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  • Thesis
  • Peer Reviewed

Aubin and Yau proved that every compact Kahler manifold with negative first Chern class admits a unique metric g such that Ric(g) =-g. Understanding how families of these metrics degenerate gives insight into their geometry and is important for understanding the compactification of the moduli space of negative Kahler-Einstein metrics. I study a special class of such families in complex dimension two. Following the work of Sun and Zhang in the Calabi-Yau case, I construct a Kahler-Einstein neck region interpolating between canonical metrics on components of the central fiber. This provides a model for the limiting geometry of metrics in the family.

    Cover page: Degenerations of Negative Kahler-Einstein Surfaces
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    • Peer Reviewed

    Background

    For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective.

    Methods

    Damaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function.

    Results

    Our CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman's ϱ = 0.9) and human clinical response to vitamin B6 (ϱ = 0.93).

    Conclusions

    We demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.
      Cover page: A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
      Cover page: Global Observing Needs in the Deep Ocean
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      • Peer Reviewed

      Background

      The Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors.

      Results

      Performance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic.

      Conclusions

      Results show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.
        Cover page: CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods