Methods to sequence or identify significant fractions of the human genome and the genetic variations within those segments are becoming commonplace. However the major impediment to understanding the health implications of the variations found in every human being remains the unraveling of the functional meaning of all sequence differences in every individual. Whole genome sequencing is the critical first step that will enable geneticists and physicians to develop a full functional understanding of the data. Any methods or approaches that fall short of this goal have little or no chance to solve the functional problem. In our still profound ignorance of the way in which the genome functions, until we have this complete data we will be prevented from moving forward rapidly and decisively to de-convolute function. Whole genome sequencing as defined by the X PRIZE remains a noble goal.

What parts of the genome would likely be missed in a selective, rather than whole genome, sequencing approach?

Personal mutations: By scoring a set of predefined variations, we will miss finding new mutations in the individual whose genome is being evaluated. Such an approach only scores known rare variations. Yet each individual is born with many more variations than can be accounted for in the maternal and paternal DNA due to spontaneous mutations that occur during formation of eggs, sperm and multiplication of cells. These will all be missed using approaches that focus on predefined variations.

Regulatory mutations: We lose information by sequencing only the regions of the genome that encode proteins or are already known to regulate genes. Some important variants (mutations) are nowhere near the coding sequences and yet have a profound effect on the expression of genes, such as the timing of expression or the amount of expression. Furthermore, preselection can prove costly and might outweigh the cost of whole genome sequencing.

Repetitive Sequences: A selective sequencing approach would likely ignore the significant fraction of the genome that is characterized by being highly repetitive. These regions are currently very difficult to sequence. Yet a significant fraction of repetitive sequences are highly conserved implying that they likely serve an important function. Such parts of the genome are currently inaccessible and their impact on human health and physiology is unknown. Development of technology to sequence the complete genome and tackle these harder problems is needed.

The "Phase" problem": Whole genome sequencing is required to know which variations or mutations are on which one of the two chromosomes. Variations on the same chromosome are likely to have different functional meaning than if they are on opposite chromosomes. Sequencing a selective part of the genome does not provide full information about this "phase" issue.

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The Archon X PRIZE for Genomics would not be possible without the generous contribution of our title sponsors and benefactors, Dr. Stewart Blusson and Mrs. Marilyn Blusson (FIX).