Abstract
Structural copy number variation (CNV) is a frequent cause of human variation and disease. Evidence is mounting that somatic acquired CNVs are prevalent, with mosaicisms of large segmental CNVs in blood found in up to one percent of both the healthy and patient populations. It is generally accepted that such constitutional mosaicisms are derived from postzygotic somatic mutations. However, few studies have tested this assumption. Here we determined the origin of CNVs which coexist with a normal cell line in nine individuals. We show that in 2/9 the CNV originated during meiosis. The existence of two cell lines with 46 chromosomes thus resulted from two parallel trisomy rescue events during postzygotic mitoses.
Highlights
Knowledge about copy number variation (CNV) in the human genome was limited to microscopically visible changes
The most parsimonious explanation is that both aberrations originated from a meiotic segregation error resulting in a trisomic conception, followed by two parallel trisomy rescue events during the successive mitotic divisions (Figure 7)
In the other seven cases, the duplication was derived from the chromosome with the same parental allele as the transmitted chromosome in the normal cell line or the deletion was on the chromosome with the same parental allele as the normal chromosome in the normal cell line
Summary
Knowledge about copy number variation (CNV) in the human genome was limited to microscopically visible changes. Advances in technology have led to the discovery of submicroscopic CNVs, ranging from kilobases to megabases in size and covering up to 13% of the human genome [1,2]. Several studies investigating in vitro fertilized embryos at the preimplantation stage demonstrated a very high number of chromosomal mosaicisms in early human embryos [7,8,9]. While many of these embryos will not reach the stage of implantation, some do continue to develop leading to fetal mosaicisms, confined placental mosaicism or mosaic infants. Mosaicism appears to be variable amongst different tissues: chromosomal aneuploidies were detected in approximately 10% of normal human brain cells [14]
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