Chromothripsis, a new catastrophic phenomenon, has been characterized by the localized shattering of one or more chromosomes followed by the random reassembly of the resulting chromosomal pieces, with the loss of others. Here, by paired-end whole genome sequencing, we analysed the genomes of 8 cases, each were preselected according to their complex rearrangements, 5 of which were carrying a small supernumerary marker chromosomes (sSMC) as detected by conventional cytogenetics and array-CGH. In first three cases, they were three families carrying de novo or inherited rearrangements, we detected a ''balanced chromothripsis'' at healthy parents, which results in a meiotic generation of its recombinant chromosome as transmitted in the probands. Our findings strongly indicate that apparently de novo complex rearrangements can in fact be recombinant chromosomes derived by a cryptic “balanced chromothripsis” present in one healthy parent. In the cases with sSMC, a disordered assembly of chromosomal segments which constitute sSMC was highlighted. Microsatellite and SNPs analysis in the five trios indicated either a maternal origin of the sSMC and a corresponding biparental origin of the related homologous chromosomes or a paternal origin of the sSMC and uniparental hetero-/isodisomy of the related homologous chromosomes. These data strongly suggest that non-recurrent sSMCs are the relic of the original supernumerary chromosome of a trisomic zygote, that has been partially rescued by anaphase lagging and chromothripsis.
La cromotripsi è un nuovo fenomeno catastrofico caratterizzato dalla distruzione localizzata di uno o più cromosomi seguita dal riassemblaggio casuale di alcuni dei pezzi ottenuti con possibile perdita di altri. In questo lavoro di tesi, abbiamo effettuato l’analisi di paired-end whole genome sequencing sul genoma di 8 casi. Mediante citogenetica tradizionale e array-CGH, in tre casi erano stati precedentemente rilevati riarrangiamenti cromosomici complessi, negli altri cinque la presenza di cromosomi marcatori sovrannumerari (sSMCs). Nei primi tre casi abbiamo rilevato la presenza di cromotripsi bilanciata nei genitori sani, che probabilmente risulta nella generazione alla meiosi di un cromosoma ricombinante che è trasmesso al probando. I nostri risultati indicano che i riarrangiamenti cromosomici apparentemente de novo possono essere cromosomi ricombinanti che derivano da una criptica cromotripsi bilanciata presente in uno dei genitori. Negli altri casi in cui era stato rilevato un sSMC abbiamo osservato che esso è costituito dall’assemblaggio disordinato di segmenti cromosomici. L’analisi dei microsatelliti e degli SNPs nei cinque trii può indicare un’origine materna del sSMC quindi un’origine biparentale dei cromosomi omologhi oppure un’origine paterna del sSMC quindi la presenza di una etero/isodisomia dei cromosomi omologhi. Questi risultati indicano che i sSMCs non ricorrenti siano un residuo dell’originale cromosoma sovrannumerario presente nello zigote trisomico che è stato parzialmente conservato mediante anaphase lagging e cromotripsi.
Cromotripsi costitutiva: analisi dei riarrangiamenti cromosomici complessi e cromosomi marcatori sovrannumerari tramite Whole genome sequencing
RUSSO, ALESSIA
2016/2017
Abstract
Chromothripsis, a new catastrophic phenomenon, has been characterized by the localized shattering of one or more chromosomes followed by the random reassembly of the resulting chromosomal pieces, with the loss of others. Here, by paired-end whole genome sequencing, we analysed the genomes of 8 cases, each were preselected according to their complex rearrangements, 5 of which were carrying a small supernumerary marker chromosomes (sSMC) as detected by conventional cytogenetics and array-CGH. In first three cases, they were three families carrying de novo or inherited rearrangements, we detected a ''balanced chromothripsis'' at healthy parents, which results in a meiotic generation of its recombinant chromosome as transmitted in the probands. Our findings strongly indicate that apparently de novo complex rearrangements can in fact be recombinant chromosomes derived by a cryptic “balanced chromothripsis” present in one healthy parent. In the cases with sSMC, a disordered assembly of chromosomal segments which constitute sSMC was highlighted. Microsatellite and SNPs analysis in the five trios indicated either a maternal origin of the sSMC and a corresponding biparental origin of the related homologous chromosomes or a paternal origin of the sSMC and uniparental hetero-/isodisomy of the related homologous chromosomes. These data strongly suggest that non-recurrent sSMCs are the relic of the original supernumerary chromosome of a trisomic zygote, that has been partially rescued by anaphase lagging and chromothripsis.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/25469