Gene and Mutation Discovery for Rare Diseases

We incorporate information about sequence conservation, genetic heterogeneity, and predicted variant consequences to create robust pipelines for prioritizing rare genetic variants that may influence human disease. Over the last decade, I have applied my evolutionary perspective and expertise in statistical genetics and bioinformatics to the analysis of sequence data for dozens of rare disease studies with the Centers for Mendelian Genomics (CMGs), the GREGoR Consortium, and Pacific Northwest Undiagnosed Diseases Network (UDN) Clinical Site. I co-chaired the CMG’s Unsolved Cases Working Group, contributing to the discovery of alternative molecular diagnoses and novel gene-phenotype relationships. I taught study design and quality control to investigators from around the globe during UW-CMG data analysis and led the integration of sequence data generated across multiple studies and platforms. One of these, our collaboration with the National Birth Defects Prevention Study, was nominated for the Shepard Award, the Centers for Disease Control’s highest scientific honor. Now, I lead the Pacific Northwest UDN Sequence Analysis team, where we identify novel disease mechanisms and complex molecular diagnoses.

Integrative Analyses

Our lab integrates population genetics, functional assays, and -omics data analysis to connect the genetics of human disease to broader biology. We zoomed in on loci previously associated with disease, finding evidence that the ancestral origin of an allele can influence its effect on risk. We looked beyond the borders of a genome-wide association study, integrating transcriptomics data, variant annotation, and literature review to discover those signals are driven by variants altering the regulation of genes differentially expressed in AD. Finally, we zoomed out, identifying unique and shared pathways enriched in genes implicated by family and association studies in AD and related dementias. I have shared this expertise at the national level, acting as co-chair for analysis- and annotation-focused working groups in the ADSP, CMG, Cystic Fibrosis Genome Project, and the Genome Sequencing Project.

Methods Development and Evaluation

As a graduate student, I developed novel methods to test specific hypotheses related to human population genetics. I developed an application of coalescent theory to test the probability of alternative demographic histories given the decreasing amounts of heterogeneity in the mitochondrial DNA of the native peoples of the American Arctic. Later, I modeled the accumulation of mutations within retrotransposons as a Poisson process to estimate the age of individual subfamilies, significantly outperforming the ad hoc approach used extensively in the literature. As a postdoctoral fellow, I developed tools to visualize IBD probabilities and use that information to select informative members of pedigrees for sequencing. Through the Genetic Analysis Workshops, I evaluated the performance of alternative approaches to relatedness estimation, genotype imputation, and linkage and association testing. Most recently, I led the development of the sequence analysis pipeline at the Pacific Northwest UDN clinical site and contributed to the FAVOR variant annotator

Population Genetics

Evolutionary and cultural events leave signatures on human genetic variation. As a graduate student with Dr. Lynn Jorde, I generated genotype data at retrotransposons, microsatellites, and haplotype-defining single nucleotide polymorphisms, and sequenced mitochondrial genomes. We used these data to describe human genetic diversity; for example, I discovered contrasting male and female patterns of genetic diversity in the Caucasus, tying these patterns to historical events. This training provided the foundation for my later work in genetic epidemiology and statistical genetics with Dr. Ellen Wijsman, including the evaluation of genetic diversity at individual loci and across the genome. As I searched for genetic modifiers of AAO of AD among Volga German families sharing the same variant causing early-onset AD (PSEN1 N141I), we traced the origin of the founder allele to the Hesse region of Germany. More recently, I described the impact of sample ascertainment for cystic fibrosis on patterns of genetic diversity beyond the CFTR locus and illustrated how to control for that ascertainment bias when hunting for genetic modifiers of the disease. We continue to evaluate the effects of both global and local ancestry on the association between genotype and phenotype across both rare disease and complex traits.

Modifiers of Heritable Disease

Individual genetic variants do not act alone on complex human phenotypes; instead, their effects can be modified by both genetic and environmental exposures. We have found this to be true for Mendelian disease as well as for late-onset Alzheimer’s Disease (AD). Age-at-onset of AD varies by decades among Volga Germans sharing the same PSEN2 N141I variant, and we have identified loci on 1q23.3 and 17p13.2, implicating regulators of amyloid beta aggregation, a neuropathologic hallmark of the disease. I led the Sequencing Analysis working group for the Cystic Fibrosis Genome Project, where we identified environmental and genetic modifiers of cystic fibrosis outcomes including diabetes, meconium ileus, lung function, and infection. Finally, our association between African ancestry at APOE and reduced risk of AD implicates local haplotypic variation beyond ε2 and ε4 in AD pathogenesis.