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MPHIL CP
Paper-II: Behavioral Foundation of Behavior

MODULE III
BIOCHEMISTRY OF THE BRAIN
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CONTENT
Biochemical and metabolic aspects of Brain:
 medical genetics;
 structure and function of chromosomes;
 molecular methods in genetics; genetic variation;
 Population genetics; single-gene inheritance; cytogenetic abnormalities;
multifactorial inheritance; biochemistry of genetic diseases.

Biochemical Correlates of Brain Structure and Function deals with the biochemical
correlates of brain structure and function, providing some examples of
contemporary work interrelating structure with function of the nervous system. The
developing brain provides a system for this kind of study, but broad correlates are
also drawn between changing biochemistry and increasing physiological activity.
This book is organized into nine chapters and begins with an overview of
biochemical, morphological, and functional changes in the developing brain, as
well as the underlying molecular basis of nerve differentiation and growth of the
developing brain. An account of the concept of the cell cycle and its control is also
given. The reader is methodically introduced to the properties of the developing
retina and its functional biochemistry, with specific reference to the cyclic
nucleotides; the use of selective lesioning to delineate GABA-ergic and cholinergic
tracts as well as the catecholamine pathways; and cerebral blood flow alteration in
concert with mental activity. The remaining chapters explore regions of the brain
with altered glucose utilization in response to changes in local functional activity;
the physiologically important factors regulating the supply of oxygen and glucose
and the relation of metabolic rate to the metabolic state of the brain; and varying
aspects of behavioral neurochemistry.

1. MEDICAL GENETICS

Medical genetics encompasses many different areas, including clinical practice

of physicians, genetic counselors, and nutritionists, clinical diagnostic
laboratory activities, and research into the causes and inheritance of genetic
disorders. Examples of conditions that fall within the scope of medical genetics
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include birth defects and dysmorphology, mental retardation, autism, and

mitochondrial disorders, skeletal dysplasia, connective tissue disorders, cancer
genetics, teratogens, and prenatal diagnosis. Medical genetics is increasingly
becoming relevant to many common diseases. Overlaps with other medical
specialties are beginning to emerge, as recent advances in genetics are revealing
etiologies for neurologic, endocrine, cardiovascular, pulmonary,
ophthalmologic, renal, psychiatric, and dermatologic conditions.

Medical genetics is the branch of medicine that involves the diagnosis and
management of hereditary disorders. Medical genetics differs from human
genetics in that human genetics is a field of scientific research that may or may
not apply to medicine, while medical genetics refers to the application of
genetics to medical care. For example, research on the causes and inheritance of
genetic disorders would be considered within both human genetics and medical
genetics, while the diagnosis, management, and counselling people with genetic
disorders would be considered part of medical genetics.

In contrast, the study of typically non-medical phenotypes such as the genetics

of eye color would be considered part of human genetics, but not necessarily
relevant to medical genetics (except in situations such as albinism). Genetic
medicine is a newer term for medical genetics and incorporates areas such as
gene therapy, personalized medicine, and the rapidly emerging new medical
specialty, predictive medicine.

Treatments

Each cell of the body contains the hereditary information (DNA) wrapped up in
structures called chromosomes. Since genetic syndromes are typically the result
of alterations of the chromosomes or genes, there is no treatment currently
available that can correct the genetic alterations in every cell of the body.
Therefore, there is currently no "cure" for genetic disorders. However, for many
genetic syndromes there is treatment available to manage the symptoms. In
some cases, particularly inborn errors of metabolism, the mechanism of disease
is well understood and offers the potential for dietary and medical management
to prevent or reduce the long-term complications. In other cases, infusion
therapy is used to replace the missing enzyme. Current research is actively
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seeking to use gene therapy or other new medications to treat specific genetic
disorders.

2. STRUCTURE AND FUNCTION OF CHROMOSOMES

Chromosomes are organized structure of DNA and proteins found in cells. they are
thread-like structures located inside the nucleus of animal and plant cells.
Chromosomes are made up of proteins and a molecule of deoxyribonucleic acid
(DNA). Chromosomes are passed on from parents to offspring. The term
chromosome is derived from a Greek word 'chroma' which means 'color' and 'soma'
which means 'body'. The chromosomes are named so because they are cellular
structures or cellular bodies and they are strongly stained by some dyes used in
research. Chromosomes play an important role that ensures DNA is copied and
distruuted accurately in the process of cell division. In most of the organisms
chromosomes are arranged in pairs in the nucleus of the cell. We have 23 pairs of
chromosomes.

Chromosome Structure
 In eukarytoic cells, chromosomes are composed of single molecule of DNA
with many copies of five types of histones.
 Histones are proteins molecules and are rich in lysine and arginine residues,
they are positively charged. Hence they bind tightly to the negatively-
charged phosphates in the DNA sequence. 
 A small number of non-histone proteins are also present, these are mostly
transcription factors. Transcription factors regulate which parts of DNA to
be transcribed into RNA. 
 During most of the cell's life cycle, chromosomes are elongated and cannot
be observed under the microscope. 
 During the S phase of the mitotic cell cycle the chromosomes are
duplicated. 
 At the beginning of mitosis the chromosomes are duplicated and they begin
to condense into short structures which can be stained and observed easily
under the light microscope.
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 These duplicated condensed chromosomes are known as dyads.

 The duplicated chromosomes are held together at the region of centromeres. 
 The centromeres in humans are made of about 1-10 million base pairs of
DNA.  
 The DNA of the centromere are mostly repetitive short sequences of DNA,
the sequences are repeated over and over in tandem arrays. 
 The attached, duplicated chromosomes are commonly called sister
chromatids. 
 Kinetochores are the attachment point for spindle fibers which helps to pull
apart the sister chromatids as the mitosis process proceeds to anaphase
stage. The kinetochores are a complex of about 80 different proteins. 
 The shorter arm of the two arms of the chromosome extending from the
centromere is called the p arm and the longer arm is known the q arm. 

Function of Chromosome:

Functions of Chromosomes are as follows: 

Genetic Code Storage: Chromosome contains the genetic material that is required
by the organism to develop and grow. DNA molecules are made of chain of units
called genes. Genes are those sections of the DNA which code for specific proteins
required by the cell for its proper functioning.

Sex Determination: Humans have 23 pairs of chromosomes out of which one pair

is the sex chromosome. Females have two X chromosomes and males have one X
and one Y chromosome. The sex of the child is determined by the chromosome
passed down by the male. If X chromosome is passed out of XY chromosome, the
child will be a female and if a Y chromosome is passed, a male child develops. 
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Control of Cell Division: Chromosomes check successful division of cells during

the process of mitosis. The chromosomes of the parent cells insure that the correct
information is passed on to the daughter cells required by the cell to grow and
develop correctly. 

Formation of Proteins and Storage: Proteins are essential for the activity of a cell.
The chromosomes direct the sequences of proteins formed in our body and also
maintain the order of DNA. The proteins are also stored in the coiled structure of
the chromosomes. These proteins bound to the DNA help in proper packaging of
the DNA.

3. MOLECULAR METHODS IN GENETICS: GENETIC

VARIATION
Genetic variation means that biological systems – individuals and populations – are
different over space. Each gene pool includes various alleles of genes. The
variation occurs both within and among populations, supported by individual
carriers of the variant genes.
Genetic variation is brought about, fundamentally, by mutation, which is a
permanent change in the chemical structure of chromosomes. Genetic
recombination also produces changes within alleles.
Among individuals within a population
Genetic variation among individuals within a population can be identified at a
variety of levels. It is possible to identify genetic variation from observations of
phenotypic variation in either quantitative traits (traits that vary continuously and
are coded for by many genes (e.g., leg length in dogs)) or discrete traits (traits that
fall into discrete categories and are coded for by one or a few genes (e.g., white,
pink, red petal color in certain flowers)).
Genetic variation can also be identified by examining variation at the level of
enzymes using the process of protein electrophoresis. Polymorphic genes have
more than one allele at each locus. Half of the genes that code for enzymes in
insects and plants may be polymorphic, whereas polymorphisms are less common
in vertebrates.
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Ultimately, genetic variation is caused by variation in the order of bases in the

nucleotides in genes. New technology now allows scientists to directly sequence
DNA which has identified even more genetic variation than was previously
detected by protein electrophoresis. Examination of DNA has shown genetic
variation in both coding regions and in the non-coding intron region of genes.
Genetic variation will result in phenotypic variation if variation in the order of
nucleotides in the DNA sequence results in a difference in the order of amino acids
in proteins coded by that DNA sequence, and if the resultant differences in amino
acid sequence influence the shape, and thus the function of the enzyme.

4. POPULATION GENETICS: SINGLE-GENE

INHERITANCE; CYTOGENETIC ABNORMALITIES;
MULTIFACTORIAL INHERITANCE; BIOCHEMISTRY
OF GENETIC DISEASES.
Population genetics

Population genetics is the study of genetic variation within populations, and

involves the examination and modelling of changes in the frequencies of genes
and alleles in populations over space and time. Many of the genes found within
a population will be polymorphic - that is, they will occur in a number of
different forms (or alleles). Mathematical models are used to investigate and
predict the occurrence of specific alleles or combinations of alleles in
populations, based on developments in the molecular understanding of genetics,
Mendel's laws of inheritance and modern evolutionary theory. The focus is the
population or the species - not the individual.
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Electron micrograph of a natural bacterial population, showing a range of size

and morphology
The collection of all the alleles of all of the genes found within a freely
interbreeding population is known as the gene pool of the population. Each
member of the population receives its alleles from other members of the gene
pool (its parents) and passes them on to other members of the gene pool (its
offspring). Population genetics is the study of the variation in alleles and
genotypes within the gene pool, and how this variation changes from one
generation to the next.
Factors influencing the genetic diversity within a gene pool include population
size, mutation, genetic drift, natural selection, environmental diversity,
migration and non-random mating patterns. The Hardy-Weinberg model
describes and predicts a balanced equilibrium in the frequencies of alleles and
genotypes within a freely interbreeding population, assuming a large population
size, no mutation, no genetic drift, no natural selection, no gene flow between
populations, and random mating patterns.
In natural populations, however, the genetic composition of a population's gene
pool may change over time. Mutation is the primary source of new alleles in a
gene pool, but the other factors act to increase or decrease the occurrence of
alleles. Genetic drift occurs as the result of random fluctuations in the transfer
of alleles from one generation to the next, especially in small populations
formed, say, as the result adverse environmental conditions (the bottleneck
effect) or the geographical separation of a subset of the population (the founder
effect). The result of genetic drift tends to be a reduction in the variation within
the population, and an increase in the divergence between populations. If two
populations of a given species become genetically distinct enough that they can
no longer interbreed, they are regarded as new species (a process called
speciation).
In many cases, the effects of natural selection on a given allele are directional.
The allele either confers a selective advantage, or spreads throughout the gene
pool, or it confers a selective disadvantage, and disappears from it. In other
cases, however, selection acts to preserve multiple alleles within the gene pool
and a balanced equilibrium is observed. This situation, labelled balanced
polymorphism, can arise because of a selective advantage for individuals
heterozygous for a given allele. For example, the disease sickle cell anaemia is
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caused by a mutation in one of the genes responsible for the production of

haemoglobin. Individuals with two copies of the mutant gene for sickle
haemoglobin (HbS/HbS) develop the disease. Individuals that are heterozygous
- one copy of the sickle gene and one copy of the normal gene (HbS/HbA) - are
carriers of the condition. It is believed that these heterozygous individuals are
more resistant to malaria than individuals homozygous for the normal gene
(HbA/HbA), and that this selective advantage maintains the presence of the
HbS gene in the population. As a result of balanced polymorphism, the gene
pools of most populations contain a number of deleterious alleles that reduces
the overall fitness of the population (known as the genetic load).
Genetic variation within populations and species can now be analysed at the
level of nucleotide sequences in DNA (genome analysis) and the amino acid
sequences of proteins (proteome analysis). The genetic differences between
species can be used to infer evolutionary history, on the basis that the closest
relatives will have gene pools that are most similar. Recent advances in the
sequencing of genomes, allied to computer-based techniques for storing and
comparing this information, have led to the construction of detailed
evolutionary trees. The use of molecular clocks - nucleotide sequences (or
amino acid sequences) in which evolutionary change accumulates at a constant
rate - allows dates to be attached to the points at which populations start to
diverge to form new species. These approaches are also proving useful in other
useful areas (for example, in tracing the transmission routes of infectious
diseases).
Single-gene Inheritance in Humans
Modes of Inheritance
1. Modes of inheritance are the rules explaining the common patterns of
inheritance.
2. A Mendelian trait is caused by a single gene.
3. Traits can be dominant or recessive and recur in a predictable pattern in
subsequent generations.
4. Autosomal Dominant Inheritance: Autosomal dominant traits do not
generally skip generations and can affect both sexes. 
5. Autosomal Recessive Inheritance: Autosomal recessive traits can skip
generations and can affect both sexes. Blood relatives that have children
together have a much higher risk of having a child with a rare recessive
disorder.
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6. Punnett squares apply Mendel's first law to predict recurrence risks for
inherited disorders or traits. 
7. A Mendelian trait applies anew to each child.
On the Meaning of Dominance and Recessiveness
1. At the biochemical level, recessive disorders often result from alleles that
cause the loss of function or production of a normal protein. 
2. Dominant disorders can result from production of an abnormal protein that
interferes with the function of a normal protein or result from a gain of function.

Cytogenic Abnormalities
Cytogenetics is a branch of genetics that is concerned with how the
chromosomes relate to cell behaviour, particularly to their behaviour during
mitosis and meiosis. Techniques used include karyotyping, analysis of G-
banded chromosomes, other cytogenetic banding techniques, as well as
molecular cytogenetics such as fluorescent in situ hybridization (FISH) and
comparative genomic hybridization (CGH).
In the event of procedures which allowed easy enumeration of chromosomes,
discoveries were quickly made related to aberrant chromosomes or
chromosome number. In some congenital disorders, such as Down syndrome,
cytogenetics revealed the nature of the chromosomal defect: a "simple" trisomy.
Abnormalities arising from nondisjunction events can cause cells with
aneuploidy (additions or deletions of entire chromosomes) in one of the parents
or in the fetus. In 1959, Lejeune discovered patients with Down syndrome had
an extra copy of chromosome 21. Down syndrome is also referred to as trisomy
21.
Other numerical abnormalities discovered include sex chromosome
abnormalities. A female with only one X chromosome has Turner syndrome,
whereas an additional X chromosome in a male, resulting in 47 total
chromosomes, has Klinefelter Syndrome. Many other sex chromosome
combinations are compatible with live birth including XXX, XYY, and XXXX.
The ability for mammals to tolerate aneuploidies in the sex chromosomes arises
from the ability to inactivate them, which is required in normal females to
compensate for having two copies of the chromosome. Not all genes on the X
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chromosome are inactivated, which is why there is a phenotypic effect seen in

individuals with extra X chromosomes.
Trisomy 13 was associated with Patau Syndrome and trisomy 18 with Edwards
Syndrome.
In 1960, Peter Nowell and David Hungerford discovered a small chromosome
in the white blood cells of patients with Chronic myelogenous leukemia (CML).
This abnormal chromosome was dubbed the Philadelphia chromosome - as both
scientists were doing their research in Philadelphia, Pennsylvania. Thirteen
years later, with the development of more advanced techniques, the abnormal
chromosome was shown by Janet Rowley to be the result of a translocation of
chromosomes 9 and 22. Identification of the Philadelphia chromosome by
cytogenetics is diagnostic for CML.
Multi Factorial Inheritance
Multifactorial inheritance means that "many factors" (multifactorial) are
involved in causing a birth defect. The factors are usually both genetic and
environmental, where a combination of genes from both parents, in addition to
unknown environmental factors, produce the trait or condition. Often one
gender (either males or females) is affected more frequently than the other in
multifactorial traits. There appears to be a different "threshold of expression",
which means that one gender is more likely to show the problem over the other
gender. For example, hip dysplasia is nine times more common in females than
males.
Multifactorial traits do recur in families, because they are partly caused by
genes. The chance for a multifactorial trait or condition to happen again
depends upon how closely the family member with the trait is related to you.
For example, the risk is higher if your brother or sister has the trait or disease,
than if your first cousin has the trait or disease. Family members share a certain
percentage of genes in common, depending upon their relationship. For
example:
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Percentage of
Degrees of
Genes in  Example
relationship
Common

First Degree  Parents, children,

50 percent
Relative siblings

 Aunts, uncles,
Second Degree
25 percent nieces, nephews,
Relative
grandparents

Third Degree
12.5 percent  First cousins
Relative

Now, if we look at a multifactorial condition, such as a neural tube defect

(NTD), the chance for this birth defect to be seen in a future pregnancy would
be:
 Three to 5 percent if you had a child with a NTD.
 Two percent if you had an aunt or uncle with a NTD.
 About 0.5 percent if your cousin had a NTD.
Biochemistry of Genetic Diseases