Exploration of rare-missense variant clustering in Mendelian disease-genes

Waring, AAJ

Oxford Thesis Collection

Thesis

Exploration of rare-missense variant clustering in Mendelian disease-genes

Abstract:: Decades of medical genetics research have yielded great insight into clinically relevant genetic variation. Despite this, the overwhelming complexity of the human genome means much still remains unknown. In this thesis, it is hypothesised that our understanding can be further enhanced by investigating the phenomenon of missense-variant clustering in disease-genes.

Missense-variants clustering is the key concept uniting this thesis. A clustering-detection method (BIN-test), a rare-variant association method (ClusterBurden), models of mutational hotspots (hotspot models), and pathogenicity prediction models (hotspot+ models), comprise the bulk of research reported here. Existing statistical methods are adapted to incorporate the clustering signal, solving either gene-discovery or rare-variant interpretation, and their performance is evaluated from multiple angles. The final chapters report auxiliary analyses including investigation into the prevalence of clustering and potential biases impacting rare-variant analyses.

The developed association methods had superior power to published alternatives when missense variants clustered. In a large inherited-heart-disease gene-panel dataset, BIN-test confirmed the existence of clustering in many definite positive-control genes and ClusterBurden gave theoretical power boosts in all of these. Hotspot models then inferred the locations of mutational hotspots in these clustered genes, enhancing variant interpretation. Extension to include pathogenicity scores in hotspot+ models, further improved interpretation. A large-scale scan in a database of clinical relevant variation yielded a huge number of significantly clustered genes and identified thousands of missense-variant clusters. Finally, supplementary analyses provide some insight into biases in rare-variant analyses of population controls.

Clustering observed in this thesis, and simultaneous publication of the opposite phenomenon regional constraint, indicate its widespread prevalence. This confirms the value of the statistical methods developed here and urges their continued development and application to increasingly large datasets. The deployment of methods developed here as an R package and web application, support their application by researchers of clinical genetics into the future.

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APA Style

Waring, A. A. J. (2020). Exploration of rare-missense variant clustering in Mendelian disease-genes [PhD thesis]. University of Oxford.

MLA Style

Waring, AAJ. Exploration of Rare-Missense Variant Clustering in Mendelian Disease-Genes. 2020. University of Oxford, PhD thesis.

Chicago Style

Waring, AAJ. 2020. “Exploration of Rare-Missense Variant Clustering in Mendelian Disease-Genes.” PhD thesis, University of Oxford.
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