De novo distal deletions are structural variants considered to be already present in the zygote. However, investigations especially in the prenatal setting have documented that they are often in mosaic with cell lines in which the same deleted chromosome shows different types of aberrations such as: 1) neutral copy variants with loss of heterozygosity that replace the deleted region with equivalent portions of the homologous chromosome and create distal uniparental disomy (UPD); 2) derivative chromosomes where the deleted one ends with the distal region of another chromosome or has the shape of a ring; 3) U-type mirror dicentric or inv-dup del rearrangements. Unstable dicentrics had already been entailed as causative of terminal deletions even when no trace of the reciprocal inv-dup del had been detected. To clarify the mechanism of origin of distal deletions, we examined PubMed using as keywords: complex/mosaic chromosomal deletions, distal UPD, U-type dicentrics, inv-dup del chromosomes, excluding the recurrent inv-dup del(8p)s which are known to originate by NAHR at the maternal meiosis. The literature has shown that U-type dicentrics leading to nearly complete trisomy and therefore incompatible with zygotic survival underlie many types of de novo unbalanced rearrangements, including terminal deletions. In the early embryo, the position of the postzygotic breaks of the dicentric, the different ways of acquiring telomeres by the broken portions and the selection of the most favorable cell lines in the different tissues determine the prevalence of one or the other rearrangement. Multiple lines with simple terminal deletions, inv-dup dels, unbalanced translocations and segmental UPDs can coexist in various mosaic combinations although it is rare to identify them all in the blood.Regarding the origin of the dicentric, among the 30 cases of non-recurrent inv-dup del with sufficient genotyping information, paternal origin was markedly prevalent with consistently identical polymorphisms within the duplication region, regardless of parental origin. The non-random parental origin made any postzygotic origin unlikely and suggested the occurrence of these dicentrics mainly in spermatogenesis.This study strengthens the evidence that non-recurrent de novo structural rearrangements are often secondary to the rescue of a zygotic genome incompatible with embryo survival.

The embryo battle against adverse genomes: Are de novo terminal deletions the rescue of unfavorable zygotic imbalances?

Zuffardi, Orsetta
Writing – Original Draft Preparation
;
Fichera, Marco
Writing – Original Draft Preparation
;
2022

Abstract

De novo distal deletions are structural variants considered to be already present in the zygote. However, investigations especially in the prenatal setting have documented that they are often in mosaic with cell lines in which the same deleted chromosome shows different types of aberrations such as: 1) neutral copy variants with loss of heterozygosity that replace the deleted region with equivalent portions of the homologous chromosome and create distal uniparental disomy (UPD); 2) derivative chromosomes where the deleted one ends with the distal region of another chromosome or has the shape of a ring; 3) U-type mirror dicentric or inv-dup del rearrangements. Unstable dicentrics had already been entailed as causative of terminal deletions even when no trace of the reciprocal inv-dup del had been detected. To clarify the mechanism of origin of distal deletions, we examined PubMed using as keywords: complex/mosaic chromosomal deletions, distal UPD, U-type dicentrics, inv-dup del chromosomes, excluding the recurrent inv-dup del(8p)s which are known to originate by NAHR at the maternal meiosis. The literature has shown that U-type dicentrics leading to nearly complete trisomy and therefore incompatible with zygotic survival underlie many types of de novo unbalanced rearrangements, including terminal deletions. In the early embryo, the position of the postzygotic breaks of the dicentric, the different ways of acquiring telomeres by the broken portions and the selection of the most favorable cell lines in the different tissues determine the prevalence of one or the other rearrangement. Multiple lines with simple terminal deletions, inv-dup dels, unbalanced translocations and segmental UPDs can coexist in various mosaic combinations although it is rare to identify them all in the blood.Regarding the origin of the dicentric, among the 30 cases of non-recurrent inv-dup del with sufficient genotyping information, paternal origin was markedly prevalent with consistently identical polymorphisms within the duplication region, regardless of parental origin. The non-random parental origin made any postzygotic origin unlikely and suggested the occurrence of these dicentrics mainly in spermatogenesis.This study strengthens the evidence that non-recurrent de novo structural rearrangements are often secondary to the rescue of a zygotic genome incompatible with embryo survival.
Clonal selection
Distal deletions
Inv-dup del
Mirror dicentric chromosomes
Mosaicism
Segmental uniparental disomy
Chromosome Aberrations
Chromosome Deletion
Chromosome Inversion
Female
Humans
Male
Pregnancy
Telomere
Chromosome Disorders
Zygote
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/541809
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