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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 Functional genomics is a field of molecular biology that attempts to describe gene (and protein) functions and interactions. Functional genomics make use of the vast data generated by genomic and transcriptomic projects (such as genome sequen ...
and
neurobiology Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions, and its disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, ...
in order to understand the nervous system as a whole from a genomic perspective. The nervous system in vertebrates is made up of two major types of cells – neuroglial cells and
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s. Hundreds of different types of neurons exist in humans, with varying functions – some of them process external stimuli; others generate a response to stimuli; others organize in centralized structures (
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
, spinal ganglia) that are responsible for cognition, perception, and regulation of motor functions. Neurons in these centralized locations tend to organize in giant networks and communicate extensively with each other. Prior to the availability of expression arrays and DNA sequencing methodologies, researchers sought to understand the cellular behaviour of neurons (including synapse formation and neuronal development and regionalization in the human nervous system) in terms of the underlying molecular biology and biochemistry, without any understanding of the influence of a neuron's genome on its development and behaviour. As our understanding of the genome has expanded, the role of networks of gene interactions in the maintenance of neuronal function and behaviour has garnered interest in the
neuroscience Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions, and its disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, ...
research community. Neurogenomics allows scientists to study the nervous system of organisms in the context of these underlying regulatory and transcriptional networks. This approach is distinct from
neurogenetics 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 ba ...
, which emphasizes the role of single genes without a network-interaction context when studying the nervous system.


Approaches


Advent of high-throughput biology

In 1999, Cirelli & Tononi first reported the association of genome-wide brain gene expression profiling (using
microarray A microarray is a multiplex (assay), multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of biological interactions. It is a two-dimensional array on a Substrate (materials science), solid substrate—usu ...
s) with a behavioural phenotype in mice. Since then, global brain gene expression data, derived from microarrays, has been aligned to various behavioural quantitative trait loci (QTLs) and reported in several publications. However, microarray based approaches have their own problems that confound analysis – probe saturation can result in very small measurable variance of gene expression between genetically unique individuals, and the presence of single nucleotide polymorphisms (SNPs) can result in hybridization artifacts. Furthermore, due to their probe-based nature, microarrays can miss out on many types of transcripts (
ncRNAs A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-cod ...
,
miRNAs Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23  nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-trans ...
, and
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
). Probes can also have species-specific binding affinities that can confound comparative analysis. Notably, the association between behavioural patterns and high
penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the pr ...
single gene loci falls under the purview of
neurogenetics 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 ba ...
research, wherein the focus is to identify a simple causative relationship between a single, high penetrance gene and an observed function/behaviour. However, it has been shown that several neurological diseases tend to be
polygenic A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type ...
, being influenced by multiple different
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s and
regulatory regions A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the Gene expression, expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living o ...
instead of one gene alone. There has hence been a shift from single gene approaches to network approaches for studying neurological development and diseases, a shift that has been greatly propelled by the advent of
next generation sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, thymine, cytosine, and guanine. The ...
methodologies.


Next-generation sequencing approaches

Twin studies Twin studies are studies conducted on Identical twin, identical or Fraternal twin, fraternal twins. They aim to reveal the importance of environmental and genetics, genetic influences for traits, phenotypes, and disorders. Twin research is consid ...
have revealed that
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
,
bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...
,
autism spectrum disorder Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...
(ASD), and
attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...
(ADHD) are highly heritable, genetically complex
psychiatric disorders A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...
. However, linkage studies have largely failed at identifying causative variants for psychiatric disorders such as these, primarily because of their complex genetic architecture. Multiple low penetrance risk variants can be aggregated in affected individuals and families, and sets of causative variants could vary across families. Studies along these lines have determined a
polygenic A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type ...
basis for several
psychiatric disorders A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...
. Several independently occurring ''
de novo mutation A de novo mutation (DNM) is any mutation or alteration in the genome of an individual organism (human, animal, plant, microbe, etc.) that was not inherited from its parents. This type of mutation spontaneously occurs during the process of DNA repl ...
s'' in patients
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
have been found to disrupt a shared set of functional pathways involved with neuronal signalling, for example. The quest to understand the causative biology of psychiatric disorders is hence greatly assisted by the ability to analyse entire genomes of affected and unaffected individuals in an unbiased manner. With the availability of massively parallel
next generation sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, thymine, cytosine, and guanine. The ...
methodologies, scientists have been able to look beyond the probe based captures of expressed genes.
RNA-seq RNA-Seq (named as an abbreviation of RNA sequencing) is a technique that uses next-generation sequencing to reveal the presence and quantity of RNA molecules in a biological sample, providing a snapshot of gene expression in the sample, also k ...
, for example, identifies 25-60% more expressed genes than microarrays do. In the upcoming field of neurogenomics, it is hoped that by understanding the genomic profiles of different parts of the brain, we might be able to improve our understanding of how the interactions between genes and pathways influence cellular function and development. This approach is expected to be able to identify the secondary gene networks that are disrupted in neurological disorders, subsequently assisting drug development stratagems for brain diseases. The
BRAIN initiative The White House BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies) is a collaborative, public-private research initiative announced by the Obama administration on April 2, 2013, with the goal of supporting the devel ...
launched in 2013, for example, seeks to "''inform the development of future treatments for brain disorders, including Alzheimer's disease, epilepsy, and traumatic brain injury''" . Rare variant association studies (RVAS) have highlighted the role of ''
de novo De novo (Latin, , used in English to mean 'from the beginning', 'anew') may refer to: Science and computers * ''De novo'' mutation, a new germline mutation not inherited from either parent * ''De novo'' protein design, the creation of a protei ...
''
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
in several
congenital A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
and early-childhood-onset disorders like
autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...
. Several of these protein disrupting mutations have been able to be identified only with the aid of
whole genome sequencing Whole genome sequencing (WGS), also known as full genome sequencing or just genome sequencing, is the process of determining the entirety of the DNA sequence of an organism's genome at a single time. This entails sequencing all of an organism's ...
efforts, and validated with
RNA-Seq RNA-Seq (named as an abbreviation of RNA sequencing) is a technique that uses next-generation sequencing to reveal the presence and quantity of RNA molecules in a biological sample, providing a snapshot of gene expression in the sample, also k ...
. Additionally, these mutations are not statistically enriched in individual genes, but rather, exhibit patterns of statistical enrichment in groups of genes associated with networks regulating neurological development and maintenance. Such a discovery would have been impossible with prior gene-centric approaches (
neurogenetics 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 ba ...
,
behavioural neuroscience Behavioral neuroscience, also known as biological psychology, biopsychology, or psychobiology,Psychobi ...
). Neurogenomics allows for a high-throughput system-based approach for understanding the
polygenic A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type ...
basis of
neuropsychiatric Neuropsychiatry is a branch of medicine that deals with psychiatry as it relates to neurology, in an effort to understand and attribute behavior to the interaction of neurobiology and social psychology factors. Within neuropsychiatry, the mind i ...
disorders.


Imaging studies and optical mapping

When
autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...
was identified as a distinct biological disorder in the 1980s, researchers found that autistic individuals showed a brain growth abnormality in the
cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...
in their early developmental years. Subsequent research has indicated that 90% of autistic children have a larger brain volume than their peers by 2 to 4 years of age, and show an expansion in the white and gray matter content in the
cerebrum The cerebrum (: cerebra), telencephalon or endbrain is the largest part of the brain, containing the cerebral cortex (of the two cerebral hemispheres) as well as several subcortical structures, including the hippocampus, basal ganglia, and olfac ...
. The white and gray matter in the cerebrum is associated with learning and cognition respectively, and the formation of
amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degeneration (medical), Degenerative neuronal ...
in the white matter has been associated with
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. These findings highlighted the influence of structural variance in the brain on psychiatric disorders, and have motivated the use of imaging technologies to map regions of divergence between healthy and diseased brains. Furthermore, while it may not always be possible to retrieve biological specimens from different areas live human brains,
neuroimaging Neuroimaging is the use of quantitative (computational) techniques to study the neuroanatomy, structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive ...
techniques offer a noninvasive means to understanding the biological basis of neurological disorders. It is hoped that an understanding of localization patterns of different psychiatric diseases could in turn inform network analysis studies in neurogenomics.


MRI

Structural Magnetic Resonance Imaging (MRI) can be used to identify the structural composition of the brain. Particularly in the context of neurogenomics, MRI has played an extensive role in the study of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
over the past four decades. It was initially used to rule out other causes of
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
, but recent studies indicated the presence of characteristic changes in patients with Alzheimer's disease. As a result, MRI scans are currently being used as a neuroimaging tool to help identify the temporal and spatial pathophysiology of Alzheimer's disease, such as specific cerebral alterations and amyloid imaging. The ease and non-invasive nature of MRI scans has motivated research projects that trace the development and onset of psychiatric diseases in the brain. Alzheimer disease has become a key candidate in this topographical approach to psychiatric diseases. For example, MRI scans are currently being used to track the resting and task-dependent functional profiles of brains in children with autosomal dominant Alzheimer disease. These studies have found indications of early onset brain alterations in at-risk individuals for Alzheimer's disease. The Autism Center of Excellence at University of California, San Diego, is also conducting MRI studies with children between 12 and 42 months, in the hopes of characterizing brain development abnormalities in children who present behavioural symptoms of autism. Additional research has indicated that there are specifics patterns of
atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...
in the cerebrum (as a repercussion of
neurodegeneration A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their cell death, death. Neurodegenerative diseases include amyotrophic lateral sc ...
) in different neurological disorders and diseases. These disease-specific patterns of progression of atrophy can be identified with MRI scans, and provide a clinical phenotype context to neurogenomic research. The temporal information about disease progression provided by this approach can also potentially inform the interpretation of gene network-level perturbations in psychiatric diseases.


Optical mapping

One prohibitive feature of 2nd generation sequencing methodologies is the upper limit on the genomic range accessible by mate-pairing.
Optical mapping Optical mapping is a technique for constructing ordered, genome-wide, high-resolution restriction maps from single, stained molecules of DNA, called "optical maps". By mapping the location of restriction enzyme sites along the unknown DNA of an or ...
is an emerging methodology used to span large-scale variants that cannot usually be detected using paired end reads. This approach has been successfully applied to detect
structural variants Genomic structural variation is the variation in structure of an organism's chromosome, such as deletions, duplications, copy-number variants, insertions, inversions and translocations. Originally, a structure variation affects a sequence length ab ...
in
oligodendroglioma Oligodendrogliomas are a type of glioma that are believed to originate from the oligodendrocytes of the brain or from a oligodendrocyte progenitor cell, glial precursor cell. They occur primarily in adults (9.4% of all primary brain and central ne ...
, a type of brain cancer. Recent work has also highlighted the versatility of optical maps in improving existing genome assemblies.
Chromosomal rearrangement In genetics, a chromosomal rearrangement is a mutation that is a type of chromosome abnormality involving a change in the structure of the native chromosome. Such changes may involve several different classes of events, like deletions, duplicati ...
s,
microdeletion In genetics, a deletion (also called gene deletion, deficiency, or Deletion anomaly, deletion mutation) (sign: delta (letter), Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA rep ...
s, and large-scale
translocations In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes "balanced" and "unbalanced" translocation, with three main types: "reciprocal", "nonreciprocal" and "Robertsonian" transloc ...
have been associated with impaired neurological and
cognitive function Cognitive skills are skills of the mind, as opposed to other types of skills such as motor skills, social skills or life skills. Some examples of cognitive skills are literacy, self-reflection, logical reasoning, abstract thinking, critical th ...
, for example in hereditary
neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
and
neurofibromatosis Neurofibromatosis (NF) refers to a group of three distinct genetic conditions in which tumors grow in the nervous system. The tumors are non-cancerous (benign) and often involve the skin or surrounding bone. Although symptoms are often mild, e ...
. Optical mapping can significantly improve variant detection and inform gene interaction network models for the diseased state in neurological disorders.


Studying other brain diseases

Apart from neurological disorders, there are additional diseases that manifest in the brain and have formed exemplar use-case scenarios for the application of brain imaging in network analysis. In a classic example of imaging-genomic analyses, a research study in 2012 compared MRI scans and gene expression profiles of 104 glioma patients in order to distinguish treatment outcomes and identify novel targetable genomic pathways in
Glioblastoma Multiforme Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nons ...
(GBM). Researchers found two distinct groups of patients with significantly different organization of
white matter White matter refers to areas of the central nervous system that are mainly made up of myelinated axons, also called Nerve tract, tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distr ...
(invasive vs non-invasive). Subsequent pathway analysis of the gene expression data indicated mitochondrial dysfunction as the top canonical pathway in an aggressive, low-mortality GBM phenotype. Expansion of brain imaging approaches to other diseases can be used to rule out other medical illnesses while diagnosing psychiatric disorders, but cannot be used to inform the presence or absence of a psychiatric disorder.


Research developmental models


In humans

The current approaches in collecting gene expression data in human brains are to use either
microarray A microarray is a multiplex (assay), multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of biological interactions. It is a two-dimensional array on a Substrate (materials science), solid substrate—usu ...
s or
RNA-seq RNA-Seq (named as an abbreviation of RNA sequencing) is a technique that uses next-generation sequencing to reveal the presence and quantity of RNA molecules in a biological sample, providing a snapshot of gene expression in the sample, also k ...
. Currently, it is rare to gather "live" brain tissue – only when treatments involve brain surgery is there a chance that brain tissue is collected during the procedure. This is the case with epilepsy. Currently, gene expression data is usually collected on post mortem brains and this is often a barrier to neurogenomics research in humans. After death, the amount of time between death and when the data from the post mortem brain is collected is known as the
post mortem interval The post-mortem interval (PMI) is the time that has elapsed since an individual's death. When the time of death is not known, the interval may be estimated, and so an approximate time of death established. Postmortem interval estimations can ra ...
(PMI). Since RNA degrades after death, a fresh brain is optimal – but not always available. This in turn can influence a variety of downstream analyses. Consideration should be taken of the following factors when working with 'omics data collected from post-mortem brains: * Ideally, human brains should be controlled for PMIs for a given study. * The cause of death is also an important variable to consider in the collection of human brain samples for the purposes of neurogenomics research. For example, brain samples of individuals with clinical depression are often collected after suicide. Certain conditions of death, such as drug overdose or self-inflicted gunshot, will alter the expression of the brain. * Another issue with studying gene expression in brains is the cellular heterogeneity of brain tissue samples. Bulk brain samples may vary in proportions of specific cell populations from case to case. This can impact the gene expression signatures and may significantly change differential expression analysis. ** One approach to address this issue is to use single cell RNA-seq. This would control for a specific cell type. However, this solution is only applicable where studies are not cell-type specific.
Differential diagnosis In healthcare, a differential diagnosis (DDx) is a method of analysis that distinguishes a particular disease or condition from others that present with similar clinical features. Differential diagnostic procedures are used by clinicians to di ...
also remains a critical pre-analytical confounder of cohort-wide studies of spectrum neurological disorders. Specifically, this has been noted to be a problem for Alzheimer's disease and autism spectrum disorder studies. Furthermore, as our understanding of the diverse symptoms and genomic underpinnings of various neurogenomic disorders improves, the diagnostic criteria itself undergoes rearrangements and review.


Animal models

Ongoing genomics research in neurological disorders tends to use animal models (and corresponding gene homologs) to understand the network interactions underlying a particular disorder due to ethical issues surrounding the retrieval of biological specimens from live human brains. This, too, is not without its roadblocks. Neurogenomic research with a model organism is contingent on the availability of a fully sequenced and annotated reference genome. Additionally, the RNA profiles (
miRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcri ...
,
ncRNA A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-co ...
,
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
) of the model organism need to be well catalogued, and any inferences applied from them to humans must have a basis in functional/sequence homology.


Zebrafish

Zebrafish The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...
development relies on gene networks that are highly conserved among all
vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...
s. Additionally, with an extremely well annotated set of 12,000 genes and 1,000 early development mutants that are actually visible in the optically clear zebrafish embryos and larvae, zebrafish offer a sophisticated system for
mutagenesis Mutagenesis () is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using lab ...
and real-time imaging of developing pathologies. This early development model has been employed to study the nervous system at cellular resolution. The zebrafish model system has already been used to study
neuroregeneration Neuroregeneration is the regrowth or repair of nervous tissues, cells or cell products. Neuroregenerative mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous ...
and severe
polygenic A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type ...
human diseases like cancer and heart disease. Several zebrafish mutants with behavioural variations in response to cocaine and alcohol dosage have been isolated and can also form a basis for studying the pathogenesis of behavioural disorders.


Rodent

Rodent models have been preeminent in studying human disorders. These models have been extensively annotated with gene homologs of several monogenic disorders in humans.
Knockout studies Gene knockouts (also known as gene deletion or gene inactivation) are a widely used genetic engineering technique that involves the targeted removal or inactivation of a specific gene within an organism's genome. This can be done through a variet ...
of these homologs have led to expansion of our understanding of network interactions of genes in human tissues. For example, the ''
FMR1 ''FMR1'' (Fragile X Messenger Ribonucleoprotein 1) is a human gene that codes for a protein called ''fragile X messenger ribonucleoprotein'', or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive developmen ...
'' gene has been implicated with autism from a number of network studies. Using a knockout of '' FMR'' 1 in mice creates the model for
Fragile X Syndrome Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...
, one of the disorders in the
Autism spectrum Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...
. Mice
xenografts Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another.anti-psychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizoph ...
drugs. The development of animal models for complex psychiatric diseases has also improved over the last few years. Rodent models have demonstrated behavioural phenotype changes resembling a positive
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
state, either after genetic manipulation or after treatment with drugs that target the areas of the brain suspected to influence hyperactivity or neurodevelopment. Interest has been generated in identifying the network disruptions mediated by these laboratory manipulations, and collection of genomic data from
rodent studies Rodents have been employed in biomedical experimentation from the 1650s. Rodent studies up to the early 19th century were mainly physiological or toxicological. The first rodent behavioral study was carried out in 1822, a purely observational st ...
has contributed significantly to a better understanding of the genomics of psychiatric diseases. The first
mouse brain A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...
transcriptome The transcriptome is the set of all RNA transcripts, including coding and non-coding, in an individual or a population of cells. The term can also sometimes be used to refer to all RNAs, or just mRNA, depending on the particular experiment. The ...
was generated in 2008. Since then, extensive work has been done with building social-stress mice models to study the pathway level expression signatures of various psychiatric diseases. A recent paper simulated features of Post Traumatic Stress Disorder (PTSD) in mice, and profiled the entire transcriptome of these mice. The authors found differential regulation in many biological pathways, some of which were implicated in anxiety disorders (
hyperactivity Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple ...
,
fear response Fear is an unpleasant emotion that arises in response to perceived dangers or threats. Fear causes physiological and psychological changes. It may produce behavioral reactions such as mounting an aggressive response or fleeing the threat, com ...
), mood disorders, and impaired cognition. These findings are backed by extensive transcriptomic analyses of anxiety disorders, and expression level changes in biological pathways involved with fear learning and memory are thought to contribute to the behavioural manifestations of these disorders. It is thought that functional enrichment of genes involved in long term synaptic potentiation, depression, and plasticity has an important role to play in the acquisition, consolidation, and maintenance of traumatic memories underlying anxiety disorders.


Experimental mice models for psychiatric disorders

A common approach to using a mouse model is to apply an experimental treatment to a pregnant mouse in order to affect a whole litter. However, a key issue in the field is the treatment of litters in a statistical analysis. Most studies consider the total number of offspring produced as that may lead to an increase in statistical power. However, the correct way is to count by the number of litters and to normalize based on litter size. It was found that several autism studies incorrectly performed their statistical analyses based on total number of offspring instead of number of litters. Several anxiety disorders such as
post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental disorder that develops from experiencing a Psychological trauma, traumatic event, such as sexual assault, domestic violence, child abuse, warfare and its associated traumas, natural disaster ...
(PTSD) involve
heterogeneous Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...
changes in several different brain regions, such as the
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
,
amygdala The amygdala (; : amygdalae or amygdalas; also '; Latin from Greek language, Greek, , ', 'almond', 'tonsil') is a paired nucleus (neuroanatomy), nuclear complex present in the Cerebral hemisphere, cerebral hemispheres of vertebrates. It is c ...
, and
nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for ' nucleus adjacent to the septum') is a region in the basal forebrain rostral to the preoptic area of the hypo ...
. The cellular encoding of traumatic events and the behavioral responses triggered by such events has been shown to lie primarily in changes in signaling molecules associated with
synaptic transmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron) ...
. Global
gene expression profiling In the field of molecular biology, gene expression profiling is the measurement of the activity (the gene expression, expression) of thousands of genes at once, to create a global picture of cellular function. These profiles can, for example, dis ...
of the various gene regions implicated in fear and anxiety processing, using mice models, has led to the identification of temporally and spatially distinct sets of differentially expressed genes. Pathway analysis of these genes has indicated possible roles in
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...
and anxiety-related behavioural responses, alongside other functional and phenotypic observations. Mice models for brain research have contributed significantly to
drug development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regu ...
and increased our understanding of the genomic underpinnings of several neurological diseases in the last generation.
Chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...
, the first
antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
drug (discovered in 1951), was identified as a viable treatment option after it was shown to suppress response to aversive stimuli in rats in a behavioural screen.


Challenges

The modelling and assessment of latent symptoms (thoughts, verbal learning, social interactions, cognitive behaviour) remains a challenge when using model organisms to study
psychiatric disorders A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...
with a complex genetic
pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
. For example, a given genotype+phenotype in a mouse model must imitate the genomic underpinnings of a phenotype observed in a human. This is a particularly crucial item of consideration in spectrum disorders such as
autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...
. Autism is a disorder whose symptoms can be divided into two categories: (i) deficits of social interactions and (ii) repetitive behaviours and restricted interests. Since mice tend to be more social creatures amongst all members of the order ''
Rodent Rodents (from Latin , 'to gnaw') are mammals of the Order (biology), order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and Mandible, lower jaws. About 40% of all mammal specie ...
ia'' currently being used as model organisms, mice are generally used to model human psychiatric disorders as closely as possible. Particularly for autism, the following work-arounds are currently in place to emulate human behavioural symptoms: * For the first diagnostic category of impaired social behaviour, mice are subject to a social assay intended to represent typical autistic social deficits. Normal social behaviour for mice includes sniffing, following, physical contact and
allogrooming Social grooming is a behavior in which social animals, including humans, clean or maintain one another's bodies or appearances. A related term, allogrooming, indicates social grooming between members of the same species. Grooming is a major s ...
. Vocal communication could be used as well. * There are a number of ways the second diagnostic category can be observed in mice. Examples of repetitive behaviours can include excessive circling, self-grooming and excessive digging. Usually these behaviours would be performed consistently within a long measurement of time (i.e. self-grooming for 10 minutes). ** While repetitive behaviours are easily observable, it is difficult to characterize actual restricted interests of mice. One aspect of restricted interests of autistic individuals is the "insistence of sameness"—the concept that autistic individuals require their environment to remain consistent. If that environment should change, the individual would experience stress and anxiety. There has been reported success in confirming a mouse model of autism by changing the mouse's environment. In any of these experiments, the 'autistic' mice have a 'normal' socializing partner and the scientists observing the mice are unaware ("blind") to the genotypes of the mice.


Gene expression in the brain

The gene expression profile of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(CNS) is unique. Eighty percent of all human genes are expressed in the brain; 5,000 of these genes are solely expressed in the CNS. The human brain has the highest amount of gene expression of all studied mammalian brains. In comparison, tissues outside of the brain will have more similar expression levels in comparison to their mammalian counterparts. One source of the increased expression levels in the human brain is from the non-protein coding region of the genome. Numerous studies have indicated that the human brain have a higher level of expression in regulatory regions in comparison to other mammalian brains. There is also notable enrichment for more
alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
events in the human brain.


Spatial differences

Gene expression profiles also vary within specific regions of the brain. A microarray study showed that the transcriptome profile of the CNS clusters together based on region. A different study characterized the regulation of gene expression across 10 different regions based on their
eQTL An expression quantitative trait locus (eQTL) is a type of quantitative trait locus (QTL), a genomic locus (region of DNA) that is associated with phenotypic variation for a specific, quantifiable trait. While the term QTL can refer to a wide ran ...
signals. The cause of the varying expression profiles relates to function, neuron migration and cellular heterogeneity of the region. Even the three layers of the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
have distinct expression profiles. A study completed at Harvard Medical School in 2014 was able to identify developmental lineages stemming from single base neuronal mutations. The researchers sequenced 36 neurons from the cerebral cortex of three normal individuals, and found that highly expressed genes, and neural associated genes, were significantly enriched for single-neuron SNVs. These SNVs, in turn, were found to be correlated with chromatin markers of transcription from fetal brain.


Development patterns in humans

Gene expression of the brain changes throughout the different phases of life. The most significant levels of expression are found during early development, with the rate of gene expression being highest during fetal development. This results from the rapid growth of neurons in the embryo. Neurons at this stage are undergoing neuronal differentiation,
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...
, migration events and dendritic and synaptic development. Gene expression patterns shift closer towards specialized functional profiles during embryonic development, however, certain developmental steps are still ongoing at parturition. Consequently, gene expression profiles of the two brain hemispheres appear asymmetrical at birth. At birth, gene expression profiles appear asymmetrical between
brain hemispheres The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for special senses s ...
. As development continues, the gene expression profiles become similar between the hemispheres. Given a healthy adult, expression profiles stay relatively consistent from the late twenties into the late forties. From the fifties onwards, there is significant decrease in the expression of genes important for regular function. Despite this, there is an increase in the diversity of genes being expressed across the brain. This age related change in expression may be correlated with
GC content In molecular biology and genetics, GC-content (or guanine-cytosine content) is the percentage of nitrogenous bases in a DNA or RNA molecule that are either guanine (G) or cytosine (C). This measure indicates the proportion of G and C bases out of ...
. At later stages of life, there is an increase in the induction of low GC-content pivotal genes as well as an increase in the repression of high GC-content pivotal genes. Another cause of the shift in gene diversity is the accumulation of mutations and DNA damage. Gene expression studies show that genes that accrue these age-related mutations are consistent between individuals in the aging population. Genes that are highly expressed at development decrease significantly at late stages in life, whereas genes that are highly repressed at development increase significantly at the late stages.


Evolution of the mammalian brain

The evolution of ''
Homo sapiens Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...
'' since the divergence from the primate common ancestor has shown a marked expansion in the size and complexity of the brain, especially in the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
. In comparison to
primate Primates is an order (biology), order of mammals, which is further divided into the Strepsirrhini, strepsirrhines, which include lemurs, galagos, and Lorisidae, lorisids; and the Haplorhini, haplorhines, which include Tarsiiformes, tarsiers a ...
s, the human
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
has a larger surface area but differs only slightly in thickness. Many large scale studies in understanding the differences of the human brain from other species have indicated expansion of gene families and changes in
alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
to be responsible for the corollary increase in cognitive capabilities and cooperative behaviour in humans. However, we are yet to determine the exact phenotypic consequences of all these changes. One difficulty is that only primates have developed subdivisions in their cerebral cortex, making the modeling of human specific neurological problems difficult to mimic in
rodent Rodents (from Latin , 'to gnaw') are mammals of the Order (biology), order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and Mandible, lower jaws. About 40% of all mammal specie ...
s. Sequence data is used to understand the evolutionary genetic changes which led to the development of the human CNS. We can then understand how the neurological phenotypes differ between species.
Comparative genomics Comparative genomics is a branch of biological research that examines genome sequences across a spectrum of species, spanning from humans and mice to a diverse array of organisms from bacteria to chimpanzees. This large-scale holistic approach c ...
entails comparison of sequence data across a
phylogeny A phylogenetic tree or phylogeny is a graphical representation which shows the evolutionary history between a set of species or Taxon, taxa during a specific time.Felsenstein J. (2004). ''Inferring Phylogenies'' Sinauer Associates: Sunderland, M ...
to pinpoint the genotypic changes that occur within specific lineages, and understand how these changes might have arisen. The increase in high quality mammalian reference sequences generally makes comparative analysis better as it increases
statistical power In frequentist statistics, power is the probability of detecting a given effect (if that effect actually exists) using a given test in a given context. In typical use, it is a function of the specific test that is used (including the choice of tes ...
. However, the increase in number of species in a
phylogeny A phylogenetic tree or phylogeny is a graphical representation which shows the evolutionary history between a set of species or Taxon, taxa during a specific time.Felsenstein J. (2004). ''Inferring Phylogenies'' Sinauer Associates: Sunderland, M ...
does risk adding unnecessary noise as the alignments of the
orthologous Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...
sequences usually decrease in quality. Furthermore, different classes of species will have significant differences in their phenotypes. Despite this, comparative genomics has allowed us to connect the genetic changes found in a phylogeny to specific pathways. In order to determine this, lineages are tested for the functional changes that accrue over time. This is often measured as a ratio of
nonsynonymous substitution A nonsynonymous substitution is a nucleotide mutation that alters the amino acid sequence of a protein. Nonsynonymous substitutions differ from synonymous substitutions, which do not alter amino acid sequences and are (sometimes) silent mutations. ...
s to
synonymous substitution A synonymous substitution (often called a ''silent'' substitution though they are not always silent) is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence ...
s or the dN/dS ratio (sometimes, further abbreviated to ω). When the dN/dS ratio is greater than 1, this indicates
positive selection In population genetics, directional selection is a type of natural selection in which one extreme phenotype is favored over both the other extreme and moderate phenotypes. This genetic selection causes the allele frequency to shift toward the ...
. A dN/dS ratio equal to 1 is evidence of no selective pressures. A dN/dS ratio less than 1 indicates negative selection. For example, the conserved regions of the genome will generally have a dN/dS ratio of less than 1 since any changes to those positions will likely be detrimental. Of the genes expressed in the human brain, it is estimated that 342 of them have a dN/dS ratio greater than 1 in the human lineage in comparison to other primate lineages. This indicates positive selection on the human lineage for brain phenotypes. Understanding the significance of the
positive selection In population genetics, directional selection is a type of natural selection in which one extreme phenotype is favored over both the other extreme and moderate phenotypes. This genetic selection causes the allele frequency to shift toward the ...
is generally the next step. For example, '' ASPM'', ''
CDK5RAP2 CDK5 regulatory subunit-associated protein 2 is a protein that in humans is encoded by the ''CDK5RAP2'' gene. It has necessary roles in the formation and stability of microtubules from the centrosome and has been found to be linked to human brai ...
'' and '' NIN'' are genes that are positively selected for on the human lineage and have been directly correlated with brain size. This finding may help elucidate why human brains are larger than other mammalian brains.


Network level expression differences between species

It is thought that gene expression changes, being the ultimate response for any genetic changes, are a good proxy for understanding
phenotypic In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
differences within biological samples. Comparative studies have revealed a range of differences in the transcriptional controls between
primate Primates is an order (biology), order of mammals, which is further divided into the Strepsirrhini, strepsirrhines, which include lemurs, galagos, and Lorisidae, lorisids; and the Haplorhini, haplorhines, which include Tarsiiformes, tarsiers a ...
s and
rodent Rodents (from Latin , 'to gnaw') are mammals of the Order (biology), order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and Mandible, lower jaws. About 40% of all mammal specie ...
s. For example, the gene ''
CNTNAP2 Contactin-associated protein-like 2 is a protein that in humans is encoded by the ''CNTNAP2'' gene. This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. Thi ...
'' is specifically enriched for in the
prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...
. The mouse homolog of ''CNTNAP2'' is not expressed in the mouse brain. ''CNTNAP2'' has been implicated in cognitive functions of language as well as
neurodevelopmental disorder Neurodevelopmental disorders are a group of mental conditions negatively affecting the development of the nervous system, which includes the brain and spinal cord. According to the American Psychiatric Association Diagnostic and Statistical Manu ...
s such as Autism Spectrum Disorder. This suggests that the control of expression plays a significant role in the development in unique human cognitive function. As a consequence, a number of studies have investigated the brain specific enhancers.
Transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s such as ''
SOX5 Transcription factor SOX-5 is a protein that in humans is encoded by the ''SOX5'' gene. Function This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development an ...
'' have been found to be positively selected for on the human lineage. Gene expression studies in humans,
chimpanzee The chimpanzee (; ''Pan troglodytes''), also simply known as the chimp, is a species of Hominidae, great ape native to the forests and savannahs of tropical Africa. It has four confirmed subspecies and a fifth proposed one. When its close rel ...
s and
rhesus macaque The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies split between two groups, the Chinese-derived and the Indian-derived. Generally brown or g ...
s, have identified human specific co-expression networks, and an elevation in gene expression in the human cortex in comparison to primates.


Disorders

Neurogenomic disorders manifest themselves as
neurological disorder Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...
s with a complex genetic architecture and a non-Mendelian-like pattern of inheritance. Some examples of these disorders include
Bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...
and
Schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
. Several genes may be involved in the manifestation of the disorder, and mutations in such disorders are generally rare and ''de novo.'' Hence it becomes extremely unlikely to observe the same (potentially causative) variant in two unrelated individuals affected with the same neurogenomic disorder. Ongoing research has implicated several ''
de novo De novo (Latin, , used in English to mean 'from the beginning', 'anew') may refer to: Science and computers * ''De novo'' mutation, a new germline mutation not inherited from either parent * ''De novo'' protein design, the creation of a protei ...
'' exonic variations and structural variations in
Autism Spectrum Disorder Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...
(ASD), for example. The allelic spectrum of the rare and common variants in neurogenomic disorders therefore necessitates a need for large cohort studies in order to effectively exclude low effect variants and identify the overarching pathways frequently mutated in the different disorders, rather than specific genes and specific high penetrance mutations.
Whole genome sequencing Whole genome sequencing (WGS), also known as full genome sequencing or just genome sequencing, is the process of determining the entirety of the DNA sequence of an organism's genome at a single time. This entails sequencing all of an organism's ...
(WGS) and
whole exome sequencing Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome). It consists of two steps: the first step is to select only the subset ...
(WES) has been used in Genome Wide Association Studies (GWAS) to characterize genetic variants associated with neurogenomic disorders. However, the impact of these variants cannot always be verified because of the non-Mendelian inheritance patterns observed in several of these disorders. Another prohibitive feature in network analysis is the lack of large-scale datasets for many psychiatric (neurogenomic) diseases. Since several diseases with neurogenomic underpinnings tend to have a
polygenic A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type ...
basis, several nonspecific, rare, and partially penetrant ''de novo'' mutations in different patients can contribute to the same observed range of phenotypes, as is the case with Autism Spectrum Disorder and schizophrenia. Extensive research in
alcohol dependence Alcohol dependence is a previous (DSM-IV and ICD-10) psychiatric diagnosis in which an individual is physically or psychologically dependent upon alcohol (also chemically known as ethanol). In 2013, it was reclassified as alcohol use disorder ...
has also highlighted the need for high-quality genomic profiling of large sample sets when studying
polygenic A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type ...
,
spectrum disorder A spectrum disorder is a Disease#Disorder, disorder that includes a range of linked conditions, sometimes also extending to include singular symptoms and trait theory, traits. The different elements of a spectrum either have a similar appearance o ...
s. The
1000 Genomes Project The 1000 Genomes Project (1KGP), taken place from January 2008 to 2015, was an international research effort to establish the most detailed catalogue of human genetic variation at the time. Scientists planned to sequence the genomes of at least o ...
was a successful demonstration of how a concerted effort to acquire representative genomic data from the broad spectrum of humans can result in identification of actionable biological insights for different diseases. However, a large-scale initiative like this is still lacking in the field of neurogenomic disorders specifically.


Modelling psychiatric disorders in neurogenomics research – issues

One major
GWAS GWAS may refer to: *Genome-wide association study, study of mutations' correlations with disease or other phenotypic expressions *''gwas'', a Welsh term for a valet * Great Western Ambulance Service, the ambulance service serving Somerset, Gloucest ...
study identified 13 new risk loci for
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
. Studying the impact of these candidates would ideally demonstrate a schizophrenia phenotype in animal models, which is usually difficult to observe due to its manifestation as a latent personality. This approach is able to determine the molecular impact the
candidate gene The candidate gene approach to conducting genetic association studies focuses on associations between genetic variation within pre-specified genes of interest, and Phenotype (clinical medicine), phenotypes or disease states. This is in contrast to ...
. Ideally the candidate genes would have a neurological impact, which in turn would suggest that it plays a role in the neurological disorder. For example, in the aforementioned schizophrenia GWAS study, Ripke and colleagues determined that these candidate genes were all involved in calcium signalling. Alternatively, one can study these variants in model organisms in the context of affected neurological function. It is important to note that the high penetrance variants of these disorders tend to be ''de novo'' mutations. A further complication to studying neurogenomic disorders is the heterogeneous nature of the disorder. In many of these disorders, the mutations observed from case to case do not stay consistent. In autism, an affected individual may experience a large amount of deleterious mutations in gene X. A different affected individual may not have any significant mutations on gene X but have a large amount of mutations in gene Y. The alternative is to determine if gene X and gene Y impact the same biochemical pathway—one that influences a neurological function. A bioinformatics network analysis is one approach to this problem. Network analyses methodologies provide a generalized, systems overview of a molecular pathway. One final complication to consider is the comorbidity of neurogenomic genes. Several disorders, especially at the more severe ends of the spectrum tend to be comorbid with each other. For example, more severe cases of ASD tend to be associated with
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
(ID). This raises the question of whether or not there are true, unique ASD genes and unique ID genes or if there are just genes just associated with neurological function that can be mutated into an abnormal phenotype. One confounding factor may be the actual diagnostic category and methods of the spectrum disorders as symptoms between severe disorders may be similar. One study investigated the comorbid symptoms between groups of ID and ASD, and found no significant difference between the symptoms of ID children, ASD children with ID and ASD children without ID. Future research may help establish a more stringent genetic basis for the diagnoses of these disorders.


Network analysis

The main goal of network analysis in neurogenomics is to identify statistically significant nonrandom associations between genes that contain risk variants. While several algorithm implementations of this approach already exist, the general steps for network analysis remain the same. * The analytical process starts out with the identification of a biological network based on experimental validation. This can be a gene co-expression network, or a protein-protein interaction (PPI) network. The nodes of the network will be clustered. * Subsequently, a specific list of genes with known associations to a particular phenotype of interest is generated. This list could be determined by experimental data, agnostic of genetic studies in psychiatric disorders. This is referred to as a 'hit list'. * Genes that belong to the hit list as well as the biological network selected in the first step are marked as such. * This is followed by a guilt-by-association (GBA) step. This means that clusters within the biological network that have a significant amount of genes from the hit list are investigated further using functional enrichment tools and database querying for the pathways in which these high scoring cluster genes participate * Thus the biological associations of the high-scoring, experimentally implicated cluster members are investigated, expanding the search area from beyond the initial hit list to include gene members of additional pathways that may have significant association with the initial biological network under consideration. This results in a set of candidate genes. The underlying principle of this approach is that the genes that cluster together, will also jointly affect the same molecular pathway. Again, they would ideally be part of a neurological function. The candidate genes can then be used to prioritize variants for wet lab validation.


Neuropharmacology

Historically, due to the behavioural stimulation manifested as a symptom in several the neurogenomic disorders, the therapies would rely mostly on anti-psychotics or antidepressants. These classes of medications would suppress common symptoms of the disorders, but with questionable efficacy. The biggest barrier to neruopharmacogenomic research was the cohort sizes. Given newly available large-cohort sequencing data, there has been a recent push to expand therapeutic options. The heterogenous nature of neurological diseases is the key motivation for personalized medicine approaches to their therapies. It is rare to find single high penetrance causative genes in neurological diseases. The genomic profiles understandably vary between cases, and logically, the therapies would need to vary between cases. Further complicating the issue is that many of these disorders are spectrum disorders. Their genetic etiology will vary within this spectrum. For example, severe ASD is associated with high penetrance de novo mutations. Milder forms of ASD is usually associated with a mixture of common variants. The key issue then is the translation of these newly identified genetic variants (from Copy Number Variant studies, candidate gene sequencing and high throughput sequencing technologies) into an intervention for patients with neurogenomic disorders. One aspect will be if the neurological disorder are medically actionable (i.e. is there a simple metabolic pathway that a therapy can target). For example, specific cases of ASD have been associated with microdeletions on TMLHE gene. This gene codes for the enzyme of
carnitine biosynthesis Carnitine biosynthesis is a method for the endogenous production of L-carnitine, a molecule that is essential for energy metabolism. In humans and many other animals, L-carnitine is obtained from both diet and by biosynthesis. The carnitine biosynth ...
. Supplements to elevate carnitine levels appeared to alleviate certain ASD symptoms but the study was confounded by many influencing factors. As mentioned earlier, using a gene network approach will help identify relevant pathways of interest. Many neuropharmacogenomic approaches have focused on targeting the downstream products of these pathways.


Blood brain barrier

Studies in animal models for several brain diseases has shown that the
blood brain barrier Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is compo ...
(BBB) undergoes modification at many levels; for example, the surface glycoprotein composition can influence the types of HIV-1 strains transported by the BBB. The BBB has been found to be key in the onset of
Alzheimer's Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
disease. It is extremely difficult, however, to be able to study this in humans due to obvious restrictions with accessing the brain and retrieving biological specimens for sequencing or morphological analysis. Mice models of the BBB and models of disease states have served well in conceptualizing the BBB as a regulatory interface between disease and good health in the brain.


Personalized neurobiology

The heterogenous nature of neurological diseases is the key motivation for personalized medicine approaches to their therapies. Genomic samples of individual patients could be used to identify predictive factors, or to better understand the specific prognosis of a neurogenomic disease, and use this information to guide treatment options. While there is a clear clinical utility to this approach, the adaptation of this approach is still nonexistent. There are various issues prohibiting the application of personalized genomics to the assessment, diagnosis, and treatment of psychiatric disorders. * Firstly, the causative network biology of several spectrum disorders with neurogenomic underpinnings is not fully understood yet, in spite of extensive studies conducted with disorders like
Autism Spectrum Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...
and
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
. Thus, the analytical validity of standing hypotheses concerning the etiology of neurogenomic disorders has still not been fully established and is subject to debate and controversy. * The clinical validity of genetic variants that have shown to be highly correlated with specific neurogenomic disorders is often a major cause of concern. The interpretation of these test results, and subsequent decision making, are a complicated undertaking given the polygenic nature of many of these disorders. Complicating things further, it has been shown that pre-emptive intervention in major psychiatric disorders does not always reduce the risk for the disorder. Such intervention might not even be available for at-risk offspring of affected adults, thereby limiting the 'medical actionability' of the data. * Ethical concerns have also been raised regarding the safeguarding of personal genomic information, and how best to approach the burden of incidental findings and family risk assessment. ** Consanguinity and in-breeding can lead to selective enrichment of rare, otherwise low penetrance genetic mutations attributed to various symptoms of neurogenomic disorders. Thus, the interpretation of family-specific genetic mutations and/or network-level disruptions in the onset of a rare psychiatric disorder requires careful consideration of the motivations of participants included in the study. ** That said, these issues can be addressed by effective education and counseling, and collection of genomic data from patients with psychiatric disorders should not be disqualified solely on this basis. The data itself serves as a dynamic health resource and can significantly further our understanding of the genomic basis of several psychiatric disorders.


See also

*
Neuroinformatics Neuroinformatics is the emergent field that combines informatics and neuroscience. Neuroinformatics is related with neuroscience data and information processing by artificial neural networks. There are three main directions where neuroinformatics ...
*
1000 Genomes Project The 1000 Genomes Project (1KGP), taken place from January 2008 to 2015, was an international research effort to establish the most detailed catalogue of human genetic variation at the time. Scientists planned to sequence the genomes of at least o ...
*
Genome-wide association study In genomics, a genome-wide association study (GWA study, or GWAS), is an observational study of a genome-wide set of Single-nucleotide polymorphism, genetic variants in different individuals to see if any variant is associated with a trait. GWA s ...


References

{{Neuroscience Genetics Neuroinformatics