects. We propose that the increased translational load caused by having too many mRNAs accelerates a decline in translational fidelity, contributing to premature aging.

Aneuploidy↗

DOE OSTI2025

Targeted genetic manipulation and yeast-like evolutionary genomics in the green alga Auxenochlorella

Auxenochlorella spp. are diploid oleaginous green algae whose streamlined genomes can be readily manipulated by homologous recombination, making them highly amenable to discovery research and bioengineering. Vegetatively diploid organisms experience specific evolutionary phenomena, including allodiploid hybridization, mitotic recombination, loss-of-heterozygosity, and aneuploidy; however, studies of these forces have largely focused on yeasts. Here, we present a telomere-to-telomere phased diploid genome assembly of Auxenochlorella UTEX 250-A (haploid length 22 Mb) and introduce a genetic toolkit for site-specific manipulation of the nuclear genome in multiple strains, featuring several selectable markers, inducible promoters, and fluorescent reporters for protein localization. UTEX 250-A is an allodiploid hybrid of Auxenochlorella protothecoides and Auxenochlorella symbiontica, two species differentiated by extensive chromosomal rearrangements. UTEX 250-A haplotypes are a mosaic of each parental species following mitotic recombination, and two chromosomes are trisomic. Loss-of-heterozygosity events are pervasive across Auxenochlorella and can evolve rapidly in the laboratory. High-quality structural annotation yielded ∼7,500 genes per haplotype. Auxenochlorella have experienced gene family loss and reduction, including core photosynthesis genes, and exhibit periodic adenine and cytosine methylation at promoters and gene bodies, respectively. Approximately 10% of genes, especially those involved in DNA repair and sex, overlap antisense long noncoding RNAs, which may participate in a regulatory mechanism. We demonstrate the utility of Auxenochlorella for fundamental research by knockout of a chlorophyll biosynthesis enzyme, and confirm one trisomy by allele-specific transformation. These results demonstrate the generality of several evolutionary forces associated with vegetative diploidy and provide a foundation for the use of Auxenochlorella as a reference organism.

CHL27↗