In order for the discipline of genomic medicine to fulfill its maximum potential and utility in the clinic, it is necessary to be able to characterize all forms of genetic variation in an individual patient's genome. This includes single or simple nucleotide variation (SNV) and copy number variation (CNV). Personal genome sequencing is becoming a reality. The complete nucleotide sequence of James Dewey Watson, 55 years after his discovery of DNA and two decades after he led the human genome project, provided tremendous insights into personal genomes. It was the first human genome sequenced by next generation sequencing [19
] and revealed extensive variation: greater than 3 million SNV differences in comparison with the reference haploid human genome sequence and a high frequency of small sized CNVs (less than 1 kb) that were beyond the detection limits of array comparative genomic hybridization. Another major finding was the amount of Alu
repetitive element polymorphisms - indels (insertions or deletions) representing dimorphisms of Alu
at a particular locus. Thus, for each personal genome the amount of structural variation related to the position of repetitive elements could be immense. The remarkable extent of genome structural variation in populations was further revealed by Conrad et al.
The next important step in personal genomics was to use whole-genome sequence to associate specific variation with clinical disease phenotypes, and thus identify medically actionable variation from the myriad of benign polymorphic variations; that is, detect signal from noise. Whole-genome sequencing (WGS) was used to identify the cause of Charcot-Marie-Tooth neuropathy. Surprisingly, this work also provided insights into genetic variation underlying common complex traits such as carpal tunnel syndrome [21
]. Whole exome sequencing (WES) has also now been used to find the medically actionable alleles in defined clinical Mendelian phenotypes for which the causative genes were unknown (for example, [3
]), and to make a definitive diagnosis for a patient with a complex trait [25
]. Further exome sequencing work recently documented that new mutations may contribute in a significant way to common traits such as mental retardation and intellectual disability [26
]. This latter study emphasizes the importance of personal genomics for assessing not only inherited variation but also de novo
However, we must not lose sight of the challenges! Exome sequencing provides essentially no information about structural variation and CNV. Whole-genome sequencing can provide structural variation information, but it is not obvious to what extent short read sequences can capture CNV, such as those of only a few hundred base pairs that may delete or duplicate single exons [27
] or delineate complex rearrangements, given the information filtering step required in matching short reads to a haploid human reference genome. Whether or not WES or WGS will discern repeat expansion, a highly significant form of pathology-associated genetic variation, also remains to be demonstrated. Nevertheless, from the insights already provided, it is clear that the information that can be gleaned from personal genome sequencing will probably be so compelling that clinicians will be motivated to rapidly adapt it into clinical practice.
James R Lupski, Section Editor, Molecular genetics, genomics and epigenetics of disease