Functional and Fitness Consequences of Human Genetic Variation

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Project Summary Along with the environment, genetic differences between cells, individuals, populations, and species drive phenotypic differences at each level of biological organization. My research program develops computational and statistical methods to quantify the functional and fitness effects of natural genetic variation. Using humans as a model, specific research themes include studying the genetic basis, molecular mechanisms, and functional and fitness consequences of 1) human aneuploidy and 2) hominin phenotypic divergence. Aneuploidy affects more than half of human embryos and is the leading cause of pregnancy loss. My lab seeks to understand the extent and phenotypic consequences of various forms of aneuploidy and sub- chromosomal structural variation, scaling from the level of gene expression up to cellular and organismal phenotypes. To this end, I have developed a statistical approach to quantify the relationship between copy number and expression of individual genes. By applying this approach to samples with combined DNA and RNA sequencing data, we will measure the expression consequences of copy number alteration and the possibility that certain genes are “buffered” against its effects. We will also improve methods for detecting mosaic aneuploidy in single-cell data, helping resolve controversy about its incidence and implications for human embryonic development. Extending beyond embryos, we will mine single-cell genomic datasets to profile tissue- wide landscapes of chromosomal mosaicism and cell-type-specific maps of dosage sensitivity. A complementary approach for studying fitness-altering mutations focuses on evolutionary timescales. Previous research has established that regulatory changes influencing gene expression play a primary role in phenotypic divergence. Introgression of Neandertal and Denisovan sequences into modern human genomes provides a unique opportunity to characterize such regulatory substitutions. Through a large-scale analysis of allele-specific expression, I recently demonstrated that one quarter of persisting Neandertal sequences confer significant cis-regulatory effects. We will extend this work to Denisovan introgression by measuring allele-specific expression in cell lines derived from Oceanic individuals. This will allow us to contrast expression effects of mutations that arose in different hominin groups, testing hypotheses about lineage-specific and shared patterns of hominin regulatory evolution. In addition to gene expression levels, genetic variation influencing alternative splicing constitutes a primary link to phenotypic variation and disease. To understand its role in hominin evolution, we will quantify the effects of archaic alleles on patterns of alternative splicing. By contrasting expression and splicing effects of introgressed and control mutations of non-archaic origin, we will seek general insights into the characteristics of regulatory changes that drive phenotypic divergence.