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 studied in the context of neurogenetics. The field
of neurogenetics emerged in the mid to late 1900s with advances closely
following advancements made in available technology. Currently,
neurogenetics is the center of much research utilizing cutting edge
techniques.
History
The field of neurogenetics emerged from advances made in molecular
biology, genetics and a desire to understand the link between genes,
behavior, the brain, and neurological disorders and diseases. The field
started to expand in the 1960s through the research of Seymour Benzer, considered by some to be the father of neurogenetics.
Seymour Benzer in his office at Caltech in 1974 with a big model of Drosophila
His pioneering work with Drosophila
helped to elucidate the link between circadian rhythms and genes, which
led to further investigations into other behavior traits. He also
started conducting research in neurodegeneration in fruit flies in an
attempt to discover ways to suppress neurological diseases in humans.
Many of the techniques he used and conclusions he drew would drive the
field forward.
Early analysis relied on statistical interpretation through processes such as LOD (logarithm of odds) scores of pedigrees and other observational methods such as affected sib-pairs, which looks at phenotype and IBD (identity by descent) configuration. Many of the disorders studied early on including Alzheimer's, Huntington's and amyotrophic lateral sclerosis (ALS) are still at the center of much research to this day. By the late 1980s new advances in genetics such as recombinant DNA technology and reverse genetics allowed for the broader use of DNA polymorphisms to test for linkage between DNA and gene defects. This process is referred to sometimes as linkage analysis.
By the 1990s ever advancing technology had made genetic analysis more
feasible and available. This decade saw a marked increase in identifying
the specific role genes played in relation to neurological disorders.
Advancements were made in but not limited to: Fragile X syndrome, Alzheimer's, Parkinson's, epilepsy and ALS.
Neurological disorders
While
the genetic basis of simple diseases and disorders has been accurately
pinpointed, the genetics behind more complex, neurological disorders is
still a source of ongoing research. New developments such as the genome wide association studies
(GWAS) have brought vast new resources within grasp. With this new
information genetic variability within the human population and possibly
linked diseases can be more readily discerned. Neurodegenerative diseases are a more common subset of neurological disorders, with examples being Alzheimer's disease and Parkinson's disease.
Currently no viable treatments exist that actually reverse the
progression of neurodegenerative diseases; however, neurogenetics is
emerging as one field that might yield a causative connection. The
discovery of linkages could then lead to therapeutic drugs, which could
reverse brain degeneration.
Gene sequencing
One
of the most noticeable results of further research into neurogenetics
is a greater knowledge of gene loci that show linkage to neurological
diseases. The table below represents a sampling of specific gene
locations identified to play a role in selected neurological diseases
based on prevalence in the United States.
| Gene loci | Neurological disease |
|---|---|
| APOE ε4, PICALM | Alzheimer's disease |
| DR15, DQ6 | Multiple sclerosis |
| LRRK2, PARK2, PARK7 | Parkinson's disease |
| HTT[12] | Huntington's disease |
Methods of research
Statistical analysis
Logarithm of odds (LOD)
is a statistical technique used to estimate the probability of gene
linkage between traits. LOD is often used in conjunction with pedigrees,
maps of a family's genetic make-up, in order to yield more accurate
estimations. A key benefit of this technique is its ability to give
reliable results in both large and small sample sizes, which is a marked
advantage in laboratory research.
Quantitative trait loci (QTL)
mapping is another statistical method used to determine the chromosomal
positions of a set of genes responsible for a given trait. By
identifying specific genetic markers for the genes of interest in a recombinant inbred strain,
the amount of interaction between these genes and their relation to the
observed phenotype can be determined through complex statistical
analysis.
In a neurogenetics laboratory, the phenotype of a model organisms is
observed by assessing the morphology of their brain through thin slices. QTL mapping can also be carried out in humans, though brain morphologies are examined using nuclear magnetic resonance imaging (MRI)
rather than brain slices. Human beings pose a greater challenge for QTL
analysis because the genetic population cannot be as carefully
controlled as that of an inbred recombinant population, which can result
in sources of statistical error.
Recombinant DNA
Recombinant DNA
is an important method of research in many fields, including
neurogenetics. It is used to make alterations to an organism's genome,
usually causing it to over- or under-express a certain gene of interest,
or express a mutated form of it. The results of these experiments can
provide information on that gene's role in the organism's body, and it
importance in survival and fitness. The hosts are then screened with the
aid of a toxic drug that the selectable marker is resistant to. The use
of recombinant DNA is an example of a reverse genetics, where
researchers create a mutant genotype and analyze the resulting
phenotype. In forward genetics, an organism with a particular phenotype is identified first, and its genotype is then analyzed.
Animal research
Drosophila
Zebrafish
Model organisms are an important tool in many areas of research,
including the field of neurogenetics. By studying creatures with
simpler nervous systems and with smaller genomes, scientists can better
understand their biological processes and apply them to more complex
organisms, such as humans. Due to their low-maintenance and highly
mapped genomes, mice, Drosophila, and C. elegans are very common. Zebrafish and prairie voles have also become more common, especially in the social and behavioral scopes of neurogenetics.
In addition to examining how genetic mutations affect the actual
structure of the brain, researchers in neurogenetics also examine how
these mutations affect cognition and behavior. One method of examining
this involves purposely engineering model organisms with mutations of
certain genes of interest. These animals are then classically
conditioned to perform certain types of tasks, such as pulling a lever
in order to gain a reward. The speed of their learning, the retention of
the learned behavior, and other factors are then compared to the
results of healthy organisms to determine what kind of an effect – if
any – the mutation has had on these higher processes. The results of
this research can help identify genes that may be associated with
conditions involving cognitive and learning deficiencies.
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 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.
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. 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, to try to determine specific genes that correlate to behavior and attempt to match these with human genes.
Cross-species gene conservation
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.
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.
Aggression
There is also research being conducted on how an individual's genes can cause varying levels of aggression and aggression control.
Outward displays of aggression are seen in most animals
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. For some species varying levels of aggression have indeed exhibited direct correlation to a higher level of Darwinian fitness.
Development
Shh and BMP gradient in the neural tube
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.
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.
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. 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. These are just a few examples of what current research in the field of neurogenetics has achieved.
