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.
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. [1]
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. [2]
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. [3] 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. [4] [5] 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. [6]
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. [7] 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. [8]
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. [9] [10] [11] [12]
Gene loci | Neurological disease |
---|---|
APOE ε4, PICALM [10] | Alzheimer's disease |
C9orf72 , SOD1 [13] | amyotrophic lateral sclerosis |
HTT [12] | Huntington's disease |
DR15 , DQ6 [11] | Multiple sclerosis |
LRRK2 , PARK2, PARK7 [9] | Parkinson's disease |
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. [14] [15]
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. [16] 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. [17]
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. [18] [19]
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 , [20] and C. elegans [21] are very common. Zebrafish [22] and prairie voles [23] 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. [24]
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. [25]
Such databases are used in genome-wide association studies (GWAS). Examples of phenotypes investigated by notable neurogenetics GWAS include:
Advances in molecular biology techniques and the species-wide genome project have made it possible to map out an individual's entire genome. Whether genetic or environmental factors are primarily responsible for an individual's personality has long been a topic of debate. [28] [29] Thanks to the advances being made in the field of neurogenetics, researchers have begun to tackle this question by beginning to map out genes and correlate them to different personality traits. [28] There is little to no evidence to suggest that the presence of a single gene indicates that an individual will express one style of behavior over another; rather, having a specific gene could make one more predisposed to displaying this type of behavior. It is starting to become clear that most genetically influenced behaviors are due to the effects of many variants within many genes, in addition to other neurological regulating factors like neurotransmitter levels. Due to fact that many behavioral characteristics have been conserved across species for generations, researchers are able to use animal subjects such as mice and rats, but also fruit flies, worms, and zebrafish, [20] [21] to try to determine specific genes that correlate to behavior and attempt to match these with human genes. [30]
While it is true that variation between species can appear to be pronounced, at their most basic they share many similar behavior traits which are necessary for survival. Such traits include mating, aggression, foraging, social behavior and sleep patterns. This conservation of behavior across species has led biologists to hypothesize that these traits could possibly have similar, if not the same, genetic causes and pathways. Studies conducted on the genomes of a plethora of organisms have revealed that many organisms have homologous genes, meaning that some genetic material has been conserved between species. If these organisms shared a common evolutionary ancestor, then this might imply that aspects of behavior can be inherited from previous generations, lending support to the genetic causes – as opposed to the environmental causes – of behavior. [29] Variations in personalities and behavioral traits seen amongst individuals of the same species could be explained by differing levels of expression of these genes and their corresponding proteins. [30]
There is also research being conducted on how an individual's genes can cause varying levels of aggression and aggression control [ citation needed ].
Throughout the animal kingdom, varying styles, types and levels of aggression can be observed leading scientists to believe that there might be a genetic contribution that has conserved this particular behavioral trait. [31] For some species varying levels of aggression have indeed exhibited direct correlation to a higher level of Darwinian fitness. [32]
A great deal of research has been done on the effects of genes and the formation of the brain and the central nervous system. The following wiki links may prove helpful:
There are many genes and proteins that contribute to the formation and development of the central nervous system, many of which can be found in the aforementioned links. Of particular importance are those that code for BMPs, BMP inhibitors and SHH. When expressed during early development, BMP's are responsible for the differentiation of epidermal cells from the ventral ectoderm. Inhibitors of BMPs, such as NOG and CHRD, promote differentiation of ectoderm cells into prospective neural tissue on the dorsal side. If any of these genes are improperly regulated, then proper formation and differentiation will not occur. BMP also plays a very important role in the patterning that occurs after the formation of the neural tube. Due to the graded response the cells of the neural tube have to BMP and Shh signaling, these pathways are in competition to determine the fate of preneural cells. BMP promotes dorsal differentiation of pre-neural cells into sensory neurons and Shh promotes ventral differentiation into motor neurons. There are many other genes that help to determine neural fate and proper development include, RELN, SOX9, WNT, Notch and Delta coding genes, HOX, and various cadherin coding genes like CDH1 and CDH2 . [33]
Some recent research has shown that the level of gene expression changes drastically in the brain at different periods throughout the life cycle. For example, during prenatal development the amount of mRNA in the brain (an indicator of gene expression) is exceptionally high, and drops to a significantly lower level not long after birth. The only other point of the life cycle during which expression is this high is during the mid- to late-life period, during 50–70 years of age. While the increased expression during the prenatal period can be explained by the rapid growth and formation of the brain tissue, the reason behind the surge of late-life expression remains a topic of ongoing research. [34]
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. As a result of the expanding neurogenetics field 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 identified 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 or a missense mutation at the DCX gene location causes a neuronal migration defect also known as lissencephaly. 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. [35] These are just a few examples of what current research in the field of neurogenetics has achieved. [36]
The zebrafish is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to India and South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio.
Genetics is the study of genes, genetic variation, and heredity in organisms. It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar working in the 19th century in Brno, was the first to study genetics scientifically. Mendel studied "trait inheritance", patterns in the way traits are handed down from parents to offspring over time. He observed that organisms inherit traits by way of discrete "units of inheritance". This term, still used today, is a somewhat ambiguous definition of what is referred to as a gene.
In genetics, the phenotype is the set of observable characteristics or traits of an organism. The term covers the organism's morphology, its developmental processes, its biochemical and physiological properties, its behavior, and the products of behavior. An organism's phenotype results from two basic factors: the expression of an organism's genetic code and the influence of environmental factors. Both factors may interact, further affecting the phenotype. When two or more clearly different phenotypes exist in the same population of a species, the species is called polymorphic. A well-documented example of polymorphism is Labrador Retriever coloring; while the coat color depends on many genes, it is clearly seen in the environment as yellow, black, and brown. Richard Dawkins in 1978 and then again in his 1982 book The Extended Phenotype suggested that one can regard bird nests and other built structures such as caddisfly larva cases and beaver dams as "extended phenotypes".
Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be more linked than markers that are far apart. In other words, the nearer two genes are on a chromosome, the lower the chance of recombination between them, and the more likely they are to be inherited together. Markers on different chromosomes are perfectly unlinked, although the penetrance of potentially deleterious alleles may be influenced by the presence of other alleles, and these other alleles may be located on other chromosomes than that on which a particular potentially deleterious allele is located.
Molecular genetics is a branch of biology that addresses how differences in the structures or expression of DNA molecules manifests as variation among organisms. Molecular genetics often applies an "investigative approach" to determine the structure and/or function of genes in an organism's genome using genetic screens.
A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen. Genetic screens can provide important information on gene function as well as the molecular events that underlie a biological process or pathway. While genome projects have identified an extensive inventory of genes in many different organisms, genetic screens can provide valuable insight as to how those genes function.
Forward genetics is a molecular genetics approach of determining the genetic basis responsible for a phenotype. Forward genetics provides an unbiased approach because it relies heavily on identifying the genes or genetic factors that cause a particular phenotype or trait of interest.
Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic gene may have an effect on several traits simultaneously, due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.
Human genetics is the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counseling.
The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.
Psychiatric genetics is a subfield of behavioral neurogenetics and behavioral genetics which studies the role of genetics in the development of mental disorders. The basic principle behind psychiatric genetics is that genetic polymorphisms are part of the causation of psychiatric disorders.
A phene is an individual genetically determined characteristic or trait which can be possessed by an organism, such as eye colour, height, behavior, tooth shape or any other observable characteristic.
Disrupted in schizophrenia 1 is a protein that in humans is encoded by the DISC1 gene. In coordination with a wide array of interacting partners, DISC1 has been shown to participate in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, mitochondrial transport, fission and/or fusion, and cell-to-cell adhesion. Several studies have shown that unregulated expression or altered protein structure of DISC1 may predispose individuals to the development of schizophrenia, clinical depression, bipolar disorder, and other psychiatric conditions. The cellular functions that are disrupted by permutations in DISC1, which lead to the development of these disorders, have yet to be clearly defined and are the subject of current ongoing research. Although, recent genetic studies of large schizophrenia cohorts have failed to implicate DISC1 as a risk gene at the gene level, the DISC1 interactome gene set was associated with schizophrenia, showing evidence from genome-wide association studies of the role of DISC1 and interacting partners in schizophrenia susceptibility.
Gamma-aminobutyric acid receptor subunit alpha-2 is a protein in humans that is encoded by the GABRA2 gene.
Neurogenomics is the study of how the genome of an organism influences the development and function of its nervous system. This field intends to unite functional genomics and neurobiology in order to understand the nervous system as a whole from a genomic perspective.
Behavioural genetics, also referred to as behaviour genetics, is a field of scientific research that uses genetic methods to investigate the nature and origins of individual differences in behaviour. While the name "behavioural genetics" connotes a focus on genetic influences, the field broadly investigates the extent to which genetic and environmental factors influence individual differences, and the development of research designs that can remove the confounding of genes and environment. Behavioural genetics was founded as a scientific discipline by Francis Galton in the late 19th century, only to be discredited through association with eugenics movements before and during World War II. In the latter half of the 20th century, the field saw renewed prominence with research on inheritance of behaviour and mental illness in humans, as well as research on genetically informative model organisms through selective breeding and crosses. In the late 20th and early 21st centuries, technological advances in molecular genetics made it possible to measure and modify the genome directly. This led to major advances in model organism research and in human studies, leading to new scientific discoveries.
Andrew B. Singleton is a British neurogeneticist currently working in the USA. He was born in Guernsey, the Channel Islands in 1972, where he lived until he was 18 years old. His secondary education was conducted at the Guernsey Grammar School. He earned a first class degree in Applied Physiology from Sunderland University and his PhD in neuroscience from the University of Newcastle upon Tyne where he studied the genetics of Alzheimer's disease and other dementias at the Medical Research Council (MRC) Neurochemical Pathology Unit. He moved to the United States in 1999, where he began working at the Mayo Clinic in Jacksonville, Florida studying the genetic basis of Parkinson's disease, ataxia, and dystonia. He moved to the National Institutes of Health in 2001 to head the newly formed Molecular Genetics unit within the Laboratory of Neurogenetics. In 2006 he took over as Chief of the Laboratory of Neurogenetics and became an NIH Distinguished Investigator in the intramural program at the National Institute on Aging (NIA) in 2017. In 2020 he stepped down as the Chief of the Laboratory of Neurogenetics and became the Acting Director of the newly formed Center for Alzheimer's and Related Dementias at the NIA. In 2021 he became the Director of CARD.
Cognitive genomics is the sub-field of genomics pertaining to cognitive function in which the genes and non-coding sequences of an organism's genome related to the health and activity of the brain are studied. By applying comparative genomics, the genomes of multiple species are compared in order to identify genetic and phenotypical differences between species. Observed phenotypical characteristics related to the neurological function include behavior, personality, neuroanatomy, and neuropathology. The theory behind cognitive genomics is based on elements of genetics, evolutionary biology, molecular biology, cognitive psychology, behavioral psychology, and neurophysiology.
The missing heritability problem arises from the difference between heritability estimates from genetic data and heritability estimates from twin and family data across many physical and mental traits, including diseases, behaviors, and other phenotypes. This is a problem that has significant implications for medicine, since a person's susceptibility to disease may depend more on the combined effect of all the genes in the background than on the disease genes in the foreground, or the role of genes may have been severely overestimated.
Locus heterogeneity occurs when mutations at multiple genomic loci are capable of producing the same phenotype, and each individual mutation is sufficient to cause the specific phenotype independently. Locus heterogeneity should not be confused with allelic heterogeneity, in which a single phenotype can be produced by multiple mutations, all of which are at the same locus on a chromosome. Likewise, it should not be confused with phenotypic heterogeneity, in which different phenotypes arise among organisms with identical genotypes and environmental conditions. Locus heterogeneity and allelic heterogeneity are the two components of genetic heterogeneity.