Complex rearrangements: mechanisms of formation and relation with the phenotype

• Grant number: 22/03989-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2022
• End date: March 31, 2027
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Maria Isabel de Souza Aranha Melaragno
• Grantee: Bruna Ferreira Burssed dos Santos
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 19/21644-0 - Impact of genetic variants on genomic stability and their effects on the phenotype, AP.TEM
• Associated scholarship(s): 23/14043-5 - Comprehensive investigation of complex chromosomal rearrangements with innovative genomic technologies, BE.EP.DR

Abstract

Structural chromosomal alterations result from breaks and rearrangements in the chromosomes and can alter the quantity of genetic material present in the cells. Examples include complex rearrangements, which involve at least three breakpoints, and ring chromosomes, which are circular DNA molecules. A number of mechanisms have been proposed to explain the formation of chromosomal rearrangements and they can be indicated by the analysis of the DNA sequence at the breakpoints. Sequencing data is also capable of pointing out risk factors for chromosomal rearrangements since they can be molded by certain characteristics related to DNA repair mechanisms. In the present study, patients with complex rearrangements and ring chromosomes will be studied by karyotyping, genomic array, fluorescent in situ hybridization (FISH), optical genome mapping, whole-genome sequencing, and Sanger sequencing of the breakpoints, with the aim of characterizing and relating them to possible mechanisms of formation. The method of optical genome mapping has been indicated for the study of complex rearrangements that hardly could be investigated by other methodologies. This way, we intend to introduce this approach, which will allow for the advancement of the study of cytogenomic alterations, in our laboratory. A karyotype-phenotype relation will also be carried out since the obtained results will allow for a better comprehension of the genetic bases involved in the altered phenotypes through the identification of possible candidate genes for the anomalies.