Looking back at genomic medicine in 2011

Abstract

Genomic medicine, in its broadest sense of being medical developments informed by ‘omic’ advances, has con­ tinued to move towards the clinic in 2011. To mark the end of the year and the beginning of 2012, the editors of the six sections within Genome Medicine were invited to provide their highlights of the past year and to hint at the developments that we are likely to see in the near future. Six different areas of progress are covered here, but the core of genomic medicine continues to be intrinsically linked to improvements in the underlying technology, and two obvious examples are sequencing and mass spec trometry. Technological advances have enabled larger studies and more complex analyses, allowing researchers and clinicians to track changes within a single cell and yet spot patterns across a whole population and within an entire physiological system. The foundations laid in 2011 should help the field to tackle the challenges of translating genomic medicine to the clinic in 2012. Complex genomic rearrangements and disease The past year has been marked by advances in the speed, accuracy and scale of genome sequencing. These improve­ ments have led to the first population­ scale genome sequencing study to provide information on structural variants [1]. Over 15,000 novel structural variants were identified from 185 individuals. Analysis of breakpoint junctions revealed that 70% of deletions and almost 90% of insertions showed microhomology ranging from 2 bp to 376 bp at the junctions. This suggests that nonhomolo­ gous recombination mechanisms are predominant in copy number variation, and that microhomology­mediated DNA replication mechanisms, such as microhomology­ mediated break­induced replication, might have a major role in human genome structural variation. Genome sequencing also revealed the extent of complex genomic rearrangements (CGRs) in disease. Over 700 genomes from different cancers were studied, and ‘chromosome catastrophes’ were identified in 2 to 3% of all cancers and in up to 25% of bone cancers [2]. This phenomenon, also termed ‘chromothripsis’ (shattering and regluing of chromosomes), is primarily localized to single chromosomes, but includes multiple structural genomic changes, such as gains, losses and inversions. As a result, chromothripsis can lead to the simultaneous occurrence of mutations in a number of different cancer ­ causing genes. Cancer is known to be driven by somati­ cally acquired point mutations and chromosomal re­ arrangements, conventionally thought to accumulate gradually over time. However, chromothripsis is a one­off event resulting in multigenic changes [2]. It remains to be shown whether chromothripsis is a major driver of cancer. Intriguingly, a similar chromosome catastrophe event that resulted in CGRs was found to be associated with a small fraction of genomic disorders [3]. This involved a germline or constitutional rearrangement event early in