| Summary: | <p>Over the last fifteen years, rapid advances in genotyping and DNA sequencing technologies have revolutionised genetic and biomedical research. In this thesis, we present some applications of these technologies in studying rare disease, population genetics and meiotic recombination. We begin by reviewing previous research in these areas in Chapter 1. Then in Chapter 2, we present some case studies of Mendelian neurological disorders that were carried out as part of a large clinical whole-genome sequencing project, WGS500. These led to the discovery of several new genes for a type of severe early-onset epilepsy called Ohtahara Syndrome, and of a particularly interesting mutation that tentatively suggests a role for a glutamate receptor gene, <em>GRIA3</em>, in circadian rhythm control. In Chapter 3, we examine some general lessons learnt from the WGS500 project, including the utility of sequencing family members to reduce the number of candidate pathogenic variants, and the perils of focusing on candidate genes. Chapter 4 describes a population sequencing project on the platypus, in which we sequenced 58 samples from across the whole species range. Our results provide insights into the population structure and history of this fascinating mammal, and also into the ongoing evolution of its remarkable chain of ten sex chromosomes. Finally, in Chapter 5, we describe a study of the effect of maternal age on meiotic recombination, the largest of its kind to date. Our results from multiple cohorts suggest a small but significant positive effect of maternal age on the number of crossovers, but with substantial heterogeneity between cohorts that is likely due to sampling noise, though confounders may also play a role. These studies illustrate the power of genomic approaches for investigating fundamental biological processes at the population, individual and cellular levels.</p>
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