Neurogenetics studies the role of genetics in the development and function of the nervous system. It considers neural characteristics as phenotypes (i.e. manifestations, measurable or not, of the genetic make-up of an individual), and is mainly based on the observation that the nervous systems of individuals, even of those belonging to the same species, may not be identical. As the name implies, it draws aspects from both the studies of neuroscience and genetics, focusing in particular how the genetic code an organism carries affects its expressed traits. Mutations in this genetic sequence can have a wide range of effects on the quality of life of the individual. Neurological diseases, behavior and personality are all studied in the context of neurogenetics. The field of neurogenetics emerged in the mid to late 20th century with advances closely following advancements made in available technology. Currently, neurogenetics is the center of much research utilizing cutting edge techniques.
History The field of neurogenetics emerged from advances made in molecular biology, genetics and a desire to understand the link between genes, behavior, the brain, and neurological disorders and diseases. The field started to expand in the 1960s through the research of Seymour Benzer, considered by some to be the father of neurogenetics. His pioneering work with Drosophila helped to elucidate the link between circadian rhythms and genes, which led to further investigations into other behavior traits. He also started conducting research in neurodegeneration in fruit flies in an attempt to discover ways to suppress neurological diseases in humans. Many of the techniques he used and conclusions he drew would drive the field forward. Early analysis relied on statistical interpretation through processes such as LOD (logarithm of odds) scores of pedigrees and other observational methods such as affected sib-pairs, which looks at phenotype and IBD (identity by descent) configuration. Many of the disorders studied early on including Alzheimer's, Huntington's and amyotrophic lateral sclerosis (ALS) are still at the center of much research to this day. By the late 1980s new advances in genetics such as recombinant DNA technology and reverse genetics allowed for the broader use of DNA polymorphisms to test for linkage between DNA and gene defects. This process is referred to sometimes as linkage analysis. By the 1990s ever advancing technology had made genetic analysis more feasible and available. This decade saw a marked increase in identifying the specific role genes played in relation to neurological disorders. Advancements were made in but not limited to: Fragile X syndrome, Alzheimer's, Parkinson's, epilepsy and ALS.
Neurological disorders While the genetic basis of simple diseases and disorders has been accurately pinpointed, the genetics behind more complex, neurological disorders is still a source of ongoing research. New developments such as the genome wide association studies (GWAS) have brought vast new resources within grasp. With this new information genetic variability within the human population and possibly linked diseases can be more readily discerned. Neurodegenerative diseases are a more common subset of neurological disorders, with examples being Alzheimer's disease and Parkinson's disease. Currently no viable treatments exist that actually reverse the progression of neurodegenerative diseases; however, neurogenetics is emerging as one field that might yield a causative connection. The discovery of linkages could then lead to therapeutic drugs, which could reverse brain degeneration.
Types of Neurogenic disorders: There are many genes linked in different Neurogenetic conditions that are involved in inheritance patterns and biological mechanisms. These disorders can range from single gene conditions through inheritance to multi-gene conditions influenced by environmental factors.
Major Categories:
Monogenic Neurogenic Disorders - These are mutations in a single gene and closely follow Mendelian inheritance patterns such as autosomal dominant, recessive, and X-linked. These are more predictable diagnoses or inheritances.
Examples of Mutations include:
SCN1A Mutation that causes epilepsy HTT genes that makes Huntington’s disease proteins SMN1 gene causes spinal muscular atrophy PMP22, MFN2, and GJB1 all cause Charcot-Marie- Tooth disease
Mechanism: The mutations are formed by the loss or gain of function leading to altered protein activity.
Inheritance pattern: Inheritance pattern varies by condition.
2. Polygenic Neurogenic disorders - These mutations are caused by many genes acting together, often with environmental contributions. They are not predictable and do not follow a clear Mendelian pattern.
Examples of polygenic risk disorders:
Alzheimer’s disease contains one or two copies of the APOE ε4, which is the strongest gene factor in the disease, causing an increased likelihood of developing the condition. Other genes such as TREM2 can raise the risk. The alleles alone do not directly cause the disease but when combined, their effects interact and raise the risk by affecting brain function. They are polygenic where the risk is shaped by the additive or interactive influence of several genes alongside environmental and epigenetic factors.
Mechanisms: Risk genes, how the environment affects them, other genes that change their effects, and why some people get the disease while others do not.
Inheritance pattern: Inheritance is influenced by multiple genes.
3. Neurodevelopment Disorders - These disorders make an appearance during brain development, often due to mutations affecting neuronal growth.
Example of Neurodevelopment disorder:
MEC2 is a genetic disorder that affects motor and cognitive functions, mostly in girls.
Mechanisms: Mutations disrupt brain formation, neurons, growth, and communication.
Inheritance pattern: Often sporadic or multifactorial inheritance.
4. Mitochondrial and Metabolic Disorders - This type of mutation or disorder affects how cells produce energy.
Example of Mitochondrial disorder:
POLG is a gene mutation led to mitochondrial encephalopathy like an infection or toxins in the bloodstream.
Mechanism: Mutation in mitochondrial or nuclear DNA disrupts energy production.
Inheritance pattern: Mitochondrial disorders are maternally inherited through mitochondrial DNA while metabolic disorders are typically autosomal recessive inheritance.
5. Movement Disorders and Ataxias - Genetic conditions that affects coordination and motor control.
Examples of Movement Disorders and Ataxias:
TMEM240 mutations cause Spinocerebellar Ataxia (SCA21).
Mechanism: Genes affecting the cerebellum and motor pathways are muted.
Inheritance pattern: The inheritance varies, can be dominant, recessive, and X-linked.
6. Peripheral Neuropathies - consists of nerve damage in the arms, legs, and feet.
Example of Peripheral Neuropathies:
PMP22 duplication causes Charcot-Marie-Tooth disease.
Mechanism: The mutation affects the myelin in the peripheral nerves.
Inheritance pattern: Common autosomal dominant or autosomal recessive.
Gene sequencing One of the most noticeable results of further research into neurogenetics is a greater knowledge of gene loci that show linkage to neurological diseases. The table below represents a sampling of specific gene locations identified to play a role in selected neurological diseases based on prevalence in the United States. Gene loci Neurological disease APOE ε4, PICALM Alzheimer's disease C9orf72, SOD1 Amyotrophic lateral sclerosis HTT Huntington's disease DR15, DQ6 Multiple sclerosis LRRK2, PARK2, PARK7 Parkinson's disease
Methods of research
Statistical analysis Logarithm of odds (LOD) is a statistical technique used to estimate the probability of gene linkage between traits. LOD is often used in conjunction with pedigrees, maps of a family's genetic make-up, in order to yield more accurate estimations. A key benefit of this technique is its ability to give reliable results in both large and small sample sizes, which is a marked advantage in laboratory research.
Quantitative trait loci (QTL) mapping is another statistical method used to determine the chromosomal positions of a set of genes responsible for a given trait. By identifying specific genetic markers for the genes of interest in a recombinant inbred strain, the amount of interaction between these genes and their relation to the observed phenotype can be determined through complex statistical analysis. In a neurogenetics laboratory, the phenotype of a model organisms is observed by assessing the morphology of their brain through thin slices.R. W. Williams (1998) Neuroscience Meets Quantitative Genetics: Using Morphometric Data to Map Genes that Modulate CNS Architecture. QTL mapping can also be carried out in humans, though brain morphologies are examined using nuclear magnetic resonance imaging (MRI) rather than brain slices. Human beings pose a greater challenge for QTL analysis because the genetic population cannot be as carefully controlled as that of an inbred recombinant population, which can result in sources of statistical error.
Recombinant DNA Recombinant DNA is an important method of research in many fields, including neurogenetics. It is used to make alterations to an organism's genome, usually causing it to over- or under-express a certain gene of interest, or express a mutated form of it. The results of these experiments can provide information on that gene's role in the organism's body, and it importance in survival and fitness. The hosts are then screened with the aid of a toxic drug that the selectable marker is resistant to. The use of recombinant DNA is an example of a reverse genetics, where researchers create a mutant genotype and analyze the resulting phenotype. In forward genetics, an organism with a particular phenotype is identified first, and its genotype is then analyzed.Ambrose, Victor (2011). Reverse Genetics .
Animal research
Model organisms are an important tool in many areas of research, including the field of neurogenetics. By studying creatures with simpler nervous systems and with smaller genomes, scientists can better understand their biological processes and apply them to more complex organisms, such as humans. Due to their low-maintenance and highly mapped genomes, mice, Drosophila, and C. elegans are very common. Zebrafish and prairie voles have also become more common, especially in the social and behavioral scopes of neurogenetics.
In addition to examining how genetic mutations affect the actual structure of the brain, researchers in neurogenetics also examine how these mutations affect cognition and behavior. One method of examining this involves purposely engineering model organisms with mutations of certain genes of interest. These animals are then classically conditioned to perform certain types of tasks, such as pulling a lever in order to gain a reward. The speed of their learning, the retention of the learned behavior, and other factors are then compared to the results of healthy organisms to determine what kind of an effect – if any – the mutation has had on these higher processes. The results of this research can help identify genes that may be associated with conditions involving cognitive and learning deficiencies.Neurogenetics and Behavior Center. Johns Hopkins U, 2011. Web. 29 Oct. 2011.
Human research