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Summary Individuals, and cells, vary in their ability to tolerate aneuploidy, an unbalanced chromosome complement. Tolerance mechanisms can be karyotype-specific or general. General tolerance mechanisms may allow cells to benefit from the phenotypic plasticity conferred by access to multiple aneuploid states. [ABSTRACT FROM AUTHOR]

Deleterious mutations in the X-linked gene encoding ornithine transcarbamylase (OTC) cause the most common urea cycle disorder, OTC deficiency. This rare but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. Individuals with neonatal onset appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death, outcomes ameliorated by rapid diagnosis and treatment. Here, we develop a high-throughput functional assay for human OTC and individually measure the impact of 1,570 variants, 84% of all SNV-accessible missense mutations. Comparison to existing clinical significance calls, demonstrated that our assay distinguishes known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation. This functional stratification allowed us to identify score ranges corresponding to clinically relevant levels of impairment of OTC activity. Examining the results of our assay in the context of protein structure further allowed us to identify a 13 amino acid domain, the SMG loop, whose function appears to be required in human cells but not in yeast. Finally, inclusion of our data as PS3 evidence under the current ACMG guidelines, in a pilot reclassification of 34 variants with complete loss of activity, would change the classification of 22 from variants of unknown significance to clinically actionable likely pathogenic variants. These results illustrate how large-scale functional assays are especially powerful when applied to rare genetic diseases. [Display omitted] OTC deficiency is the most common urea cycle disorder. Here, we measure the functional impact of 1,570 single-nucleotide-variant-accessible amino acid substitutions in human OTC. Our assay distinguishes benign from pathogenic variants and neonatal from late-onset disease variants, supporting its use as PS3 evidence under the current ACMG guidelines. [ABSTRACT FROM AUTHOR]

Summary Modern transportation networks have facilitated the migration and mingling of previously isolated populations of plants, animals, and insects. Human activities can also influence the global distribution of microorganisms. The best-understood example is yeasts associated with winemaking. Humans began making wine in the Middle East over 9,000 years ago [ 1, 2 ]. Selecting favorable fermentation products created specialized strains of Saccharomyces cerevisiae [ 3, 4 ] that were transported along with grapevines. Today, S. cerevisiae strains residing in vineyards around the world are genetically similar, and their population structure suggests a common origin that followed the path of human migration [ 3–7 ]. Like wine, coffee and cacao depend on microbial fermentation [ 8, 9 ] and have been globally dispersed by humans. Theobroma cacao originated in the Amazon and Orinoco basins of Colombia and Venezuela [ 10 ], was cultivated in Central America by Mesoamerican peoples, and was introduced to Europeans by Hernán Cortés in 1530 [ 11 ]. Coffea , native to Ethiopia, was disseminated by Arab traders throughout the Middle East and North Africa in the 6 th century and was introduced to European consumers in the 17 th century [ 12 ]. Here, we tested whether the yeasts associated with coffee and cacao are genetically similar, crop-specific populations or genetically diverse, geography-specific populations. Our results uncovered populations that, while defined by niche and geography, also bear signatures of admixture between major populations in events independent of the transport of the plants. Thus, human-associated fermentation and migration may have affected the distribution of yeast involved in the production of coffee and chocolate. [ABSTRACT FROM AUTHOR]