Mosaic Uniparental Disomies and Aneuploidies as Large Structural Variants of the Human Genome

Abstract

Mosaicism is defined as the coexistence of cells with different genetic composition within an individual, caused by postzygotic somatic mutation. Although somatic mosaicism for chromosomal abnormalities is a well-established cause of developmental and somatic disorders and has also been detected in different tissues, its frequency and extent in the adult normal population are still unknown. We provide here a genome-wide survey of mosaic genomic variation obtained by analyzing Illumina 1M SNP array data from blood or buccal DNA samples of 1991 adult individuals from the Spanish Bladder Cancer/EPICURO genome-wide association study. We found mosaic abnormalities in autosomes in 1.7% of samples, including 23 segmental uniparental disomies, 8 complete trisomies, and 11 large (1.5-37 Mb) copy-number variants. Alterations were observed across the different autosomes with recurrent events in chromosomes 9 and 20. No case-control differences were found in the frequency of events or the percentage of cells affected, thus indicating that most rearrangements found are not central to the development of bladder cancer. However, five out of six events tested were detected in both blood and bladder tissue from the same individual, indicating an early developmental origin. The high cellular frequency of the anomalies detected and their presence in normal adult individuals suggest that this type of mosaicism is a widespread phenomenon in the human genome. Somatic mosaicism should be considered in the expanding repertoire of inter- and intraindividual genetic variation, some of which may cause somatic human diseases but also contribute to modifying inherited disorders and/or late-onset multifactorial traits.

Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

“…The additional advantage of the method is that deviation of BAF values from 0.5 for heterozygous SNP probes allows estimation of the number of cells containing a variant genotype. This platform is sensitive for detection of structural mosaicism in samples containing as few as 5% of cells with a variant genotype (Conlin et al 2010;Razzaghian et al 2010;Rodriguez-Santiago et al 2010;Forsberg et al 2012Forsberg et al , 2013Forsberg et al , 2014. Nevertheless, we performed 21 validation experiments on UM and PT samples from nine subjects (BK152, DH74, DM138, JU32, KK123, ME114, PI33, SE135, and ML36) by NimbleGen 720K genomewide arrays, using standard array CGH methodology, and applying blood DNA from the same subject as a normal control sample.…”

A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders

“…Therefore, we believed that most of the regions of segmental homozygosity in the WTCCC were not reflective of segmental UPD events and we considered that estimating population of prevalence of segmental UPD events from this data set would not be appropriate. Analyses of segmental UPD, which are typically mosaic (Rodriguez-Santiago et al 2010), are better suited to algorithms that interrogate the B allele frequency, rather than genotype data.…”

Mosaic copy number variation in schizophrenia

“…In contrast, mosaicism in a bladder cancer study of 1991 individuals (957 controls) was 1.7%. 11 Increased rate of mosaicism is frequently observed in cancer cells, which is likely the driver of this difference. We detected almost a twofold increase in large deletion/duplication variation in the SCZ population, suggesting that with greater power, significant differences between groups might arise.…”

“…Recent reports suggest that somatic structural changes in the nuclear genome are not uncommon and can be identified using SNP genotyping arrays, [10][11][12] at least when using DNA from white blood cells. These studies have detected a mosaicism rate from 0.23 to 2% and mosaicism has been observed in 7 to 95% of lymphocytes based on probe intensity measures.…”