The past year has been marked by advances in the speed, accuracy and scale of genome sequencing. These improvements 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 nonhomologous recombination mechanisms are predominant in copy number variation, and that microhomology-mediated DNA replication mechanisms, such as microhomology-mediated break-induced 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 somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. However, chromothripsis is a one-off 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 embryogenesis rather than somatically acquired mutations and seemed to occur via a DNA-replication-based mechanism. Triplicated genomic segments were also identified within the rearrangements, and microhomology was present at many of the breakpoint junctions. The triplication cannot readily be explained by chromothripsis, as it requires a gain of genetic information, probably resulting from DNA replication. Other CGRs identified in association with genomic disorders included triplications; triplicated dosage-sensitive genes conveyed a more severe clinical phenotype than duplication. Triplications seem to occur by a double crossover event within a flanking low-copy repeat and are tandem in nature, similar to earlier predictions from an unequal crossing-over or non-allelic homologous recombination (NAHR) model [4
]. However, many of the observed triplications have a complex 'duplication-inverted triplication-duplication' structure, which requires only two breakpoint junctions. One of these is generated by an initial NAHR event between inverted repeats, and the other occurs by a nonhomologous mechanism, potentially a DNA replication-based mechanism that results in microhomology at the breakpoint junction [5
]. The inversion allows distant genomic regions to be brought into spatial proximity.
A summary of 2011 would not be complete without highlighting exome sequencing and its role in the elucidation of the gene(s) responsible for a number of different Mendelian disorders [6
]. Genomic studies have so far revealed the tremendous extent of rare variants in individual genomes. This has led to the concept of 'clan genomics' [7
], wherein the most relevant medically actionable variation may be rare variants that occurred as novel combinations or as new mutations in your personal genome or that of your nearest relatives.
James R Lupski, Section Editor, Molecular genetics, genomics & epigenetics of disease