Neurogenetics

Human karyogram

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 aspects of man studied in the context of neurogenetics. The field of neurogenetics emerged in the mid to late 1900's with advances closely following advancements made in available technology. Currently neurogenetics is the center of much research utilizing the cutting edge of research techniques.

History

The field of neurogenetics emerged in the late 1970’s primarily as a way to understand how genetic code correlated to diseases and other neurological disorders. 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.^[1]By the late 1980’s 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. ^[2][3] By the 1990’s ever advancing technology had made genetic analysis more feasible and available. This decade saw a marked increase in indentifying 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.^[4]

Methods of research

Quantitative Trait Loci

Mutations are changes in an organism’s genetic sequence and vary from individual to individual. Most mutations are innocuous, others are harmful, and a small amount can even be beneficial to the organism. Since most mutations have no effect on the viability of an organism, a great deal of genetic variation can exist within a population with regard to a single trait. Within the scope of neurogenetics, this can pose a challenge to researchers when trying to identify genes linked to neurological diseases. Mutations that are observed across a population have a lower likelihood of being the main cause of a disease since they can be found in many healthy individuals. Without a sense of the amount of variation of this gene in the population at large, it is impossible to say whether the mutation observed truly is an outlier or whether it falls within normal levels.

The process used to determine the amount of normal genetic variation for a particular trait is called quantitative trait loci (QTL) mapping. QTL mapping is preferable over many other investigative techniques because it gives researchers a discrete number to work with, as opposed to the qualitative results of alternative methods. Quantitative results are easily compared, making it easier to distinguish extreme mutations from milder ones.

QTL mapping is carried out by inserting the gene of interest into a recombinant inbred strain of mice, and analyzing the subsequent phenotypes to the subsequent genotypes. Mice are ideal model organisms for research because 1) they are easy to maintain and care for 2) as mammals they are genetically similar to humans, and 3) their genome is extensively mapped, allowing for ease of analysis. Inbred strains in particular are preferred because the genome throughout the strain is nearly identical, due to the intentional breeding of siblings. Therefore, researchers do not need to analyze the entire genome of each mouse used, but can merely focus instead on the locus of interest. From the average of the distribution of the population, the normal bounds of variation of the gene can be determined, thus providing a basis for comparison to more extreme mutations.^[5]

QTL mapping can also be carried out in humans, though with slightly different techniques. Since the brain is not accessible for direct examination in human models as it is in mice models, another method of observation must be used. Nuclear magnetic resonance imaging (MRI) is used to take a collection of cross-sectional images of the individual’s brain, which can later be compiled into a three-dimensional model. This model is then compared to the sequence of the individual’s genetic code in a manner similar to the mice QTL analysis, in order to identify the genes responsible for the observed phenotype. Human beings pose a greater challenge than mice for QTL analysis because the genetic population cannot be as carefully controlled as that of recombinant mice strains. Therefore, it is more difficult to define the parameters of normal variation for a trait, and as a result more difficult to identify any abnormal mutations.^[6]

Animal behavior research

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. Model organisms, such as lab mice, are engineered with mutations to certain genes of interest. The mice 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 mice to determine what kind of an effect – if any – the mutation has had on these higher processes. The results of this research can confirm potential disease-linked genes identified by quantitative trait loci analysis, as well as implicate other genes for further investigation.^[7]

Human research

Many research facilities, in addition to animal research, actively seek out volunteers with certain conditions or illnesses to participate in studies. Model organisms, while important, cannot completely model the complexity of the human body, making volunteers absolutely vital to the progression of research. Along with gathering some basic information about medical history and the extent of their symptoms, samples are taken from the participants, including blood, cerebrospinal fluid, and/or muscle tissue. These tissue samples are then genetically sequenced, and the genomes are added to current database collections. The growth of these data bases will eventually allow researchers to better understand the genetic nuances of these conditions and bring therapy treatments closer to reality. Current areas of interest in this field have a wide range, spanning anywhere from the maintenance of circadian rhythms,^[8] the progression of neurodegenerative disorders, the persistence of periodic disorders, and the effects of mitochondrial decay on metabolism.^[9]

Behavioral Neurogenetics

Advances in molecular biology techniques and the species wide genome project, have made it possible to map out an individuals entire genome. It has been debated for ages whether an individuals personality is genetically or environmentally derived. With advancing being made in neurogenetics, scientists have started to map out genes and various gene expression and correlate them to different personality traits.^[10] To be clear, as of yet, there is little to no evidence that suggests that the presence of a single gene will absolutely determine that an individual will portray one trait over another, at least in humans. Having a specific gene might make one more susceptible to this behavior, but the individual’s environment and experiences, such as habitat and level of stress, also play a determining role. It is starting to become clear that most behaviors that are influenced by genes are influence by numerous genes and other neurological regulating factors, such as neurotransmitter levels. Aggression, for example, has been linked to at least 16 different genes, many of which have been shown to have different influences on levels of serotonin, dopamine, neurotransmitter density and other aspects of brain structure and chemistry. Similar findings have been found during the study of impulsivity and alcoholism.^[11] Current researchers have been using animal subjects such as mice and rats to trying and correlate their findings to humans, and due to the fact that many behavioral characteristics have been conserved across many species and generations, these studies, more often than not, result in viable information that can reveal why some people are more prone to act one way versus another, and also explain how two individuals can very so drastically even though they share so many of the same anatomical structures and basic physiological elements.^[12]

Cross species gene conservation

While it is true that species vary widely, at their most basic, they all share some very similar behavior traits that are absolutely essential for survival. These include but are not limited to feeding, mating, aggression, and learning. This conservation of behavior cross specially has lead biologists to hypothesize that these traits could possibly have the similar, if not the same, genetic causes and pathways. Studies conducted on the genome of many different organisms have reveled that much of the genetic material has been conserved throughout evolution. Biologist however were faced with a challenge when they tried to determine which genes were related to different behaviors because outside environmental factors play a large part in determining an individuals behavior at any time. Through the study of knockout species and mutations, specifically those having to do with serotonin and dopamine, biologists were able to quantify an individuals response to environmental factors and start to determine if some aspect of behavior is determine by a genetic factor or if it just arises due to the environment. Through varying studies, biologists have been able to identify different genes that lead to variations in mating, aggression, foraging, social behavior, and sleep to name a few. Many of these same genes, can be found in a multitude of species, including humans. This implies that some aspects of an individual’s behavior can indeed be inherited from the previous generation, and that variations in personality and behavioral traits seen amongst individuals of the same species can be explained by varying levels of the expression of these genes and their corresponding proteins and enzymes.^[12]

Impulse control

Impulsivity, known as behavioral inhibition,. An individual with low impulsivity will be more likely to act in ways that are not generally beneficial, or are outside the normal range of action one would expect to see. There is strong evidence supported by fMRI imaging, PET scans, as well as research done using new techniques in molecular genetics, suggesting that differences in impulsivity are directly influenced by a right lateralized neural circuit. This suggests that there are specific areas of the brain that play a direct role in the regulation of behavior. This is interesting because all human brains have the same general anatomical make up. This indicates that there must be some other driving factor for the differences in personality seen among human. For impulsivity, there is support for the idea that various levels of brain density, specifically the density of white and grey matter and levels of myelination play a direct role in the level of impulsivity exhibited by individuals. In terms of the white matter, in individuals that exhibited a high level of impulsivity, axon and myelin fiber integrity was low and that varying levels of the white matter microstructure enabled researches to predict an individual level of impulsivity. In terms of the grey matter, a low level of density, or one that is lower than the average, would tend to indicate an individual had a low level of impulsivity control.

However, brain structure is not the only contributing factor, there is increasing evidence to support the idea that genes play a direct role in such things as the level of impulsivity, and other personality traits. An individual’s genes could directly affect their level of impulsivity by coding for various mediation of neurotransmitter systems such as serotonin and dopamine. Both of which are known to play a role in behavior. For dopamine some genes that have been shown to possibly affect levels of impulsivity are DAT and DRD4, both of which contribute to the density of the prefrontal gray matter. For individuals with ADHD, specifically those with a DRD 4/4 genotype were found to have small prefrontal gray matter volume than those without the 4/4 genotype, indicating that their level of impulse control would be lower than normal. There are many other genes that can contribute to either brain density or its composition, and further studies are being conducted to determine the significance of each.^[10]

Higher Cognitive Function

Many of the genes indicated in varying levels of impulsivity control, specifically those related to dopamine genes expression in frontostriatal circuitry, such as COMT, DARPP-32, DAT1, DRD2, and DRD4, also play a role in higher cognitive functions such as learning, and motivation. It has been shown that these factors are highly heritable and while many executive functions can be learned through experience and environmental factors, individuals with these specific genes, or those with high expression of these genes, were shown to posses higher cognitive function than those with different levels of expression. One possible explanation for this is that these individuals posses a high genetic motivational factor, making them more likely to naturally develop better cognitive function, or participate in activities that result in higher cognitive function due to experience. Much of this motivation may arise from reward based learning, where the outcome was more positive than expected, which leads to a high level of dopamine being release. Over time synaptic plasticitywill increase due to the seeking of a reward, resulting in more neuronal connections and faster response times.^[13]

Aggression and serotonin

In addition to work being done on general impulsivity control, which could lead to possible treatments for conditions like ADHD, there is also work being done on how an individuals genes can cause varying levels of aggression and aggression control. Studies conducted by the World Health Organization state that the number of violent interactions between human individuals has almost risen to one per minute. The reason that scientists suspect that there is a genetic contribution to aggression is because, throughout the animal kingdom, varying styles, types, and levels of aggression have been witnessed. These aggressive tendencies are also not restricted to only one or a few individuals, implying that it every individual has the capacity to be aggressive, some are just more effective than others. This variation in levels of aggression most likely arose from the fact that different types and levels of aggression have been seen to lead to an increase in an individual’s genetic fitness. This is especially true for species where males display aggressively towards other males to either attract female partners or to assert dominance. Seeing as aggression is a trait that spans many different species, it would make sense to assume that there is some sort of genetic link. One popular pathway being studies in relation to aggression is serotonin, 5-HT, and the varying genes, proteins, and enzymes that interact with it. This pathway has been linked to aggression through its influences on early brain development and morphology, as well as directly regulating an individual’s level of impulsive aggression. Most of the studies in regards to aggression have been conducted on mice or rats, but due to high levels of genetic conservation seen between different species in regards to the 5-HT pathway, most findings will directly correlate to humans. The enzyme MAO, which is partially responsible for the degradation of serotonin, has been seen to be especially important in aggression control. In studies where the gene for MAO A were knocked out, test subjects exhibited high levels of aggression, as well as significant decreases in the 5-HIAA(the main metabolite of serotonin):5-HT(serotonin) ratio in the brain meaning that serotonin replacement and repair would decrease, reducing its efficiency and availability. Interestingly, in studies conducted with knockout mice for the MOA B enzyme, no change in levels of aggression were witnessed, nor was there any change in the levels of serotonin available, implying that it must have some other function than to regulate aggression. Studies into human genetics have also indicated that MAO A plays an important role in aggression control, brain development, and general social interaction. For example, a Dutch family, with a point mutation in the 8th exon of the structural MAO A gene, was observed for four generations. During this time, 14 men were seen to suffer from borderline mental retardation as well low levels of impulsive aggression control. While there may have been other genetic factors that contributed to this, the fact that all 14 of these men suffered from this particular mutation seems to lend itself to the idea that MAO A does play some part in an individuals ability to interact and control aggression. In addition to this specific gene, the genes for the 5-HT receptor, as well as the 5-Ht transporter (SERT), have a direct affect on the level of aggression seen in test subjects. The up regulation of a specific 5-HT receptor (5-HT1A) and the down regulation of SERT both individually contribute to lower an individual’s level of aggression.^[11]

Alcohol dependency

The study into alcoholism and the neurogenetic factors that make some individuals more susceptible than others is currently a budding field of study. As of now, there have been a multitude of genes found to be associated and indicate an individuals predisposition to alcoholism. Polymorphisms in ALDH2 and ADH1B, alcohol digestive enzymes that do not function properly, have been found to be strong indicators of alcoholism, along with the presence of GABRA2, which codes for a GABA receptor. How GABRA2 leads to alcohol dependence is still unclear, but it is thought to interact incorrectly with alcohol, altering the behavioral effect, and resulting in dependency.. In general, these genes code for either receptor or digestive proteins, and while having these particular genes does indicate a predisposition towards alcoholism, it is not a determining factor. Like all behavioral traits, genes alone do not determine an individuals personality or behavior, much of it is influenced by the environment.^[14]

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 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.^[15] In the past few years, as more research has been dedicated to neurogenetics, a better understanding of specific neurological disorders and phenotypes has arisen with direct correlation to genetic mutations. With severe disorders such as epilepsy, brain malformations, or mental retardation a single gene or causative condition has been indentified 60% of the time; however, the milder the intellectual handicap the lower chance a specific genetic cause has been pinpointed. Autism for example is only linked to a specific, mutated gene about 15-20% of the time while the mildest forms of mental handicaps are only being accounted for genetically less than 5% of the time. Research in neurogenetics has yielded some promising results, though, in that mutations at specific gene loci have been linked to harmful phenotypes and their resulting disorders. For instance a frameshift mutation, caused by either a deletion or splicing , or a missense mutation at the DCX gene location causes a neuronal migration defect also known as lissencephaly. This gives the brain a smooth appearance instead of folded. Another example is the ROBO3 gene where a mutation alters axon length negatively impacting neuronal connections. Horizontal gaze palsy with progressive scoliosis (HGPPS) accompanies a mutation here.^[16]

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, genetics is emerging as one field that might yield a causative connection. Specifically with Parkinson’s the LRRK2 gene has been identified to play a part in causing Parkinson’s disease. This linkage poses as a possible source for therapeutic drugs, which reverse brain degeneration. From here the jump could be made to other neurological disorders in finding a cure genetically.^[17]

Gene sequencing

One of the most noticeable results of further research into neurogenetics is a greater knowledge of gene loci that affect neurological development. The table below represents a portion of the specific gene locations identified to play a neurological role.

Gene	Neurological Effect when Mutated
DCX	Lissencephaly: brain appears smooth as a result of improper neuronal migration
ROBO3	Horizontal gaze palsy with progressive scoliosis (HGPPS)
TUBB3	Congenital fibrosis of the extraocular muscles (CFEOM) type 3
LRRK2	Parkinson's disease

See also

Neuroscience portal

• Genes, Brain and Behavior
• International Behavioural and Neural Genetics Society
• Journal of Neurogenetics

References

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8. ^ Fu, Ying-Hui, and Louis Ptacek, dirs. "Research Projects." Fu and Ptacek's Laboratories of Neurogenetics. U of California, San Fransisco, n.d. Web. 29 Oct. 2011.<http://neugenes.org/index.htm>.
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11. ^ ^{a b} Popova, Nina K. (2006). "From Genes to Aggressive Behavior: The Role of Serotonergic System" (Print). BioEssays 28 (5): 495–503. 
12. ^ ^{a b} Reaume, Christopher J.; Sokolowski, Marla B. (2011). "Conservation of Gene Function in Behavior" (Print). Philosophical Transactions of the Royal Society B-Biological Sciences 366 (1574): 2100–10. 
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