Micro-homology Templated Insertions in Alzheimer's Disease

The objective of our research is to characterize genomic rearrangements associated with various human disease including Alzheimer’s. The overarching hypothesis guiding our research is that repair of DNA double-strand breaks (DSBs) by using ‘risky’ inaccurate pathways can lead to genomic destabilization. Our focus is on two DSB repair pathways: break-induced replication (BIR) and microhomology-mediated BIR (MMBIR). BIR is initiated by a broken DNA end invading into a homologous template followed by extensive DNA synthesis that is highly mutagenic. Interruptions of BIR leads to initiation of MMBIR, a template-switching event that often leads to complex genomic rearrangements and has been linked to neurological conditions and to cancer. The overall goal of our proposed research is to define the molecular mechanisms of MMBIR, and to identify factors that inhibit or promote cells entering into MMBIR.

We aim to achieve this using our MMBSearch tool to detect MMBIR events that are often missed by other methods in human WGS analyses. Using MMBSearch we will analyze data from NIAGADS, specifically data on neurological disease associated whole genome sequencing (WGS) and whole exome sequencing (WES) to detect MMBIR events associated with neurodegenerative disorders.

The results of this analyses will be used to determine the frequency of MMBIR in various types of human cells and their association with neurodegenerative disorders. In addition, we will identify chromosomal locations where MMBIR events are especially abundant and specific features in humans that predispose them to MMBIR. We will identify genetic variations predisposing cells to MMBIR, which may uncover that specific SNPs, structural variations, certain gene mutations, etc. are associated with MMBIR events. We specifically hypothesize that mutations in DNA repair, DNA replication, chromatin maintenance, and DNA damage checkpoint genes could promote MMBIR. These studies will shed light on the etiology and mechanism of MMBIR to potentially develop biomarkers for early detection and design targeted therapies to treat human disorders.

The goal of our research is to understand the underlying mechanisms of genomic instability that lead to human disease. In particular, we are interested to investigate the molecular mechanism of an essentially uncharacterized DNA repair pathway, microhomology-mediated break-induced replication (MMBIR) that has been implicated in DNA mutations and found in a variety of human cancers and in association with neurological diseases. We have recently described a diagnostic pattern of mutations associated with MMBIR using a yeast model, which has allowed us to develop a novel algorithm to search for MMBIR events in sequenced human genomes. We are planning to apply this new algorithm to identify MMBIR events in analyzing human genome databases. The proposed research will allow us to further understand mechanisms of leading to various human diseases including cancer and neurological human diseases and to refine our software that is aimed to detect MMBIR in human genomes. The proposed research will be focused on analyzing the data from NIAGADS database.