Comprehensive investigation of complex chromosomal rearrangements with innovative genomic technologies

• Grant number: 23/14043-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: March 01, 2024
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Maria Isabel de Souza Aranha Melaragno
• Grantee: Bruna Ferreira Burssed dos Santos
• Supervisor: Alexander Hoischen
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: Radboud University Medical Center (Radboudumc), Netherlands
• Associated to the scholarship: 22/03989-2 - Complex rearrangements: mechanisms of formation and relation with the phenotype, BP.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, damage genes or 're-shuffle' (regulatory) genomic elements. Examples include complex rearrangements, which involve at least three breakpoints, and ring chromosomes, which are circular DNA molecules. A number of mechanisms, which can be indicated by the analysis of the DNA sequence at the breakpoints, have been proposed to explain the formation of chromosomal rearrangements. 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 a comprehensive suite of genomic technologies including karyotyping, chromosomal microarray, optical genome mapping, and (long-read) sequencing, with the aim of characterizing and relating them to possible mechanisms of formation while also understanding the possibly associated pathophysiology. This project will benefit from the application of two innovative genomic technologies: 1) optical genome mapping to accelerate the study of complex rearrangements that hardly could be investigated by other methodologies; 2) long-read sequencing to fully resolve the rearrangements to base-pair level even in complex regions of the human genome. A karyotype-phenotype correlation will also be carried out since the obtained results will allow for a better comprehension of the genetic basis (coding and regulatory) involved in the altered phenotypes through the identification of possible candidate genes for the anomalies. With the use of these innovative genomic technologies in this project, we intend to solve "old cytogenetic problems".