DNA Copy Number Variation in a Cohort of Healthy Australian Women

Abstract

The investigation and characterisation of genetic variation has progressed rapidly in the past decade. Concomitant with this is the advancement in technology facilitating the interrogation of the genome for different types of genetic variants. The global aim is to develop a complete map of genetic variation. Several fundamental studies have provided the impetus for the investigation of structural variation. However early research was hindered by study design, differing quality control criteria, technical limitations and poorly defined “normal” populations culminating in low levels of reproducibility and inconsistency between studies. Few studies documented genetic variation in general population cohorts. Reported here is a study of 64 Australian women representing a Western European descendent population using high resolution SNP microarray. This cohort represents a “healthy” general population that is clinically documented differentiating it from other studies. The focus of this thesis is to characterise the properties, chromosome distribution, gene content and identify rare and common events of copy number variation (CNV) and long contiguous stretches of homozygosity (LCSH). The cause and effect of technical limitations on the detection and reporting of these variants is considered with respect to the impact for diagnostic interpretation. The findings in this thesis demonstrate a non-random chromosome distribution of CNV and predominance of small deletion (<10Kb) although the relative contribution of duplication and deletion equalised in CNV >100kb. Comparison against clinical cohorts revealed a predominance of duplication, in particular CNV <250kb in the clinical cohort, a concept not previously reported. The breakpoint sequence signature of selected benign CNV identified base pair microhomology and investigation of the intervening genomic architecture provided the structure indicative of a replication repair mechanism. Long contiguous stretches of homozygosity (LCSH) has roles in genetic diversity and pathogenesis of disease. The contribution of LCSH to the genome of outbred populations is reported to be greater than first indicated and population variation is apparent. This thesis describes the LCSH chromosomal landscape, identifies population specific events and illustrates the technical challenges of LCSH detection. The ascertainment of the background level of LCSH in the local population (0.7% of the genome) enabled determination of appropriate thresholds for interpretation in clinical diagnostics. Documenting CNV and LCSH in a cohort of the general population contributes to the common goal of defining genetic variation in the human genome. Comparison against clinical cohorts identifies similarities and differences which will provide insight for the direction of further investigation. Furthermore the documentation of common and rare variants in a general population cohort provides evidence for the interpretation in clinical diagnostics.