Empire Genomics

Advancements in the field of genomics have revolutionized research and diagnostic capabilities, allowing us to delve deeper into the human genome than ever before. Empire Genomics seeks to harness this momentum and help facilitate entry into an era of "Personalized Medicine." We have provided excerpts from peer-reviewed journals and other noteworthy sources which offer insight into a few important applications of our research, products, and services.

Pharmacogenomics

The relationship between genetic determinants and drug response was established nearly 50 years ago, with the discovery that deficiency in glucose-6-phosphate dehydrogenase (G6PD) results in hemolytic anemia following ingestion of primaquine. In 1960, Evans and colleagues demonstrated inherited differences in isoniazid acetylation, resulting in ‘slow inactivator’ and ‘rapid inactivator’ phenotypes. More recent investigations have shown single nucleotide polymorphisms (SNPs) in genes encoding important metabolizing enzymes (such as the cytochrome P450 enzyme superfamily) to be associated with clinical phenotypes of drug efficacy/toxicity. These and other ongoing studies are resulting in an increasing list of important associations touching nearly all medical specialties.

However, the utilization of pharmacogenomics in day-to-day practice has lagged behind its potential, and most current therapeutic monitoring still relies upon the quantitation of drug and/or metabolites in the patient’s blood. Fully integrating pharmacogenomic testing in clinical practice will require health practitioners to know the relationship between genotypes and clinical outcomes, and to have specific data that can be used to modify drug selection or dosage. The Human Genome Project has provided a critical tool for generating this information: a ‘reference sequence’ upon which DNA sequence variation can be cataloged and subsequently associated with different phenotypes. Despite the availability of the sequence data, our collective understanding of the form and scope of interindividual genetic variation is still in its infancy. While phenotypic associations with sequence variants in metabolizing enzymes have been established, it is believed that SNPs alone may not predict all phenotypes, and therefore certain drugs may require studies involving other aspects of genomic variation, to explain interindividual variations in efficacy, metabolism, and/or toxicity. Copy number variants (CNVs), a recently described class of genomic variation that is distinct from SNPs, hold promise for such new pharmacogenetic discoveries.

Source: Ouahchi, K., Lindeman, N., Lee, C. 2006. Copy number variants and pharmacogenomics. Pharmacogenomics 7(1):25-29

Genetic Variation

DNA copy number variation (CNV) represents considerable source of human genetic diversity. Recently,( a global map of copy number variation in the genome has been drawn up which reveals not only ubiquity but also the complexity of this type of variation. Thus, two human genomes may differ by more than and it is likely that the full extent of CNV still remains discovered. Nearly 3000 genes are associated with This high degree of variability with regard to gene number between two individuals challenges definitions of normality. Many CNVs are located in regions complex genomic structure and this currently limits extent to which these variants can be genotyped by tagging SNPs. However, some CNVs are already amenable to genome-wide association studies so that influence on human phenotypic diversity and disease susceptibility may soon be determined.

In addition to single nucleotide polymorphisms (SNPs), copy number variations (CNVs) of genomic segments contribute considerably to the submicroscopic genomic diversity in humans. These CNVs include deletions, insertions and duplications larger than 1 kb up to several Mb but do not include those variants that arise from the insertion/deletion of transposable elements alone. CNVs are not specific to the human genome since they have also been observed in other mammals such as mice and chimpanzees. Initially, CNVs were identified during locus-specific studies or during the analysis of gene families. Genome-wide screens have however revealed that copy number variation is a ubiquitous phenomenon with no large genomic regions being spared from such variation.

The overall impact of copy number variations on human genomic diversity is striking. Since CNVs are enriched in regions of complex genomic structure, the inherent instability of these regions might also give rise to somatic CNVs that contribute to cancer progression(29) or bipolar disorders.(30) Currently the number of genes by which two normal individuals may differ is unknown but could be quite considerable. Copy number variations also challenge the definition of what is ‘normal’. Copy number variations and copy number mutations might actually represent parts of a continuum. For example, triplication of the trypsinogen locus causes hereditary pancreatitis but heterozygous carriers of the triplication can be clinically unaffected.(31) Doubtlessly, copy number variation has a major influence on normal human phenotypic diversity and inter-individual disease susceptibility, the extent of which has yet to be defined.

Source: Kehrer-Sawatzki, H. BioEssays 29:311–313, 2007. Copyright 2007 Wiley Periodicals, Inc.