Neurogenetics
Encyclopedia
Neurogenetics studies the role of genetics
in the development and function of the nervous system
. It considers neural characteristics as phenotype
s (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. Mutation
s 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.
(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 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. 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.
are changes in an organism’s genetic sequence that are responsible for the vast amount of variability seen within a population. Since mutations can either be harmful, helpful, or innocuous to an organism’s fitness, the challenge for researchers is to determine whether particular mutations are in fact responsible for specific traits or diseases or if they are merely coincidental. Identifying the genes responsible can pave the way for the development of therapies for currently crippling diseases.
is a statistical technique used to estimate the probability of gene linkage between traits. Based on a set of data, a series of calculations are made to determine the likelihood that one observable trait is linked to a genetic marker. Each calculation yields a LOD score, and probability with the highest LOD score is used to determine the chromosomal position of that trait relative to the generic marker. 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 the laboratory, the phenotype of a model organisms is observed by assessing the morphology of their brain through thin slices. QTL mapping can also be carried out in humans, though brain morphologies are examined using nuclear magnetic resonance imaging (MRI)
rather than brain slices. An MRI is used to take a collection of cross-sectional images which can then be compiled into a three-dimensional model. 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 is made by creating a plasmid consisting of the gene of interest, a selectable marker and vector DNA. The plasmid is then transfected into a simple organism, such as E. coli, to amplify it before it is transfected into the intended host organism. The hosts are then screened with the aid of a toxic drug that the selectable marker is resistant to. Therefore, the organisms that successfully incorporated the plasmid into their genome will survive while those without the plasmid will die. The surviving organisms can then be observed for any changes in their behavior or gene expression.
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.
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 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.
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. 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. 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.
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.
is the inclination of an individual to initiate behavior without adequate forethought. An individual with high 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.
ry, 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 plasticity
will increase due to the seeking of a reward, resulting in more neuronal connections and faster response times.
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.
, and the neurogenetic factors that make one susceptible to it, is currently a budding field of study. A multitude of genes associated with the condition have been found which can act as indicators for an individual’s predisposition to alcoholism. Polymorphisms in ALDH2
and ADH1B
- alcohol digestive enzymes which function improperly – have been found to be strong indicators of alcoholism, along with the presence of GABRA2
, a gene which codes for a GABA receptor. How GABRA2 leads to alcohol dependence is still unclear, but it is thought to interact negatively with alcohol, altering the behavioral effect and resulting in dependency. In general these genes code for receptor or digestive proteins, and while having these particular genes does indicate a predisposition towards alcoholism, it is not a definitive determining factor. Like all behavioral traits, genes alone do not determine an individual’s personality or behavior, for the influence of the environment is just as important.
(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. In the past few years, as more research has been dedicated to neurogenetics, a better understanding of specific neurological disorders and phenotype
s 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.
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.
.
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
in the development and function of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. It considers neural characteristics as phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
s (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
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
, may not be identical. As the name implies, it draws aspects from both the studies of neuroscience
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...
and genetics, focusing in particular how the genetic code an organism carries affects its expressed traits. Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s 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 LODGenetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
(logarithm of odds) scores of pedigrees
Pedigree chart
A pedigree chart is a diagram that shows the occurrence and appearance or phenotypes of a particular gene or organism and its ancestors from one generation to the next, most commonly humans, show dogs, and race horses....
and other observational methods such as affected sib-pairs, which looks at phenotype and IBD
Identity by descent
Two or more alleles are identical by descent if they are identical copies of the same ancestral allele. This property is often used in genetic linkage to identify alleles which are potential candidates for harboring mutations causing a genetic disease....
(identity by descent) configuration. Many of the disorders studied early on including Alzheimer’s
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, Huntington's and amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
(ALS) are still at the center of much research to this day.By the late 1980’s new advances in genetics such as recombinant DNA
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
technology and reverse genetics
Reverse genetics
Reverse genetics is an approach to discovering the function of a gene by analyzing the phenotypic effects of specific gene sequences obtained by DNA sequencing. This investigative process proceeds in the opposite direction of so-called forward genetic screens of classical genetics...
allowed for the broader use of DNA polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
to test for linkage between DNA and gene defects. This process is referred to sometimes as linkage analysis. 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
Fragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
, Alzheimer’s, Parkinson’s
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
and ALS.
Methods of research
MutationsMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
are changes in an organism’s genetic sequence that are responsible for the vast amount of variability seen within a population. Since mutations can either be harmful, helpful, or innocuous to an organism’s fitness, the challenge for researchers is to determine whether particular mutations are in fact responsible for specific traits or diseases or if they are merely coincidental. Identifying the genes responsible can pave the way for the development of therapies for currently crippling diseases.
Statistical Analysis
Logarithm of odds (LOD)Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
is a statistical technique used to estimate the probability of gene linkage between traits. Based on a set of data, a series of calculations are made to determine the likelihood that one observable trait is linked to a genetic marker. Each calculation yields a LOD score, and probability with the highest LOD score is used to determine the chromosomal position of that trait relative to the generic marker. 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)
Quantitative trait locus
Quantitative traits refer to phenotypes that vary in degree and can be attributed to polygenic effects, i.e., product of two or more genes, and their environment. Quantitative trait loci are stretches of DNA containing or linked to the genes that underlie a quantitative trait...
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
Recombinant inbred strain
A recombinant inbred strain is an organism with chromosomes that incorporate an essentially permanent set of recombination events between chromosomes inherited from two or more inbred strains...
, the amount of interaction between these genes and their relation to the observed phenotype can be determined through complex statistical analysis.
In a neurogenetics the laboratory, the phenotype of a model organisms is observed by assessing the morphology of their brain through thin slices. QTL mapping can also be carried out in humans, though brain morphologies are examined using nuclear magnetic resonance imaging (MRI)
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
rather than brain slices. An MRI is used to take a collection of cross-sectional images which can then be compiled into a three-dimensional model. 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.Recombinant DNA is made by creating a plasmid consisting of the gene of interest, a selectable marker and vector DNA. The plasmid is then transfected into a simple organism, such as E. coli, to amplify it before it is transfected into the intended host organism. The hosts are then screened with the aid of a toxic drug that the selectable marker is resistant to. Therefore, the organisms that successfully incorporated the plasmid into their genome will survive while those without the plasmid will die. The surviving organisms can then be observed for any changes in their behavior or gene expression.
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.
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. Zebra fish 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 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.
Human research
Many research facilities 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 a key part 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, the progression of neurodegenerative disorders, the persistence of periodic disorders, and the effects of mitochondrial decay on metabolism.Behavioral Neurogenetics
Advances in molecular biologyMolecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
techniques and the species wide genome project
Human Genome Project
The Human Genome Project is an international scientific research project with a primary goal of determining the sequence of chemical base pairs which make up DNA, and of identifying and mapping the approximately 20,000–25,000 genes of the human genome from both a physical and functional...
, 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. 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. 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.
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 conservedConserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
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
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
species and mutations, specifically those having to do with serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, 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.
Impulse control
ImpulsivityImpulsivity
Impulsivity is a personality trait characterized by the inclination of an individual to initiate behavior without adequate forethought as to the consequences of their actions, acting on the spur of the moment. Eysenck and Eysenck related impulsivity to risk-taking, lack of planning, and making up...
is the inclination of an individual to initiate behavior without adequate forethought. An individual with high 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
Lateralization of brain function
A longitudinal fissure separates the human brain into two distinct cerebral hemispheres, connected by the corpus callosum. The sides resemble each other and each hemisphere's structure is generally mirrored by the other side. Yet despite the strong anatomical similarities, the functions of each...
. 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
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
and myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
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
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
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.
Higher Cognitive Function
Many of the genes indicated in varying levels of impulsivity control, specifically those related to dopamine genes expression in frontostriatal circuitFrontostriatal circuit
Frontostriatal circuits are neural pathways that connect frontal lobe regions with the basal ganglia that mediate motor, cognitive, and behavioural programs within the brain and receive inputs from dopaminergic, serotonergic, noradrenergic, and cholinergic cell groups that modulate information...
ry, 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 plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
will increase due to the seeking of a reward, resulting in more neuronal connections and faster response times.
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 aggressionAggression
In psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...
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
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
, 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
5-Hydroxyindoleacetic acid
5-Hydroxyindoleacetic acid is the main metabolite of serotonin in the human body. In chemical analysis of urine samples, 5-HIAA is used to determine the body's levels of serotonin.- Clinical significance :...
(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.
Alcohol dependency
The study of alcoholismAlcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
, and the neurogenetic factors that make one susceptible to it, is currently a budding field of study. A multitude of genes associated with the condition have been found which can act as indicators for an individual’s predisposition to alcoholism. Polymorphisms in ALDH2
ALDH2
Aldehyde dehydrogenase 2 family , also known as ALDH2, is a human gene found on chromosome 12.-Function:The enzyme encoded by this gene belongs to the aldehyde dehydrogenase family of enzymes that catalyze the chemical transformation from acetaldehyde to acetic acid...
and ADH1B
ADH1B
Alcohol dehydrogenase 1B is an enzyme that in humans is encoded by the ADH1B gene.The protein encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols,...
- alcohol digestive enzymes which function improperly – have been found to be strong indicators of alcoholism, along with the presence of GABRA2
GABRA2
Gamma-aminobutyric acid receptor subunit alpha-2 is a protein that in humans is encoded by the GABRA2 gene....
, a gene which codes for a GABA receptor. How GABRA2 leads to alcohol dependence is still unclear, but it is thought to interact negatively with alcohol, altering the behavioral effect and resulting in dependency. In general these genes code for receptor or digestive proteins, and while having these particular genes does indicate a predisposition towards alcoholism, it is not a definitive determining factor. Like all behavioral traits, genes alone do not determine an individual’s personality or behavior, for the influence of the environment is just as important.
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 studiesGenome-wide association study
In genetic epidemiology, a genome-wide association study , also known as whole genome association study , is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait...
(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. In the past few years, as more research has been dedicated to neurogenetics, a better understanding of specific neurological disorders and phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
s has arisen with direct correlation to genetic mutations
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
. With severe disorders such as epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, brain malformations, or mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
a single gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
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
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
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
Frameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
, caused by either a deletion or splicing
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
, or a missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
at the DCX gene
Doublecortin
Doublecortex; lissencephaly, X-linked , also known as DCX, is a gene.Doublecortin is a microtubule-associated protein expressed by neuronal precursor cells and immature neurons in embryonic and adult cortical structures...
location causes a neuronal migration defect also known as lissencephaly
Lissencephaly
Lissencephaly, which literally means smooth brain, is a rare brain formation disorder caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a lack of development of brain folds and grooves . It is a form of cephalic disorder...
. This gives the brain a smooth appearance instead of folded. Another example is the ROBO3
ROBO3
Roundabout homolog 3 is a protein that in humans is encoded by the ROBO3 gene.-Further reading:...
gene where a mutation alters axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
length negatively impacting neuronal connections. Horizontal gaze palsy with progressive scoliosis (HGPPS) accompanies a mutation here.
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
LRRK2
Leucine-rich repeat kinase 2 , also known as dardarin, is an enzyme that in humans is encoded by the LRRK2 gene. LRRK2 is a member of the leucine-rich repeat kinase family...
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.
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 |
Current Research
Neurogenetics is a field that is rapidly expanding and growing. The current areas of research are very diverse in their focuses. One area deals with molecular processes and the function of certain proteins, often in conjunction with cell signaling and neurotransmitter release, cell development and repair, or neuronal plasticity. Behavioral and cognitive areas of research continue to expand in an effort to pinpoint contributing genetic factors. Disease research is also flourishing, focusing on illnesses such as Alzheimer’s, ALS, epilepsy, and many others. Many of the most recent developments in this field can be found in the Journal of NeuroscienceJournal of Neuroscience
The Journal of Neuroscience is a weekly scientific journal published by the Society for Neuroscience. The journal publishes peer-reviewed empirical research articles in the field of neuroscience...
.
See also
- Genes, Brain and BehaviorGenes, Brain and BehaviorAccording to the Journal Citation Reports, its 2009 impact factor is 4.061, ranking Genes, Brain and Behavior 63rd out of 237 listed journals in the category "Neurosciences" and 6th out of 48 listed journals in the category "Behavioral Sciences"....
- International Behavioural and Neural Genetics SocietyInternational Behavioural and Neural Genetics SocietyThe International Behavioural and Neural Genetics Society was founded in 1996. The goal of IBANGS is "to promote the field of neurobehavioural genetics".- Mission :...
- Journal of NeurogeneticsJournal of NeurogeneticsThe Journal of Neurogenetics is a quarterly peer-reviewed scientific journal that publishes research on the genetic basis of normal and abnormal function of the nervous system. It is published by Informa...