The defining feature of Lewy body dementia is the presence of alpha-synuclein protein clumps known as Lewy bodies.

Tau and Tauopathies

Tau proteins are essential for maintaining the stability of microtubules in neurons. Microtubules provide structural support to the cell and facilitate the transport of molecules within the cell. Tau proteins are predominantly found in the axons of neurons and are absent in dendrites. The gene that codes for tau protein is located on chromosome 17.

When tau proteins become hyperphosphorylated, they clump together, forming neurofibrillary tangles. This process leads to the disintegration of cells, which is a hallmark of several neurodegenerative disorders collectively known as tauopathies.

The major tauopathies include Alzheimer’s disease, Pick’s disease (frontotemporal dementia), progressive supranuclear palsy, and corticobasal degeneration. These disorders are characterized by the accumulation of tau protein in the brain, leading to the degeneration of neurons and cognitive decline. Understanding the role of tau proteins in these disorders is crucial for developing effective treatments for these devastating diseases.

The heritability estimate does not provide any information about specific individuals.

Heritability: Understanding the Concept

Heritability is a concept that is often misunderstood. It is not a measure of the extent to which genes cause a condition in an individual. Rather, it is the proportion of phenotypic variance attributable to genetic variance. In other words, it tells us how much of the variation in a condition seen in a population is due to genetic factors. Heritability is calculated using statistical techniques and can range from 0.0 to 1.0. For human behavior, most estimates of heritability fall in the moderate range of .30 to .60.

The quantity (1.0 – heritability) gives the environment ability of the trait. This is the proportion of phenotypic variance attributable to environmental variance. The following table provides estimates of heritability for major conditions:

Condition Heritability estimate (approx)
ADHD 85%
Autism 70%
Schizophrenia 55%
Bipolar 55%
Anorexia 35%
Alcohol dependence 35%
Major depression 30%
OCD 25%

It is important to note that heritability tells us nothing about individuals. It is a population-level measure that helps us understand the relative contributions of genetic and environmental factors to a particular condition.

Genetics plays a role in the development of Alzheimer’s disease, with different genes being associated with early onset and late onset cases. Early onset Alzheimer’s, which is rare, is linked to three genes: amyloid precursor protein (APP), presenilin one (PSEN-1), and presenilin two (PSEN-2). The APP gene, located on chromosome 21, produces a protein that is a precursor to amyloid. The presenilins are enzymes that cleave APP to produce amyloid beta fragments, and alterations in the ratios of these fragments can lead to plaque formation. Late onset Alzheimer’s is associated with the apolipoprotein E (APOE) gene on chromosome 19, with the E4 variant increasing the risk of developing the disease. People with Down’s syndrome are also at high risk of developing Alzheimer’s due to inheriting an extra copy of the APP gene.

Understanding Endophenotypes in Psychiatry

Endophenotypes are measurable components that are not visible to the naked eye, but are present along the pathway between disease and distal genotype. These components may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, of neuropsychological. They provide simpler clues to genetic underpinnings than the disease syndrome itself, making genetic analysis more straightforward and successful.

Endophenotypes are important in biological psychiatry research as they specifically require heritability and state independence. They must segregate with illness in the general population, be heritable, manifest whether illness is present of in remission, cosegregate with the disorder within families, be present at a higher rate within affected families than in the general population, and be a characteristic that can be measured reliably and is specific to the illness of interest.

Understanding endophenotypes is crucial in delineating the pathophysiology of mental illness, as genes are the biological bedrock of these disorders. By identifying and measuring endophenotypes, researchers can gain insight into the underlying genetic causes of mental illness and develop more effective treatments.

Lyonization: The Process of X-Inactivation

The X chromosome is crucial for proper development and cell viability, containing over 1,000 essential genes. However, females carry two copies of the X chromosome, which can result in a potentially toxic double dose of X-linked genes. To address this imbalance, females undergo a process called Lyonization, of X-inactivation, where one of their two X chromosomes is transcriptionally silenced. The silenced X chromosome then condenses into a compact structure known as a Barr body, which remains in a silent state.

X-inactivation occurs randomly, with no preference for the paternal or maternal X chromosome. It takes place early in embryogenesis, soon after fertilization when the dividing conceptus is about 16-32 cells big. This process occurs in all somatic cells of women, but not in germ cells involved in forming gametes. X-inactivation affects most, but not all, genes on the X chromosome. If a cell has more than two X chromosomes, the extra Xs are also inactivated.

Enzymes called RNA polymerases, not transferases, transcribe RNA from DNA.

Genomics: Understanding DNA, RNA, Transcription, and Translation

Deoxyribonucleic acid (DNA) is a molecule composed of two chains that coil around each other to form a double helix. DNA is organised into chromosomes, and each chromosome is made up of DNA coiled around proteins called histones. RNA, on the other hand, is made from a long chain of nucleotide units and is usually single-stranded. RNA is transcribed from DNA by enzymes called RNA polymerases and is central to protein synthesis.

Transcription is the synthesis of RNA from a DNA template, and it consists of three main steps: initiation, elongation, and termination. RNA polymerase binds at a sequence of DNA called the promoter, and the transcriptome is the collection of RNA molecules that results from transcription. Translation, on the other hand, refers to the synthesis of polypeptides (proteins) from mRNA. Translation takes place on ribosomes in the cell cytoplasm, where mRNA is read and translated into the string of amino acid chains that make up the synthesized protein.

The process of translation involves messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). Transfer RNAs, of tRNAs, connect mRNA codons to the amino acids they encode, while ribosomes are the structures where polypeptides (proteins) are built. Like transcription, translation also consists of three stages: initiation, elongation, and termination. In initiation, the ribosome assembles around the mRNA to be read and the first tRNA carrying the amino acid methionine. In elongation, the amino acid chain gets longer, and in termination, the finished polypeptide chain is released.

Transcription is the process of converting DNA into messenger RNA (mRNA) and takes place in the nucleus of a cell. RNA is similar to DNA, but with a ribose sugar backbone instead of deoxyribose, and uracil (U) instead of thymine (T).

After transcription, the mRNA is transported out of the nucleus and undergoes translation in the cytoplasm to form a protein. Ribosomes bind to the mRNA, and transfer RNA (tRNA) reads the genetic code to create the protein.

Recombination is the process of DNA detaching from one chromosome and attaching to another, resulting in new variations of chromosomes. In eukaryotes, this typically occurs during meiosis between homologous chromosome pairs.

X-linked transmission is characterized by a Knight’s move pattern.

Modes of Inheritance

Genetic disorders can be passed down from one generation to the next in various ways. There are four main modes of inheritance: autosomal dominant, autosomal recessive, X-linked (sex-linked), and multifactorial.

Autosomal Dominant Inheritance

Autosomal dominant inheritance occurs when one faulty gene causes a problem despite the presence of a normal one. This type of inheritance shows vertical transmission, meaning it is based on the appearance of the family pedigree. If only one parent is affected, there is a 50% chance of each child expressing the condition. Autosomal dominant conditions often show pleiotropy, where a single gene influences several characteristics.

Autosomal Recessive Inheritance

In autosomal recessive conditions, a person requires two faulty copies of a gene to manifest a disease. A person with one healthy and one faulty gene will generally not manifest a disease and is labelled a carrier. Autosomal recessive conditions demonstrate horizontal transmission.

X-linked (Sex-linked) Inheritance

In X-linked conditions, the problem gene lies on the X chromosome. This means that all males are affected. Like autosomal conditions, they can be dominant of recessive. Affected males are unable to pass the condition on to their sons. In X-linked recessive conditions, the inheritance pattern is characterised by transmission from affected males to male grandchildren via affected carrier daughters.

Multifactorial Inheritance

Multifactorial conditions result from the interaction between genes from both parents and the environment.

ADHD and Genetics

Decades of research have shown that genetics play a crucial role in the development of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. However, twin estimates of heritability being less than 100% suggest that environmental factors also play a role. Parents and siblings of a child with ADHD are more likely to have ADHD themselves, but the way ADHD is inherited is complex and not related to a single genetic fault. The heritability of ADHD is around 74%, and longitudinal studies show that two-thirds of ADHD youth will continue to have impairing symptoms of ADHD in adulthood. Adoption studies suggest that the familial factors of ADHD are attributable to genetic factors rather than shared environmental factors. The heritability is similar in males and females, and studies suggest that the diagnosis of ADHD is the extreme of a continuous distribution of ADHD symptoms in the population. Several candidate genes, including DAT1, DRD4, DRD5, 5 HTT, HTR1B, and SNAP25, have been identified as significantly associated with ADHD.

Source: Faraone (2019) Genetics of attention deficit hyperactivity disorder. Molecular Psychiatry volume 24, pages 562–575 (2019).

Genetics plays a role in the development of Alzheimer’s disease, with different genes being associated with early onset and late onset cases. Early onset Alzheimer’s, which is rare, is linked to three genes: amyloid precursor protein (APP), presenilin one (PSEN-1), and presenilin two (PSEN-2). The APP gene, located on chromosome 21, produces a protein that is a precursor to amyloid. The presenilins are enzymes that cleave APP to produce amyloid beta fragments, and alterations in the ratios of these fragments can lead to plaque formation. Late onset Alzheimer’s is associated with the apolipoprotein E (APOE) gene on chromosome 19, with the E4 variant increasing the risk of developing the disease. People with Down’s syndrome are also at high risk of developing Alzheimer’s due to inheriting an extra copy of the APP gene.

Molecular biology techniques are essential in the study of biological molecules such as DNA, RNA, and proteins. Southern blotting is a technique used to detect DNA, while Northern blotting is used to detect RNA. Western blotting, on the other hand, is used to detect proteins by separating them through gel electrophoresis based on their 3D structure. An example of Western blotting is the confirmatory HIV test.

Another technique commonly used in molecular biology is the enzyme-linked immunosorbent assay (ELISA). This biochemical assay is used to detect antigens and antibodies by attaching a colour-changing enzyme to the antibody of antigen. The sample changes colour if the antigen of antibody is detected. ELISA is commonly used in medical diagnosis, and an example includes the initial HIV test.

Linkage and LOD Scores in Genetics

In genetics, when genes are located close to each other on a chromosome, they tend to be inherited together and are referred to as linked genes. Conversely, genes that are far apart of located on different chromosomes are inherited independently and are said to follow independent assortment. To determine the relative distance between two genes, scientists can analyze the offspring of an organism that displays two strongly linked traits and calculate the percentage of offspring where the traits do not co-segregate.

To determine if there is evidence for linkage between two genes, scientists use a statistical method called the LOD score (logarithm of the odds). A LOD score of >3 is considered significant evidence for linkage, while a LOD score of <-2 excludes linkage. The LOD score is calculated by comparing the likelihood of the observed data under the assumption of linkage to the likelihood of the data under the assumption of independent assortment. The LOD score provides a measure of the strength of evidence for linkage between two genes and is widely used in genetic research.

Cytokinesis: The Final Stage of Cell Division

Cytokinesis is the final stage of cell division, where the cell splits into two daughter cells, each with a nucleus. This process is essential for the growth and repair of tissues in multicellular organisms. In mitosis, cytokinesis occurs after telophase, while in meiosis, it occurs after telophase I and telophase II.

During cytokinesis, a contractile ring made of actin and myosin filaments forms around the cell’s equator, constricting it like a belt. This ring gradually tightens, pulling the cell membrane inward and creating a furrow that deepens until it reaches the center of the cell. Eventually, the furrow meets in the middle, dividing the cell into two daughter cells.

In animal cells, cytokinesis is achieved by the formation of a cleavage furrow, while in plant cells, a cell plate forms between the two daughter nuclei, which eventually develops into a new cell wall. The timing and mechanism of cytokinesis are tightly regulated by a complex network of proteins and signaling pathways, ensuring that each daughter cell receives the correct amount of cytoplasm and organelles.

Overall, cytokinesis is a crucial step in the cell cycle, ensuring that genetic material is equally distributed between daughter cells and allowing for the growth and development of multicellular organisms.

Splicing of mRNA

After the transcription of DNA into mRNA, the mRNA undergoes a crucial process known as splicing. This process involves the removal of certain portions of the mRNA, called introns, leaving behind the remaining portions known as exons. The exons are then translated into proteins. The resulting spliced form of RNA is referred to as mature mRNA. This process of splicing is essential for the proper functioning of genes and the production of functional proteins.

Robertsonian translocations can involve chromosomes with very small p arms, which are known as acrocentric chromosomes.

Understanding Centromeres

A centromere is a crucial part of DNA that connects two sister chromatids. It plays a vital role in cell division by keeping the sister chromatids aligned and allowing the chromosomes to be lined up during metaphase. The position of the centromere divides the chromosome into two arms, the long (q) and the short (p). Chromosomes are classified based on the position of the centromere. Metacentric chromosomes have arms of roughly equal length, and they can be formed by Robertsonian translocations. Acrocentric chromosomes can also be involved in Robertsonian translocations. Monocentric chromosomes have only one centromere and form a narrow constriction, while holocentric chromosomes have the entire length of the chromosome acting as the centromere. Understanding the role and classification of centromeres is essential in comprehending the process of cell division.

Hardy-Weinberg Principle and Allele Frequency

Allele frequency refers to the proportion of a population that carries a specific variant at a particular gene locus. It can be calculated by dividing the number of individual alleles of a certain type by the total number of alleles in a population. The Hardy-Weinberg Principle states that both allele and genotype frequencies in a population remain constant from generation to generation unless specific disturbing influences are introduced. To remain in equilibrium, five conditions must be met, including no mutations, no gene flow, random mating, a sufficiently large population, and no natural selection. The Hardy-Weinberg Equation is used to predict the frequency of alleles in a population, and it can be used to estimate the carrier frequency of genetic diseases. For example, if the incidence of PKU is one in 10,000 babies, then the carrier frequency in the general population is 1/50. Couples with a previous child with PKU have a 25% chance of having another affected child.

Schizophrenia is a complex disorder that is associated with multiple candidate genes. No single gene has been identified as the sole cause of schizophrenia, and it is believed that the more genes involved, the greater the risk. Some of the important candidate genes for schizophrenia include DTNBP1, COMT, NRG1, G72, RGS4, DAOA, DISC1, and DRD2. Among these, neuregulin, dysbindin, and DISC1 are the most replicated and plausible genes, with COMT being the strongest candidate gene due to its role in dopamine metabolism. Low activity of the COMT gene has been associated with obsessive-compulsive disorder and schizophrenia. Neuregulin 1 is a growth factor that stimulates neuron development and differentiation, and increased neuregulin signaling in schizophrenia may suppress the NMDA receptor, leading to lowered glutamate levels. Dysbindin is involved in the biogenesis of lysosome-related organelles, and its expression is decreased in schizophrenia. DISC1 encodes a multifunctional protein that influences neuronal development and adult brain function, and it is disrupted in schizophrenia. It is located at the breakpoint of a balanced translocation identified in a large Scottish family with schizophrenia, schizoaffective disorder, and other major mental illnesses.

Genomic Imprinting and its Role in Psychiatric Disorders

Genomic imprinting is a phenomenon where a piece of DNA behaves differently depending on whether it is inherited from the mother of the father. This is because DNA sequences are marked of imprinted in the ovaries and testes, which affects their expression. In psychiatry, two classic examples of genomic imprinting disorders are Prader-Willi and Angelman syndrome.

Prader-Willi syndrome is caused by a deletion of chromosome 15q when inherited from the father. This disorder is characterized by hypotonia, short stature, polyphagia, obesity, small gonads, and mild mental retardation. On the other hand, Angelman syndrome, also known as Happy Puppet syndrome, is caused by a deletion of 15q when inherited from the mother. This disorder is characterized by an unusually happy demeanor, developmental delay, seizures, sleep disturbance, and jerky hand movements.

Overall, genomic imprinting plays a crucial role in the development of psychiatric disorders. Understanding the mechanisms behind genomic imprinting can help in the diagnosis and treatment of these disorders.

Schizophrenia: A Genetic Disorder

Adoption studies have consistently shown that biological relatives of patients with schizophrenia have an increased risk of developing the disorder. Schizophrenia is a complex disorder with incomplete penetrance, as evidenced by the fact that monozygotic twins have a concordance rate of approximately 50%, while dizygotic twins have a concordance rate of 17%. This indicates a significant genetic contribution to the disorder, with an estimated heritability of 80%. Segregation analysis suggests that schizophrenia follows a multifactorial model.

Segregation and Linkage Analysis in Genetics

In genetics, segregation analysis is a statistical approach that helps determine the mode of inheritance of a specific phenotype using family data. On the other hand, linkage analysis is a method used to identify the genetic location of a disease gene. The primary objective of linkage analysis is to find a piece of DNA that is inherited by all affected family members and not by any unaffected members. Once this DNA segment is identified, it indicates that the disease gene is located nearby. Both segregation and linkage analysis are crucial tools in genetic research, helping scientists understand the inheritance patterns of genetic traits and diseases. By using these methods, researchers can identify the genetic basis of various disorders and develop effective treatments.

Recombination Fraction: A Measure of Distance Between Loci

When two loci are located on different chromosomes, they segregate independently during meiosis. However, if they are on the same chromosome, they tend to segregate together, unless crossing over occurs. Crossing over is a process in meiosis where two homologous chromosomes exchange genetic material, resulting in the shuffling of alleles. The likelihood of crossing over between two loci on a chromosome decreases as their distance from each other increases.

Hence, blocks of alleles on a chromosome tend to be transmitted together through generations, forming a haplotype. The recombination fraction is a measure of the distance between two loci on a chromosome. The closer the loci are, the lower the recombination fraction, and the more likely they are to be transmitted together. Conversely, the further apart the loci are, the higher the recombination fraction, and the more likely they are to be separated by crossing over. The recombination fraction can range from 0% if the loci are very close to 50% if they are on different chromosomes.

Gene Chromosome
APP 21
PSEN-1 14
PSEN-2 1
APOE 19

Genetics plays a role in the development of Alzheimer’s disease, with different genes being associated with early onset and late onset cases. Early onset Alzheimer’s, which is rare, is linked to three genes: amyloid precursor protein (APP), presenilin one (PSEN-1), and presenilin two (PSEN-2). The APP gene, located on chromosome 21, produces a protein that is a precursor to amyloid. The presenilins are enzymes that cleave APP to produce amyloid beta fragments, and alterations in the ratios of these fragments can lead to plaque formation. Late onset Alzheimer’s is associated with the apolipoprotein E (APOE) gene on chromosome 19, with the E4 variant increasing the risk of developing the disease. People with Down’s syndrome are also at high risk of developing Alzheimer’s due to inheriting an extra copy of the APP gene.

Wilson’s disease, also known as hepatolenticular degeneration, is identified by the accumulation of copper in the liver and brain.

Tau and Tauopathies

Tau proteins are essential for maintaining the stability of microtubules in neurons. Microtubules provide structural support to the cell and facilitate the transport of molecules within the cell. Tau proteins are predominantly found in the axons of neurons and are absent in dendrites. The gene that codes for tau protein is located on chromosome 17.

When tau proteins become hyperphosphorylated, they clump together, forming neurofibrillary tangles. This process leads to the disintegration of cells, which is a hallmark of several neurodegenerative disorders collectively known as tauopathies.

The major tauopathies include Alzheimer’s disease, Pick’s disease (frontotemporal dementia), progressive supranuclear palsy, and corticobasal degeneration. These disorders are characterized by the accumulation of tau protein in the brain, leading to the degeneration of neurons and cognitive decline. Understanding the role of tau proteins in these disorders is crucial for developing effective treatments for these devastating diseases.

Genomic Imprinting and its Role in Psychiatric Disorders

Genomic imprinting is a phenomenon where a piece of DNA behaves differently depending on whether it is inherited from the mother of the father. This is because DNA sequences are marked of imprinted in the ovaries and testes, which affects their expression. In psychiatry, two classic examples of genomic imprinting disorders are Prader-Willi and Angelman syndrome.

Prader-Willi syndrome is caused by a deletion of chromosome 15q when inherited from the father. This disorder is characterized by hypotonia, short stature, polyphagia, obesity, small gonads, and mild mental retardation. On the other hand, Angelman syndrome, also known as Happy Puppet syndrome, is caused by a deletion of 15q when inherited from the mother. This disorder is characterized by an unusually happy demeanor, developmental delay, seizures, sleep disturbance, and jerky hand movements.

Overall, genomic imprinting plays a crucial role in the development of psychiatric disorders. Understanding the mechanisms behind genomic imprinting can help in the diagnosis and treatment of these disorders.

Inheritance Patterns:

Autosomal Dominant Conditions:
– Can be transmitted from one generation to the next (vertical transmission) through all forms of transmission observed (male to male, male to female, female to female).
– Males and females are affected in equal proportions.
– Usually, one parent is an affected heterozygote and the other is an unaffected homozygote.
– If only one parent is affected, there is a 50% chance that a child will inherit the mutated gene.

Autosomal Recessive Conditions:
– Males and females are affected in equal proportions.
– Two copies of the gene must be mutated for a person to be affected.
– Both parents are usually unaffected heterozygotes.
– Two unaffected people who each carry one copy of the mutated gene have a 25% chance with each pregnancy of having a child affected by the disorder.

X-linked Dominant Conditions:
– Males and females are both affected, with males typically being more severely affected than females.
– The sons of a man with an X-linked dominant disorder will all be unaffected.
– A woman with an X-linked dominant disorder has a 50% chance of having an affected fetus.

X-linked Recessive Conditions:
– Males are more frequently affected than females.
– Transmitted through carrier females to their sons (knights move pattern).
– Affected males cannot pass the condition onto their sons.
– A woman who is a carrier of an X-linked recessive disorder has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers.

Y-linked Conditions:
– Every son of an affected father will be affected.
– Female offspring of affected fathers are never affected.

Mitochondrial Inheritance:
– Mitochondria are inherited only in the maternal ova and not in sperm.
– Males and females are affected, but always being maternally inherited.
– An affected male does not pass on his mitochondria to his children, so all his children will be unaffected.

Inheritance Patterns and Examples

Autosomal Dominant:
Neurofibromatosis type 1 and 2, tuberous sclerosis, achondroplasia, Huntington disease, and Noonan’s syndrome are all examples of conditions that follow an autosomal dominant inheritance pattern. This means that only one copy of the mutated gene is needed to cause the condition.

Autosomal Recessive:
Phenylketonuria, homocystinuria, Hurler’s syndrome, galactosaemia, Tay-Sach’s disease, Friedreich’s ataxia, Wilson’s disease, and cystic fibrosis are all examples of conditions that follow an autosomal recessive inheritance pattern. This means that two copies of the mutated gene are needed to cause the condition.

X-Linked Dominant:
Vitamin D resistant rickets and Rett syndrome are examples of conditions that follow an X-linked dominant inheritance pattern. This means that the mutated gene is located on the X chromosome and only one copy of the gene is needed to cause the condition.

X-Linked Recessive:
Cerebellar ataxia, Hunter’s syndrome, and Lesch-Nyhan are examples of conditions that follow an X-linked recessive inheritance pattern. This means that the mutated gene is located on the X chromosome and two copies of the gene are needed to cause the condition.

Mitochondrial:
Leber’s hereditary optic neuropathy and Kearns-Sayre syndrome are examples of conditions that follow a mitochondrial inheritance pattern. This means that the mutated gene is located in the mitochondria and is passed down from the mother to her offspring.

Heritability: Understanding the Concept

Heritability is a concept that is often misunderstood. It is not a measure of the extent to which genes cause a condition in an individual. Rather, it is the proportion of phenotypic variance attributable to genetic variance. In other words, it tells us how much of the variation in a condition seen in a population is due to genetic factors. Heritability is calculated using statistical techniques and can range from 0.0 to 1.0. For human behavior, most estimates of heritability fall in the moderate range of .30 to .60.

The quantity (1.0 – heritability) gives the environment ability of the trait. This is the proportion of phenotypic variance attributable to environmental variance. The following table provides estimates of heritability for major conditions:

Condition Heritability estimate (approx)
ADHD 85%
Autism 70%
Schizophrenia 55%
Bipolar 55%
Anorexia 35%
Alcohol dependence 35%
Major depression 30%
OCD 25%

It is important to note that heritability tells us nothing about individuals. It is a population-level measure that helps us understand the relative contributions of genetic and environmental factors to a particular condition.

The Aminoacyl tRNA Synthetases (AARSs) are a group of enzymes that attach a specific amino acid to its corresponding tRNA molecule. There are 21 different AARS enzymes, each responsible for a different amino acid, except for lysine, which has two AARSs.

Genomics: Understanding DNA, RNA, Transcription, and Translation

Deoxyribonucleic acid (DNA) is a molecule composed of two chains that coil around each other to form a double helix. DNA is organised into chromosomes, and each chromosome is made up of DNA coiled around proteins called histones. RNA, on the other hand, is made from a long chain of nucleotide units and is usually single-stranded. RNA is transcribed from DNA by enzymes called RNA polymerases and is central to protein synthesis.

Transcription is the synthesis of RNA from a DNA template, and it consists of three main steps: initiation, elongation, and termination. RNA polymerase binds at a sequence of DNA called the promoter, and the transcriptome is the collection of RNA molecules that results from transcription. Translation, on the other hand, refers to the synthesis of polypeptides (proteins) from mRNA. Translation takes place on ribosomes in the cell cytoplasm, where mRNA is read and translated into the string of amino acid chains that make up the synthesized protein.

The process of translation involves messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). Transfer RNAs, of tRNAs, connect mRNA codons to the amino acids they encode, while ribosomes are the structures where polypeptides (proteins) are built. Like transcription, translation also consists of three stages: initiation, elongation, and termination. In initiation, the ribosome assembles around the mRNA to be read and the first tRNA carrying the amino acid methionine. In elongation, the amino acid chain gets longer, and in termination, the finished polypeptide chain is released.

Tau and Tauopathies

Tau proteins are essential for maintaining the stability of microtubules in neurons. Microtubules provide structural support to the cell and facilitate the transport of molecules within the cell. Tau proteins are predominantly found in the axons of neurons and are absent in dendrites. The gene that codes for tau protein is located on chromosome 17.

When tau proteins become hyperphosphorylated, they clump together, forming neurofibrillary tangles. This process leads to the disintegration of cells, which is a hallmark of several neurodegenerative disorders collectively known as tauopathies.

The major tauopathies include Alzheimer’s disease, Pick’s disease (frontotemporal dementia), progressive supranuclear palsy, and corticobasal degeneration. These disorders are characterized by the accumulation of tau protein in the brain, leading to the degeneration of neurons and cognitive decline. Understanding the role of tau proteins in these disorders is crucial for developing effective treatments for these devastating diseases.

Huntington’s Disease: Genetics and Pathology

Huntington’s disease is a genetic disorder that follows an autosomal dominant pattern of inheritance. It is caused by a mutation in the Huntington gene, which is located on chromosome 4. The mutation involves an abnormal expansion of a trinucleotide repeat sequence (CAG), which leads to the production of a toxic protein that damages brain cells.

The severity of the disease and the age of onset are related to the number of CAG repeats. Normally, the CAG sequence is repeated less than 27 times, but in Huntington’s disease, it is repeated many more times. The disease shows anticipation, meaning that it tends to worsen with each successive generation.

The symptoms of Huntington’s disease typically begin in the third of fourth decade of life, but in rare cases, they can appear in childhood of adolescence. The most common symptoms include involuntary movements (chorea), cognitive decline, and psychiatric disturbances.

The pathological hallmark of Huntington’s disease is the gross bilateral atrophy of the head of the caudate and putamen, which are regions of the brain involved in movement control. The EEG of patients with Huntington’s disease shows a flattened trace, indicating a loss of brain activity.

Macroscopic pathological findings include frontal atrophy, marked atrophy of the caudate and putamen, and enlarged ventricles. Microscopic findings include neuronal loss and gliosis in the cortex, neuronal loss in the striatum, and the presence of inclusion bodies in the neurons of the cortex and striatum.

In conclusion, Huntington’s disease is a devastating genetic disorder that affects the brain and causes a range of motor, cognitive, and psychiatric symptoms. The disease is caused by a mutation in the Huntington gene, which leads to the production of a toxic protein that damages brain cells. The pathological changes in the brain include atrophy of the caudate and putamen, neuronal loss, and the presence of inclusion bodies.

Fragile X is associated with speech that is cluttered.

Fragile X Syndrome: A Genetic Disorder Causing Learning Disability and Psychiatric Symptoms

Fragile X Syndrome is a genetic disorder that causes mental retardation, an elongated face, large protruding ears, and large testicles in men. Individuals with this syndrome tend to be shy, avoid eye contact, and have difficulties reading facial expressions. They also display stereotypic movements such as hand flapping. Fragile X Syndrome is the most common inherited cause of learning disability.

The speech of affected individuals is often abnormal, with abnormalities of fluency. This disorder is caused by the amplification of a CGG repeat in the 5 untranslated region of the fragile X mental retardation 1 gene (FMR1). These CGG repeats disrupt synthesis of the fragile X protein (FMRP), which is essential for brain function and growth. The gene is located at Xq27. The greater number of repeats, the more severe the condition, as with other trinucleotide repeat disorders.

The fragile X phenotype typically involves a variety of psychiatric symptoms, including features of autism, attention deficit/hyperactivity disorder, anxiety, and aggression. Both males and females can be affected, but males are more severely affected because they have only one X chromosome. The prevalence estimate of Fragile X Syndrome is 1/3600-4000.

Genetics and Alcoholism

Alcoholism tends to run in families, and several studies confirm that biological children of alcoholics are more likely to develop alcoholism even when adopted by parents without the condition. Monozygotic twins have a greater concordance rate for alcoholism than dizygotic twins. Heritability estimates range from 45 to 65 percent for both men and women. While genetic differences affect risk, there is no “gene for alcoholism,” and both environmental and social factors weigh heavily on the outcome.

The genes with the clearest contribution to the risk for alcoholism and alcohol consumption are alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2). The first step in ethanol metabolism is oxidation to acetaldehyde, by ADHs. The second step is metabolism of the acetaldehyde to acetate by ALDHs. Individuals carrying even a single copy of the ALDH2*504K display the “Asian flushing reaction” when they consume even small amounts of alcohol. There is one significant genetic polymorphism of the ALDH2 gene, resulting in allelic variants ALDH2*1 and ALDH2*2, which is virtually inactive. ALDH2*2 is present in about 50 percent of the Taiwanese, Han Chinese, and Japanese populations. It is extremely rare outside Asia. Nearly no individuals of European of African descent carry this allele. ALDH2*504K has repeatedly been demonstrated to have a protective effect against alcohol use disorders.

The three different class I gene loci, ADH1A (alpha), ADH1B (beta), and ADH1C (gamma) are situated close to each other in the region 4q2123. The alleles ADH1C*1 and ADH1B*2 code for fast metabolism of alcohol. The ADH1B*1 slow allele is very common among Caucasians, with approximately 95 percent having the homozygous ADH1B*1/1 genotype and 5 percent having the heterozygous ADH1B*1/2 genotype. The ADH1B*2 allele is the most common allele in Asian populations. In African populations, the ADH1B*1 allele is the most common.

Inheritance of knight’s move pattern is observed in disorders that are caused by recessive X-linked genes, rather than dominant X-linked genes.

Modes of Inheritance

Genetic disorders can be passed down from one generation to the next in various ways. There are four main modes of inheritance: autosomal dominant, autosomal recessive, X-linked (sex-linked), and multifactorial.

Autosomal Dominant Inheritance

Autosomal dominant inheritance occurs when one faulty gene causes a problem despite the presence of a normal one. This type of inheritance shows vertical transmission, meaning it is based on the appearance of the family pedigree. If only one parent is affected, there is a 50% chance of each child expressing the condition. Autosomal dominant conditions often show pleiotropy, where a single gene influences several characteristics.

Autosomal Recessive Inheritance

In autosomal recessive conditions, a person requires two faulty copies of a gene to manifest a disease. A person with one healthy and one faulty gene will generally not manifest a disease and is labelled a carrier. Autosomal recessive conditions demonstrate horizontal transmission.

X-linked (Sex-linked) Inheritance

In X-linked conditions, the problem gene lies on the X chromosome. This means that all males are affected. Like autosomal conditions, they can be dominant of recessive. Affected males are unable to pass the condition on to their sons. In X-linked recessive conditions, the inheritance pattern is characterised by transmission from affected males to male grandchildren via affected carrier daughters.

Multifactorial Inheritance

Multifactorial conditions result from the interaction between genes from both parents and the environment.

Lewy bodies, which are present in Parkinson’s disease, are composed of alpha-synuclein.

Genetic Contributors to Parkinson’s Disease

Genetic contributors to Parkinson’s disease can range from highly penetrant DNA variants to variants that individually increase the lifetime risk of the disease. These genetic risks are often divided into rare DNA variants with high effect sizes, typically associated with familial Parkinson’s disease, and more common, smaller effect variants, usually identified in sporadic cases. While rare variants in over 20 genes have been reported to cause Parkinson’s disease, most cases are idiopathic.

One gene implicated in Parkinson’s disease is SNCA, which codes for alpha-synuclein. Autosomal dominant mutations of SNCA have been identified in several families with inherited Parkinson’s disease. Mutant forms of alpha-synuclein aggregate and induce other proteins to incorporate into the aggregate, forming Lewy bodies, which are similar to the beta-amyloid plaques found in Alzheimer’s patients. Another gene implicated in Parkinson’s disease is the Parkin gene.

It is important to note that the known genes responsible for Parkinson’s disease are responsible for a minority of cases, with the majority being sporadic.

Inheritance Patterns and Examples

Autosomal Dominant:
Neurofibromatosis type 1 and 2, tuberous sclerosis, achondroplasia, Huntington disease, and Noonan’s syndrome are all examples of conditions that follow an autosomal dominant inheritance pattern. This means that only one copy of the mutated gene is needed to cause the condition.

Autosomal Recessive:
Phenylketonuria, homocystinuria, Hurler’s syndrome, galactosaemia, Tay-Sach’s disease, Friedreich’s ataxia, Wilson’s disease, and cystic fibrosis are all examples of conditions that follow an autosomal recessive inheritance pattern. This means that two copies of the mutated gene are needed to cause the condition.

X-Linked Dominant:
Vitamin D resistant rickets and Rett syndrome are examples of conditions that follow an X-linked dominant inheritance pattern. This means that the mutated gene is located on the X chromosome and only one copy of the gene is needed to cause the condition.

X-Linked Recessive:
Cerebellar ataxia, Hunter’s syndrome, and Lesch-Nyhan are examples of conditions that follow an X-linked recessive inheritance pattern. This means that the mutated gene is located on the X chromosome and two copies of the gene are needed to cause the condition.

Mitochondrial:
Leber’s hereditary optic neuropathy and Kearns-Sayre syndrome are examples of conditions that follow a mitochondrial inheritance pattern. This means that the mutated gene is located in the mitochondria and is passed down from the mother to her offspring.

Genes Associated with Dementia

Dementia is a complex disorder that can be caused by various genetic and environmental factors. Several genes have been implicated in different forms of dementia. For instance, familial Alzheimer’s disease, which represents less than 1-6% of all Alzheimer’s cases, is associated with mutations in PSEN1, PSEN2, APP, and ApoE genes. These mutations are inherited in an autosomal dominant pattern. On the other hand, late-onset Alzheimer’s disease is a genetic risk factor associated with the ApoE gene, particularly the APOE4 allele. However, inheriting this allele does not necessarily mean that a person will develop Alzheimer’s.

Other forms of dementia, such as familial frontotemporal dementia, Huntington’s disease, CADASIL, and dementia with Lewy bodies, are also associated with specific genes. For example, C9orf72 is the most common mutation associated with familial frontotemporal dementia, while Huntington’s disease is caused by mutations in the HTT gene. CADASIL is associated with mutations in the Notch3 gene, while dementia with Lewy bodies is associated with the APOE, GBA, and SNCA genes.

In summary, understanding the genetic basis of dementia is crucial for developing effective treatments and preventive measures. However, it is important to note that genetics is only one of the many factors that contribute to the development of dementia. Environmental factors, lifestyle choices, and other health conditions also play a significant role.

Hardy-Weinberg Principle and Allele Frequency

Allele frequency refers to the proportion of a population that carries a specific variant at a particular gene locus. It can be calculated by dividing the number of individual alleles of a certain type by the total number of alleles in a population. The Hardy-Weinberg Principle states that both allele and genotype frequencies in a population remain constant from generation to generation unless specific disturbing influences are introduced. To remain in equilibrium, five conditions must be met, including no mutations, no gene flow, random mating, a sufficiently large population, and no natural selection. The Hardy-Weinberg Equation is used to predict the frequency of alleles in a population, and it can be used to estimate the carrier frequency of genetic diseases. For example, if the incidence of PKU is one in 10,000 babies, then the carrier frequency in the general population is 1/50. Couples with a previous child with PKU have a 25% chance of having another affected child.

Fragile X syndrome is inherited in an X-linked manner and is caused by a mutation in the FMR1 gene. The condition is characterized by excessive trinucleotide repeats (CGG). While women can be mildly affected, the severity of cognitive impairment is directly related to the length of the trinucleotide repeat sequence.

Fragile X Syndrome: A Genetic Disorder Causing Learning Disability and Psychiatric Symptoms

Fragile X Syndrome is a genetic disorder that causes mental retardation, an elongated face, large protruding ears, and large testicles in men. Individuals with this syndrome tend to be shy, avoid eye contact, and have difficulties reading facial expressions. They also display stereotypic movements such as hand flapping. Fragile X Syndrome is the most common inherited cause of learning disability.

The speech of affected individuals is often abnormal, with abnormalities of fluency. This disorder is caused by the amplification of a CGG repeat in the 5 untranslated region of the fragile X mental retardation 1 gene (FMR1). These CGG repeats disrupt synthesis of the fragile X protein (FMRP), which is essential for brain function and growth. The gene is located at Xq27. The greater number of repeats, the more severe the condition, as with other trinucleotide repeat disorders.

The fragile X phenotype typically involves a variety of psychiatric symptoms, including features of autism, attention deficit/hyperactivity disorder, anxiety, and aggression. Both males and females can be affected, but males are more severely affected because they have only one X chromosome. The prevalence estimate of Fragile X Syndrome is 1/3600-4000.

Inheritance Patterns:

Autosomal Dominant Conditions:
– Can be transmitted from one generation to the next (vertical transmission) through all forms of transmission observed (male to male, male to female, female to female).
– Males and females are affected in equal proportions.
– Usually, one parent is an affected heterozygote and the other is an unaffected homozygote.
– If only one parent is affected, there is a 50% chance that a child will inherit the mutated gene.

Autosomal Recessive Conditions:
– Males and females are affected in equal proportions.
– Two copies of the gene must be mutated for a person to be affected.
– Both parents are usually unaffected heterozygotes.
– Two unaffected people who each carry one copy of the mutated gene have a 25% chance with each pregnancy of having a child affected by the disorder.

X-linked Dominant Conditions:
– Males and females are both affected, with males typically being more severely affected than females.
– The sons of a man with an X-linked dominant disorder will all be unaffected.
– A woman with an X-linked dominant disorder has a 50% chance of having an affected fetus.

X-linked Recessive Conditions:
– Males are more frequently affected than females.
– Transmitted through carrier females to their sons (knights move pattern).
– Affected males cannot pass the condition onto their sons.
– A woman who is a carrier of an X-linked recessive disorder has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers.

Y-linked Conditions:
– Every son of an affected father will be affected.
– Female offspring of affected fathers are never affected.

Mitochondrial Inheritance:
– Mitochondria are inherited only in the maternal ova and not in sperm.
– Males and females are affected, but always being maternally inherited.
– An affected male does not pass on his mitochondria to his children, so all his children will be unaffected.

Genomic Imprinting and its Role in Psychiatric Disorders

Genomic imprinting is a phenomenon where a piece of DNA behaves differently depending on whether it is inherited from the mother of the father. This is because DNA sequences are marked of imprinted in the ovaries and testes, which affects their expression. In psychiatry, two classic examples of genomic imprinting disorders are Prader-Willi and Angelman syndrome.

Prader-Willi syndrome is caused by a deletion of chromosome 15q when inherited from the father. This disorder is characterized by hypotonia, short stature, polyphagia, obesity, small gonads, and mild mental retardation. On the other hand, Angelman syndrome, also known as Happy Puppet syndrome, is caused by a deletion of 15q when inherited from the mother. This disorder is characterized by an unusually happy demeanor, developmental delay, seizures, sleep disturbance, and jerky hand movements.

Overall, genomic imprinting plays a crucial role in the development of psychiatric disorders. Understanding the mechanisms behind genomic imprinting can help in the diagnosis and treatment of these disorders.