Projects / Programmes
Identification of novel genetic factors and mechanisms for neurodegenerative diseases using next-generation sequencing approaches
| Code |
Science |
Field |
Subfield |
| 3.05.00 |
Medical sciences |
Human reproduction |
|
| Code |
Science |
Field |
| B220 |
Biomedical sciences |
Genetics, cytogenetics |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
Neurodegenerative diseases, next-generation sequencing, disease gene discovery, whole human genome analysis, personalised medicine
Researchers (17)
Organisations (1)
Abstract
Neurodegenerative diseases (NDD) represent a broad group of conditions of central nervous system, which represent a leading cause of disability and early death in the developed world, and include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, multiple sclerosis, ataxias and multiple distinct rare neurodegenerative disorders. Although the genetic component has been convincingly shown to contribute to the development of NDD, the specific genetic causes of most NDDs remain unknown. Therefore, understanding of genetic architecture of neurodegenerative diseases remains one of the key challenges in the field of human genetics and reproduction.
Despite technological developments and the discovery of several novel genes, the cause of NDD in the majority of patients remains unknown. Identification of novel rare variants with a large effect is possible foremost with genome sequencing, however the later has so far remained focused on a small panel of known or candidate NDD genes due to technological limitations and high prices. Novel, high-throughput next generation sequencing approaches have offered a new opportunity to bridge the gap in understanding of genetic etiology of NDD, by enabling the sequencing and analysis of the entire human genome. By using these approaches, it is possible to simultaneously determine the coding regions of all human genes (whole exome sequencing) and recently with whole genome sequencing, analysis of intronic, regulatory and intergenic regions, has also become more accessible. NGS approach offers unprecedented opportunities for identification of novel genes and mechanisms for unexplained NDDs and shows promise in familial cases of NDD where the probability of genetic etiology is particularly high. By using high-parallel sequencing methods it is today possible to simultaneously perform genetic analyses as well as global mRNA sequencing, expression and splicing (alternative codon use) analyses (using RNA-seq), thus enabling concurrent analysis of genetic and consequent functional changes in patients.
As part of the project we aim to select patients with genetically unexplained familial forms of various NDDs. In these patients we will perform sequencing of coding regions of all genes in the human genome (whole exome sequencing analysis) or sequencing of the whole genome (whole genome sequencing analysis). In selected cases we will simultaneously perform transcriptome analysis by RNA sequencing (RNA-seq). Extensive bioinformatics analyses will be used to identify potential causative changes in known and novel genes involved in disease in these families.
The aims of the project include the (1) identification of novel genes and mechanisms in NDD by using next generation sequencing approaches, (2) development of a comprehensive and unified approach for the identification of genetic aetiology of NDD, based on whole genome sequencing analysis (3) evaluation of the contribution of functional transcriptomic analysis using next-generation sequencing in understanding identified genetic changes in NDD patients, and finally the development of novel diagnostic algorithms for improved, faster and more cost-efficient diagnostics of NDD.
The use of state-of-the-art methods for genetic analysis and their innovative implementation as outlined in this project, offers an opportunity to characterise novel genes and novel mechanisms involved in NDD. Based on experience so far, the discovery of a new gene or pathological mechanisms can form a basis for completely novel research avenues and understanding of the disease, and in some cases even an opportunity to develop novel approaches to therapy. The development and evaluation of the described procedure forms the basis for the implementation of improved and more cost-effective diagnostics of NDD that would directly translate into a more accurate diagnostics, better possiblity to predict the NDD and their progression, and that may in some cases enable prevention o
Significance for science
The characterisation of the genetic aetiology of neurodegenerative diseases (NDD) represents one of the key challenges in modern medicine in view of the large socioeconomic burden of these diseases on one hand, and the opportunities offered by improved understanding of their genetic aetiology on the other.
The use of state-of-the-art methods for genetic analysis and their innovative implementation as outlined in this project, offers an opportunity to characterise novel genes and novel mechanisms involved in NDD. Based on experience so far, the discovery of a new gene or pathological mechanisms can form a basis for completely novel research avenues and understanding of the disease, and in some cases even an opportunity to develop novel approaches to therapy.
The development and evaluation of the described procedure forms the basis for the implementation of improved and more cost-effective diagnostics of NDD that would directly translate into a more accurate diagnostics, a possiblity to predict the disease and its progression, and that may in some cases enable prevention or treatment of the patients. The approach that will be used in the project would also ensure faster and more cost-effective diagnostic options for patients with NDD.
Because the genetic aspects of NDD in Slovenia haven't yet been systematically and comprehensively analysed, our study will provide data that will improve the knowledge on the genetic epidemiology of neurodegenerative changes in Slovenia.
Significance for the country
The characterisation of the genetic aetiology of neurodegenerative diseases (NDD) represents one of the key challenges in modern medicine in view of the large socioeconomic burden of these diseases on one hand, and the opportunities offered by improved understanding of their genetic aetiology on the other.
The use of state-of-the-art methods for genetic analysis and their innovative implementation as outlined in this project, offers an opportunity to characterise novel genes and novel mechanisms involved in NDD. Based on experience so far, the discovery of a new gene or pathological mechanisms can form a basis for completely novel research avenues and understanding of the disease, and in some cases even an opportunity to develop novel approaches to therapy.
The development and evaluation of the described procedure forms the basis for the implementation of improved and more cost-effective diagnostics of NDD that would directly translate into a more accurate diagnostics, a possiblity to predict the disease and its progression, and that may in some cases enable prevention or treatment of the patients. The approach that will be used in the project would also ensure faster and more cost-effective diagnostic options for patients with NDD.
Because the genetic aspects of NDD in Slovenia haven't yet been systematically and comprehensively analysed, our study will provide data that will improve the knowledge on the genetic epidemiology of neurodegenerative changes in Slovenia.
Most important scientific results
Interim report
Most important socioeconomically and culturally relevant results
