Characterization of Large Structural Genetic Mosaicism in Human Autosomes

Abstract

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

“…The frequency of detectable CMEs in autosomes is low in individuals ,50 years (,0.5%), but it has been shown to increase with age and to be strongly associated with a higher risk of hematological cancer and slightly related to some solid tumors (OR 5 4). 2,3,7 The frequency of CMEs is also higher in conditions of accelerated aging, such as type 2 diabetes, with a higher prevalence of cardiovascular complications among individuals with CMEs. 8 We hypothesized that genome instability disorders with impaired DNA repair, such as FA, could show a higher rate of CMEs at an early age and that CME detection could herald the high risk of hematological and mucosal cancers in these patients.…”

Mosaic chromosome 20q deletions are more frequent in the aging population

“…29,30 The gender (males have elevated del[20q] frequency) and ancestry (African ancestry has a lower del[20q] frequency) associations observed for del(20q) have also been observed with overall mosaicism and may not be specific to del(20q). 19 One hypothesis that could partially account for the observed gender and ancestry differences in frequency is gender and ancestry specific differences in recombination rate 31,32 ; although, further research is needed to robustly link gender and ancestry specific recombination rate to clonal mosaicism. Interestingly, individuals with high proportions of African ancestry (.30%) were observed to have a smaller mean event size (13.1 vs 17.5 Mb) and on average fewer cells affected (39.3% vs 43.0%), although these differences were not significant (P 5 .05 and .58, respectively) and no differences were observed in the genomic location of events in individuals with a high proportion of African ancestry.…”

“…19 Scans involving hematologic malignancies (ie, non-Hodgkin lymphoma or chronic lymphocytic leukemia) were excluded from analyses. As described earlier, blood or buccal DNA (20% overall) was previously extracted and genotyped on one or more commercially available Illumina Infinium human single nucleotide polymorphism (SNP) microarrays (Hap300, Hap240, Hap550, Hap610, Hap660, Hap 1, Omni Express, Omni 1, Omni 2.5, and Omni 5).…”

“…Mosaic del(20q) was the most commonly detected autosomal event in previous surveys of large structural mosaic alterations (.2 Mb) in genome-wide association studies conducted with DNA extracted from either leukocytes or buccal material. [17][18][19] Herein, we aim to further characterize mosaic del(20q) in nonhematologic cancer cases and cancer-free controls, and compare mosaic del(20q) to reported del(20q) in myeloid neoplasms. Investigating the clinical and molecular features favoring the development of mosaic del(20q) could provide new insights into del(20q) acquisition, advance our understanding of how some individuals tolerate mosaic del(20q), and determine whether del(20q) could be investigated as a biomarker for early detection of myeloid disorders.…”

“…19 One event was complex in nature and not amenable to distinct copy number state classification. When restricted to events detected on the q arm of chromosome 20, mosaic losses were the primary event detected (n 5 91).…”