Genetics dentistry part 1 2017

What is Genetics?
• The branch of science concerned with the means and consequences of
transmission and generation of the components of biological
inheritance.
• The study of the structure and function of genes and the transmission
of genes from parents to offspring.
• The branch of biology that deals with heredity, especially the
mechanisms of hereditary transmission and the variation of inherited
characteristics among similar or related organisms.
• The scientific study of heredity how particular qualities or traits are
transmitted from parents to offspring.

Genetics, genes, genomics
• Genetics is the study of biologically inherited traits
determined by elements of heredity that are
transmitted from parents to offspring in reproduction.
• These inherited elements are called genes.
• Genomics is the latest advance in the study of the
chemical nature of genes and the ways that genes
function to affect certain traits.
• Recent advances in the field of genomics have led to
development of methods that can determine the
complete deoxyribonucleic acid (DNA) sequence of
an organism.

Genetics Branches (Approaches)
There are four major branches or approaches of genetics:
• Classical genetics (transmission genetics)
• Cytogenetics (study of chromosome and karyotyping)
• Molecular genetics (recombinant DNA technology)
• Population genetics. (genetic variation in populations).
• All genetics before 1970s are classical and Cytogenetics.
• Molecular genetics promoted our knowledge on
understanding of genes and their behavior.
• Population genetics tries to answer questions about gene
behavior at population level

Genetics and Genes
Genetic Material (DNA), Packaged as Chromosomes, Encodes
Proteins and Cellular Materials that Influence How Cells Grow and
Develop.

>>> Genetics and Genes
• Genes are:
• The functional and physical unit of heredity passed from
parent to offspring. Genes are pieces of DNA, and most
genes contain the information for making a specific protein.
• The basic unit of heredity, consisting of a segment of DNA
arranged in a linear manner along a chromosome, which
codes for a specific protein or segment of protein leading to
a particular characteristic or function.
• The fundamental physical and functional unit of heredity. A
gene is an ordered sequence of nucleotides located in a
particular position on a particular chromosome that encodes
a specific functional product (i.e., a protein or RNA
molecule).

• Humans have approximately 20,000 to 25,000 genes.
• We share about:
• 80% with a mouse
50% with a fruit fly
20% with a tiny worm
• Therefore Genetics could be defined as the study of genes:
How do they work?
How do mistakes in genes cause disease?
How are they passed on from generation to generation
How can genes be changed?
How can genes be added to an animal or a plant?
What job does each gene in a human have?

• A gene gives only the potential for the
development of a trait. However, how this
potential is achieved depends:
• Partly on the interaction of the gene with other genes.
• It also depends partly on the environment.
• For example, a person may have a genetic
tendency toward being overweight. But the
person's actual weight will depend on such
environmental factors as how what kinds of food
the person eats and how much exercise that
person does.

• Diagnosis and Treat of Diseases.
• Improves crops to feed the world's population.
• Develops new drugs and therapies.
• Conserves endangered species.
• Preserves our Environment
Genetics in the Real World

What is the difference between genetics and heredity
• Heredity is the passing on of characteristics from
one generation to the next.
• The process of heredity occurs among all living
things including animals, plants, bacteria, protists
and fungi.
• The study of heredity is called Genetics and
scientists that study heredity are called Geneticists

Congenital vs. Hereditary
• It can be very confusing for individuals trying to gain an
understanding of illnesses or disorders to understand the difference
between a congenital and a hereditary abnormalities or disorders
• A hereditary condition is one that is genetically predetermined. It
is dependent on the genetic material or chromosomes that a person
inherits from one or both biological parents. Colorblindness and
Thalassaemia are two hereditary conditions that are passed on to a
fetus from the genes of the mother and father .
• While congenital means that a condition is present at birth. These
malformations and abnormities of structure and, consequently,
function of the human body arising during development.
• Thus, cleft lip or palate represents an example of a congenital
malformation.
• Not all genetic disorders are congenital in terms of age of onset (e.g.,
Huntington disease), nor are all congenital abnormalities genetic in
origin (e.g., fetal disruptions, birth defects ).
• Of all neonates, 2% to 3% have at least one major congenital
abnormality, of which at least 50% are caused exclusively or partially
by genetic factors

Heredity and Heritability
• Heredity is the passing on of characteristics from
one generation to the next.
• Heritability is the extent to which the phenotype is
determined by the genetic makeup of the
individual.
• Some traits are purely genetic, and these traits have
a high heritability.
• Other traits are strongly influenced by the
individual's environment, and their heritability is
low.
• Many traits are produced by a complex mixture of
genetics and environment.

The History and Impact of Genetics in Science Medicine
• Humans have understood genetics on some
level for thousands of years.
• Improving crops and animals through selecting
desirable traits and attempting to propagate
them.
• People noting that members of certain families
tend to have distinctive anatomical features.
The Habsburgs of Austria, for example, are
famous for their prognathic jaws.

Prognathic jaws in Habsburgs family of Austria

Historical Background of Genetics
• However, the science of genetics is one of
the most youthful of the major biological
sciences.
• It originated in 1900 with the rediscovery
of a scientific article originally published
in 1866 by a monk named Gregor Mendel.

Timeline of notable discoveries
• 1865 Gregor Mendel's paper, Experiments on Plant Hybridization
• 1903 Chromosomes are discovered to be hereditary units
• 1905 British biologist William Bateson coins the term "genetics"
• 1910 Thomas Hunt Morgan shows that genes reside on chromosomes
• 1913 Gene maps show chromosomes containing linear arranged genes
• 1927 Physical changes in genes are called mutations
• 1928 Frederick Griffith discovers a hereditary molecule that is transmissible between
bacteria
• 1931 Crossing over is the cause of recombination
• 1941 Edward Lawrie Tatum and George Wells Beadle show that genes code for proteins;
• 1944 Oswald Theodore Avery, Colin McLeod and Maclyn McCarty isolate DNA as the
genetic material (transforming principle)
• 1950 Erwin Chargaff shows that the four nucleotides are not present in nucleic acids in
stable proportions, but that some general rules appear to hold (e.g., that the amount of
adenine, A, tends to be equal to that of thymine, T).

>>> Timeline of notable discoveries
• 1952 The Hershey-Chase experiment proves the genetic information of phages (and
all other organisms) to be DNA
• 1953 DNA structure is resolved to be a double helix by James D. Watson and
Francis Crick
• 1958 The Meselson-Stahl experiment demonstrates that DNA is
semiconservatively replicated
• 1961 The genetic code is arranged in triplets
• 1977 DNA is sequenced
• 1997 First genome sequenced
• 2001 First draft sequences of the human genome are released.
• 2003 (14 April) Successful completion of Human Genome Project with 99% of the
genome sequenced to a 99.99% accuracy

• The characters which provide individuality to a species are
said to cause variation among the species.
The variations may be of following two kinds:
• 1. Hereditary variations-Among the sexually reproducing
organisms no two individuals have the same heredity. The
differences in the hereditary constitutions of the individuals of
a species are known as hereditary or genetic variations.
• 2. Environmental variations- The variations which are not
inherited but are due to the effects of temperature, moisture,
food, light or other environmental factors on the development
of the organism, are called environmental variations. For
example, the differences between a well-nourished and
malnourished person are environmental because these are
caused by the food factor.

Classical Genetics Mendelian Genetics
• In 1865, the monk Gregor Mendel published some
remarkable observations about peas Pisum sativum)
which received little attention at the time.
• Mendel work, entitled “Experiments on HybridExperiments on Hybrid
PlantsPlants,”
• Mendel observed that certain traits in garden peas
(Pisum sativum) are inherited independently of one
another.
• Mendel described certain regularities in the pattern of
occurrence of individual traits in consecutive
generations

Classical Genetics: Mendelian Genetics
• In 1900 Mendel’s principles were awaiting rediscovery,
chromosomes were hardly visible, and the science of
molecular genetics did not exist.
• In the last decade, chromosomes can be rapidly analyzed to
an extraordinary level of sophisticated techniques and the
sequence of the entire human genome has been published.
• Some 13,000 human genes with known sequence are listed
and nearly 6500 genetic diseases or phenotypes have been
described, of which the molecular genetic basis is known in
approximately 2650.

• Our present understanding of human genetics owes much to
the work of the Austrian monk Gregor Mendel (1822–1884)
who, upon his experiments, established four main principles
or postulates.
• He observed that each pair of traits was inherited
independently from all other pairs of traits.
• Mendel’s main observation was that independent traits are
inherited in certain predictable patterns.
• This was a fundamental new insight into the process of
heredity.
Classical Genetics: Mendelian Genetics

Classical Genetics Mendelian Genetics
• Simple Mendelian Genetics
• Mendel's Four Postulates
Unit factors in pairs
Dominance/ excessiveness
Segregation
Independent assortment

Unit factors in pairs
• Genetic characteristics are controlled by unit
factors which exist in pairs in individual
organisms
• Modern terminology
– genes on homologous chromosomes; diploid individuals

Dominance/ recessiveness
– When two unlike unit factors are present in a
single individual, one is usually dominant to the
other, which is recessive
One allele may be dominant to a second;
heterozygotes express phenotype of dominant
allele

Segregation
• During the formation of gametes, the
paired unit factors separate
(segregate) randomly so that each
gamete receives one or the other
• Homologous chromosomes segregate
into different gametes.

Independent assortment
• During the formation of gametes,
segregating pairs of unit factors assort
independently of each other
• Genes on non-homologous chromosomes
will assort into gametes independently of
one another
–Aa Bb --> AB Ab aB ab

Chromosomes
• Chromosomes are the means by which the genes are
transmitted from generation to generation.
• The exact location of a gene on a chromosome is known as its
locus, and the array of loci constitutes the human gene map.
• Homologous copies of a gene are termed alleles.
• If alleles are truly identical, their coding sequences and the
number of copies do not vary, so the individual is homozygous
at that specific locus.
• However, if the DNA is analyzed using either restriction
enzyme examination or nucleotide sequencing, then, despite
having the same functional identity, the alleles would be
viewed as different and the individual would be heterozygous
for that locus. (not to differences in the protein products).

Heterozygous
• A heterozygous individual or genotype
frequently results when different alleles are
inherited from the egg and the sperm, but it
may also occur as a consequence of
spontaneous alteration in nucleotide sequence
that results in a mutation

Variation or change in the genetic material
• The variation or change in the genetic material (Mutation)
could occur at the gene level or at the chromosome level.
• At the gene level it is called mutation or gene mutation
• at the chromosome level it is called chromosomal
Aberration (Chromosome mutations) and involving
whole chromosomes or parts of chromosomes

Occurrence of mutation
• Mutations can occur spontaneously as a result of
natural biochemical processes, or they can be induced
by external factors, such as chemicals or radiation.
• Single-gene mutations cause a wide variety of human
diseases.
• Organisms depend on a number of DNA repair
mechanisms to counteract mutations. These
mechanisms range from proofreading and correction
of replication errors and base excision repair.
• Mutations in genes whose products control DNA
repair lead to genome hypermutability, human DNA
repair diseases, and cancers.

Gene Mutation
• A mutation is a permanent change or alternation in the
DNA sequence that makes up a gene.
• Mutation is a source of genetic variation that contributes to
cell death, genetic diseases, and cancer.
• Mutations have a wide range of effects on organisms
depending on the type of base-pair alteration, the location of
the mutation within the chromosome, and the function of the
affected gene product
• A mutation may comprise a single base-pair substitution, a
deletion or insertion of one or more base pairs.
• Mutations range in size from a single base pair to a large
segment of a chromosome.

Germinal and Somatic Mutations
• Mutations can occur in somatic cells or within germ cells.
• A germinal mutation occurs during (gametogenesis) formation of an
egg or a sperm.
• Germinal mutations are heritable and are the basis for the
transmission of genetic diversity and genetic diseases.
• If the change occurs after conception, it is termed a somatic
mutation.
• somatic mutations also known as acquired are not transmitted to the
next generation but may lead to altered cellular function or tumors.
• somatic mutations occur in the DNA of individual cells at some time
during a person’s life. These changes can be caused by environmental
factors or can occur if a mistake is made as DNA copies itself during
cell division.
• The role of somatic mutation is now increasingly recognized as a key
factor in the etiology of human disease

Gene Mutations
• Gene mutations occur in two ways:
– Mutations inherited from a parent.
– de novo mutations: present for the first time in one family member
• Mutations that occur only in an egg or sperm cell, or those
that occur just after fertilization, are called new (de novo)
mutations.
• de novo mutations may explain genetic disorders in which
an affected child has a mutation in every cell, but has no
family history of the disorder.
• Novel mutation: mutation that has not been discovered or
mentioned before.

Mosaicism
• Mutations may also occur in a single cell within an
early embryo.
• As all the cells divide during growth and
development, the individual will have some cells with
the mutation and some cells without the genetic
change. This situation is called mosaicism.

Types of Mutation
• Mutations can range from single base substitutions, through
insertions and deletions of single or multiple bases to loss or gain
of entire chromosomes. Base substitutions are most prevalent.
• A substitution is the replacement of a single nucleotide by another.
These are the most common type of mutation.
• If the substitution involves replacement by the same type of
nucleotide—a pyrimidine for a pyrimidine (C for T or vice versa) or
a purine for a purine (A for G or vice versa); this is termed a
transition.
• Substitution of a pyrimidine by a purine or vice versa is termed a
transversion.
• Transitions occur more frequently than transversions

Deletions and Insertions
• A Deletion involves the loss of one or more nucleotides.
• An Insertion involves the addition of one or more
nucleotides into a gene.
• Frameshift mutation: If deletion or insertion occurs in
coding sequences and involves one, two, or more
nucleotides that are not a multiple of three, the reading
frame will be disrupted.
• Larger deletions or insertions may result in partial or
whole gene deletions and may arise through unequal
crossover between repeat sequences.

Structural Effects of Mutations on the Protein
• Mutations can also be subdivided into two main groups according to the
effect on the polypeptide sequence of the encoded protein, being either:
• Synonymous or silent mutation: If a mutation does not alter the
polypeptide product of the gene. A single base-pair substitution, particularly
if it occurs in the third position of a codon because of the degeneracy of the
genetic code, will often result in another triplet that codes for the same
amino acid with no alteration in the properties of the resulting protein.
• Non-synonymous mutation: If a mutation leads to an alteration in the
encoded polypeptide. The alteration of the amino acid sequence of the
protein product of a gene is likely to result in abnormal function, which is
usually associated with disease, or lethality, which has an obvious selective
disadvantage.
• Non-synonymous mutations can occur in one of three main ways:
– Missense
– None-sense
– Framshift

Non-Synonymous Mutations: Missense
• In Missense : A single base-pair substitution can result in
coding for a different a.a and the synthesis of an altered
protein.
• If the mutation codes for a.a that is chemically dissimilar,
for example has a different charge, the structure of the
protein will be altered. This is termed a non-conservative
substitution and can lead to a gross reduction, or even a
complete loss, of biological activity.
• Some single base-pair substitutions result in the replacement
of a different a.a that is chemically similar, and may have
no functional effect. These are termed conservative
substitutions.

Non-Synonymous Mutations: Nonsense
• In Nonsense, A substitution that leads to the generation of one of
the stop codons will result in premature termination of
translation of a peptide chain, or what is termed a nonsense
mutation.
• In most cases the shortened chain is unlikely to retain normal
biological activity, particularly if the termination codon results in
the loss of an important functional domain(s) of the protein.
• mRNA transcripts containing premature termination codons are
frequently degraded by a process known as nonsense-mediated
decay.
• This is a form of RNA surveillance (monitoring) that is believed
to have evolved to protect the body from the possible consequences
of truncated proteins interfering with normal function.

Non-Synonymous Mutations: framshift
• If a mutation involves the insertion or deletion of
nucleotides that are not a multiple of three, it will disrupt
the reading frame and constitute what is known as a
frameshift mutation.
• The amino-acid sequence of the protein subsequent to the
mutation bears no resemblance to the normal sequence and
may have an adverse effect on its function.
• Most frameshift mutations result in a premature stop codon
downstream to the mutation. This may lead to expression of
a truncated protein, unless the mRNA is degraded by
nonsense-mediated decay.

Mutations in Non-Coding DNA
• In general, mutations in non-coding DNA are less
likely to have a phenotypic effect.
• Exceptions include mutations in promoter sequences
or other regulatory regions that affect the level of gene
expression.
• Splicing Mutations: Mutations of the highly
conserved splicing regions (Intron-exon boundaries)
usually result in aberrant or abnormal splicing. This
can result in the loss of coding sequence (exon
skipping) or retention of intronic sequence, and may
lead to frameshift mutations.

Functional Effects of Mutations on the Protein
• In general mutations exert their phenotypic effect in one of
two ways, through either: loss or gain of function
• Loss of function: results in either reduced activity or
complete loss of the gene product.
• The reduced activity can be the result of reduced activity or of
decreased stability of the gene product and is known as a
hypomorph.
• Complete loss: being known as a null allele or amorph.
• Loss-of-function mutations involving enzymes are usually
inherited in an autosomal or X-linked recessive manner,
because the catalytic activity of the product of the normal
allele is more than adequate to carry out the reactions of most
metabolic pathways.

Gain-of-Function Mutations
• Gain-of-function mutations, result in either increased levels of gene
expression or the development of a new function(s) of the gene
product.
• Mutations that alter the timing or tissue specificity of the expression of
a gene can also be considered to be gain of-function mutations.
• Increased expression levels from activating point mutations or increased
gene dosage are other examples.
• The expanded triplet repeat mutations in the Huntington gene cause
qualitative changes in the gene product that result in its aggregation in
the central nervous system leading to the classic clinical features of the
disorder.
• Gain-of-function mutations are usually dominantly inherited and the
rare instances of gain-of-function mutations occurring in the
homozygous state are often associated with a much more severe
phenotype, which is often a prenatally lethal disorder

Dominant-Negative Mutations
• A dominant-negative mutation is one in which a mutant
gene in the heterozygous state results in the loss of protein
activity or function, as a consequence of the mutant gene
product interfering with the function of the normal gene
product of the corresponding allele.
• Dominant-negative mutations are particularly common in
proteins that are dimers or multimers.

Mutations and Mutagenesis
• Naturally occurring mutations are referred to
as spontaneous mutations and are thought to
arise through chance errors in chromosomal
division or DNA replication.
• Environmental agents that cause mutations
are known as mutagens. These include natural
or artificial ionizing radiation and chemical or
physical mutagens.

Ionizing radiation
• Ionizing radiation includes electromagnetic waves of:
– Very short wavelength (x-rays and γ rays)
– High-energy particles (α particles, β particles, and neutrons).
• x-rays and γ rays and neutrons have great penetrating power.
• But α particles can penetrate soft tissues to a depth of only a fraction
of a millimeter
• β particles only up to a few millimeters.
• The dose of radiation is expressed in relation to the amount received
by the gonads because it is the effects of radiation on germ cells rather
than somatic cells that are important as far as transmission of
mutations to future progeny is concerned.
• The gonad dose of radiation is often expressed as the amount
received in 30 years. This period has been chosen because it
corresponds roughly to the generation time in humans.

Genetic Effects of ionizing radiation
• The number of mutations produced by irradiation is
proportional to the dose: the larger the dose, the greater the
number of mutations produced. The total number of radiation-
induced mutations is directly proportional to the total gonadal
dose.
• It is believed that there is no threshold below which
irradiation has no effect—even the smallest dose of radiation
can result in a mutation.
• The genetic effects of ionizing radiation are also cumulative,
so that each time a person is exposed to radiation, the dose
received has to be added to the amount of radiation already
received.

Chemical Mutagens
• In humans, chemical mutagenesis may be more important than
radiation in producing genetic damage.
• Experiments have shown that certain chemicals, such as mustard
gas, formaldehyde, benzene, some basic dyes, and food additives,
are mutagenic in animals.
• Exposure to environmental chemicals may result in the formation of
DNA adducts, chromosome breaks, or aneuploidy.
• DNA adducts are a form of DNA damage caused by covalent
attachment of a chemical molecules or compound to DNA.
• Adducts are products of a direct addition of two or more distinct
molecules that are not removed by the cell so can cause mutations
that may give rise to cancer
• Consequently all new pharmaceutical products are subject to a
battery of mutagenicity tests that include both in vitro and in vivo
studies in animals.

Chromosome mutations or Chromosome aberrations
• The most dramatic type of mutation is an alteration in the number or physical
structure of chromosomes, a phenomenon called a chromosomal aberration,
to distinguish them from gene mutations.
• Diploid species normally contain precisely two haploid chromosome sets,
however, many known cases vary from this pattern. Variations include a
change in:
– the total number of chromosomes (addition or loss) .
– the deletion or duplication of genes or segments of a chromosome
– rearrangements of the genetic material either within or among chromosomes.
• Because the genetic component of an organism is precisely balanced, even
minor alterations of either content or location of genetic information within
the genome can result in some form of phenotypic variation.
• Approximately 1 in every 200 live-born infants has a chromosomal aberration
that is detected because of some effect on phenotype.
• More substantial changes may be lethal, particularly in animals
• By the end of the first trimester of gestation, most fetuses with abnormal
numbers of chromosomes have been lost through spontaneous abortion.

Variation in chromosome number: Numerical Abnormalities
• Variation in chromosome number ranges from the addition or loss of one or
more chromosomes to the addition of one or more haploid sets of
chromosomes.
• Aneuploidy: an organism gains or loses one or more chromosomes but not a
complete set. The loss of a single chromosome is called monosomy, while the
gain of one chromosome results in trisomy.
• Euploidy, where complete haploid sets of chromosomes are present. If more
than two sets are present, the term polyploidy applies.
• Organisms with three sets are specifically triploid, those with four sets are
tetraploid,
• Such chromosomal variation originates from nondisjunction during
gametogenesis , whereby paired homologs fail to disjoin during segregation.
• The cause of non-disjunction is uncertain. The most favored explanation is that
of an aging effect on the primary oocyte, which can remain in a state of
suspended inactivity for up to 50 years.
• This is based on the well-documented association between advancing maternal
age and increased incidence of Down syndrome in offspring. A maternal age
effect has also been noted for trisomies 13 and 18.

Does advancing maternal age predispose to non-disjunction?
• It is not known how or why advancing maternal age predisposes to non-
disjunction, although research has shown that absence of recombination
(crossover) in prophase I predisposes to subsequent non-disjunction.
• This is not surprising, as the chiasmata that are formed after crossover are
responsible for holding each pair of homologous chromosomes together
until subsequent separation occurs in diakinesis. Thus failure of chiasmata
formation could allow each pair of homologs to separate prematurely and
then segregate randomly to daughter cells.
• In the female, however, crossover occurs before birth whereas the non-
disjunctional event occurs any time between 15 and 50 years later.
• This suggests that at least two factors can be involved in causing non-
disjunction:
• an absence of recombination between homologous chromosomes in the fetal
ovary.
• an abnormality in spindle formation many years later.

Polyploidy
• Polyploidy originates in two ways:
• The addition of one or more extra sets of chromosomes, identical to the
normal haploid complement of the same species, resulting in
autopolyploidy.
• The combination of chromosome sets from different species occurring
as a consequence of hybridization, resulting in allopolyploidy
• Autotriploids arise in several ways. A failure of all chromosomes to
segregate during meiotic divisions can produce a diploid gamete. If such
a gamete is fertilized by a haploid gamete, a zygote with three sets of
chromosomes is produced.
• Rarely, two sperm may fertilize an ovum, resulting in a triploid
zygote.
• Triploids are also produced under experimental conditions by crossing
diploids with tetraploids. Diploid organisms produce gametes with n
chromosomes, while tetraploids produce 2n gametes. Upon fertilization,
the desired triploid is produced.

Polyploidy
• Because they have an even number of chromosomes, autotetraploids (4n)
are theoretically more likely to be found in nature than are autotriploids.
• Unlike triploids, which often produce genetically unbalanced gametes with
odd numbers of chromosomes, tetraploids are more likely to produce
balanced gametes when involved in sexual reproduction.
• How polyploidy arises experimentally ?
• This is accomplished by applying
• cold or heat shock to meiotic cells
• Colchicine to cells undergoing division. Colchicine, an alkaloid,
interferes with spindle formation, and thus replicated chromosomes cannot
separate at anaphase and do not migrate to the poles.
• Gout disease, familial Mediterranean fever (FMF) and impairment of
spermatogenesis

Triploidy in humans
• In humans, triploidy is found relatively often in material grown from
spontaneous miscarriages, but survival beyond mid-pregnancy is rare.
• Only a few triploid live births have been described and all died soon after
birth
• Triploidy can be caused by failure of a maturation meiotic division in an
ovum or sperm, leading, for example, to retention of a polar body or to the
formation of a diploid sperm.
• Alternatively it can be caused by fertilization of an ovum by two sperm: this
is known as dispermy.
• When triploidy results from the presence of an additional set of paternal
chromosomes, the placenta is usually swollen with what are
known as hydatidiform changes .
• In contrast, when triploidy results from an additional set of maternal
chromosomes, the placenta is usually small.
• Triploidy usually results in early spontaneous miscarriage.

Chromosome Structural Abnormalities
• Structural Abnormalities are due to structural chromosome rearrangements
result from chromosome breakage with subsequent reunion in a different
configuration.
• Rearrangements can be balanced or unbalanced.
• In balanced rearrangements the chromosome complement is complete, with no
loss or gain of genetic material. Consequently, balanced rearrangements are
generally harmless with the exception of rare cases in which one of the
breakpoints damages an important functional gene.
• carriers of balanced rearrangements are often at risk of producing children
with an unbalanced chromosomal complement.
• In unbalanced the chromosomal complement contains an incorrect amount of
chromosome material and the clinical effects are usually serious.
• If either parent carries a balanced translocation, it is possible that their child
may inherit an unbalanced translocation in which there is an extra piece of
one chromosome and/or a missing piece of another chromosome.

Translocations
• A translocation refers to the transfer of genetic material from one
chromosome to another.
• A reciprocal translocation is formed when a break occurs in each
of two chromosomes with the segments being exchanged to form
two new derivative chromosomes.
• A Robertsonian translocation is a particular type of reciprocal
translocation in which the breakpoints are located at, or close to, the
centromeres of two acrocentric chromosomes.

Reciprocal Translocations
• A reciprocal translocation involves breakage of at least two
chromosomes with exchange of the fragments.
• Usually the chromosome number remains at 46 and, if the
exchanged fragments are of roughly equal size, a reciprocal
translocation can not be identified by simple karyotyping,
however it be identified only by detailed chromosomal banding
studies or FISH (Fluorescence in situ hybridization: a cytogenetic
technique that uses fluorescent probes that bind to Chromosome).
• In general, reciprocal translocations are unique to a particular
family, although, for reasons that are unknown, a particular
balanced reciprocal translocation involving the long arms of
chromosomes 11 and 22 is relatively common.
• The overall incidence of reciprocal translocations in the general
population is approximately 1 in 500.

Segregation of balanced reciprocal translocations at Meiosis
• The importance of balanced reciprocal translocations lies in their behavior
at meiosis, when they can segregate to generate significant chromosome
imbalance. This can lead to early pregnancy loss or to the birth of an infant
with multiple abnormalities.
• Problems arise at meiosis because the chromosomes involved in the
translocation cannot pair normally to form bivalents. Instead they form
a cluster known as a pachytene quadrivalent chromosome
• The key point to note is that each chromosome aligns with homologous
material in the quadrivalent.
• Two modes of segregation in the pachytene quadrivalent :
2 : 2 Segregation
3 : 1 Segregation

Balanced reciprocal translocation of chromosomes 11 and 22 leading to the
formation of a quadrivalent at pachytene in meiosis I.
The quadrivalent is formed to maintain homologous pairing.
Quadrivalent chromosome

2:2 Segregation: alternates segregation
• When the constituent
chromosomes in the
quadrivalent separate during
anaphase I, they can do so in
several different ways:
• 1- alternates segregation. If
alternate chromosomes
segregate to each gamete, the
gamete will carry a normal or
balanced haploid
complement and with
fertilization the embryo will
either have normal
chromosomes or carry the
balanced rearrangement.

2:2 Segregation: adjacent segregation
• 2- adjacent segregation. If,
however, adjacent chromosomes
segregate together, this will always
result in the gamete acquiring an
unbalanced chromosome
complement.
• For example, if the gamete inherits
the normal number 11 chromosome
(A) and the derivative number 22
chromosome (C), then fertilization
will result in an embryo with
monosomy for the distal long arm
of chromosome 22 and trisomy for
the distal long arm of chromosome
11.

3 : 1 Segregation
• Another possibility is that three chromosomes segregate to one gamete with
only one chromosome in the other gamete.
• If, for example, chromosomes 11 (A), 22 (D) and the derivative 22 (C)
segregate together to a gamete that is subsequently fertilized, this will result in
the embryo being trisomic for the material present in the derivative 22
chromosome. This is referred to as tertiary trisomy.
• This particular tertiary trisomy for the derivative 22 chromosome is the only
viable unbalanced product.
• All other patterns of malsegregation lead to early pregnancy loss.
• Unfortunately, tertiary trisomy for the derivative 22 chromosome is a serious
condition in which affected children have multiple congenital abnormalities
and severe learning difficulties.

Robertsonian Translocations
• A Robertsonian translocation results from the breakage of two
acrocentric chromosomes (numbers 13, 14, 15, 21, and 22) at or close
to their centromeres, with subsequent fusion of their long arms.
• This is also referred to as centric fusion.
• The short arms of each chromosome are lost, this being of no clinical
importance as they contain genes only for ribosomal RNA, for which
there are multiple copies on the various other acrocentric
chromosomes.
• The total chromosome number is reduced to 45.
• Because there is no loss or gain of important genetic material,
Robertsonian translocation is a functionally balanced rearrangement.
• The overall incidence of Robertsonian translocations in the general
population is approximately 1 in 1000, with by far the most common
being fusion of the long arms of chromosomes 13 and 14 (13q14q)

Robertsonian translocations: Segregation at Meiosis
• As with reciprocal translocations, the importance of Robertsonian translocations
lies in their behavior at meiosis
• For example, a carrier of a 14q21q translocation can produce gametes with:
– A normal chromosome complement (i.e., a normal 14 and a normal 21).
– A balanced chromosome complement (i.e., a 14q21q translocation chromosome).
– An unbalanced chromosome complement possessing both the translocation chromosome and a
normal 21. This will result in the fertilized embryo having Down syndrome.
– An unbalanced chromosome complement with a normal 14 and a missing 21.
– An unbalanced chromosome complement with a normal 21 and a missing 14.
– An unbalanced chromosome complement with the translocation chromosome and a normal 14
chromosome.
• The last three combinations will result in zygotes with monosomy 21, monosomy
14, and trisomy 14, respectively. All of these combinations are incompatible with
survival beyond early pregnancy.

Formation of a 14q21q Robertsonian translocation and the possible
gamete chromosome patterns that can be produced at meiosis

Deletions
• A deletion involves loss of part of a chromosome and results in monosomy
for that segment of the chromosome.
• A very large deletion is usually incompatible with survival to term, and
as a general rule any deletion resulting in loss of more than 2% of the total
haploid genome will have a lethal outcome.
• Deletions are now recognized as existing at two levels:
– A ‘large’ chromosomal deletion can be visualized under the light microscope. Such
deletion syndromes include Wolf-Hirschhorn ( facial appearance, delayed growth and
development, intellectual disability, and seizures) and cri du chat (intellectual disability and
delayed development, small head size), which involves loss of material from the short arms
of chromosomes 4 and 5, respectively.
– Submicroscopic microdeletions were identified with the help of high-resolution
prometaphase cytogenetics augmented by FISH studies and include Prader-Willi (weak
muscle tone, feeding difficulties, poor growth, and delayed development intellectual
impairments) and Angelman syndromes (neurodevelopmental disorder with severe
intellectual and developmental disability, sleep disturbance, seizures, jerky movements ).

Insertions
• An insertion occurs when a segment of one chromosome becomes inserted
into another chromosome.
• If the inserted material has moved from elsewhere in another chromosome
then the karyotype is balanced.
• Otherwise an insertion causes an unbalanced chromosome complement.
Carriers of a balanced deletion–insertion rearrangement are at a 50% risk
of producing unbalanced gametes, as random chromosome segregation
at meiosis will result in 50% of the gametes inheriting either the deletion or
the insertion, but not both.

Inversions
• An inversion is a two-break rearrangement involving a single
chromosome in which a segment is reversed in position (i.e., inverted).
• If the inversion segment involves the centromere it is termed a pericentric
inversion.
• If it involves only one arm of the chromosome it is known as a
paracentric inversion.
• Inversions are balanced rearrangements that rarely cause problems in
carriers unless one of the breakpoints has disrupted an important gene.
• A pericentric inversion involving chromosome number 9 occurs as a
common structural variant or polymorphism, also known as a
heteromorphism, and is not thought to be of any functional importance.
• However, other inversions, although not causing any clinical problems in
balanced carriers, can lead to significant chromosome imbalance in
offspring, with important clinical consequences

Ring Chromosomes
• A ring chromosome is formed when a break occurs on each arm
(telomeric) of a chromosome leaving two ‘sticky’ ends on the central
portion that reunite as a ring.
• The two distal chromosomal fragments are lost so that, if the involved
chromosome is an autosome, the effects are usually serious.
• Ring chromosomes are often unstable in mitosis so that it is common to
find a ring chromosome in only a proportion of cells. The other cells in the
individual are usually monosomic because of the absence of the ring
chromosome.

Isochromosome
• Isochromosome is an abnormal chromosome that has
two identical arms due to duplication of one arm and
loss of the other.
• Isochromosome having a median (metacentric)
centromere and two identical arms, formed by
transverse, rather than normal longitudinal, splitting of
a replicating chromosome.
• Normally centromere divides vertically. In
Isochromosome case it divides horizontally.

Mixoploidy: Mosaicism and Chimerism
• Mosaicism can be defined as the presence in an individual, or in a tissue, of two or
more cell lines that differ in their genetic constitution but are derived from a single
zygote, that is, they have the same genetic origin.
• Chromosome mosaicism usually results from non-disjunction in an early embryonic
mitotic division with the persistence of more than one cell line.
• If, for example, the two chromatids of a number 21 chromosome failed to separate at the
second mitotic division in a human zygote, this would result in the four-cell zygote
having two cells with 46 chromosomes, one cell with 47 chromosomes (trisomy 21), and
one cell with 45 chromosomes (monosomy 21).
• The resultant cell line with 45 chromosomes would probably not survive, so that the
resulting embryo would be expected to show approximately 33% mosaicism for
trisomy 21.
• Mosaicism accounts for 1% to 2% of all clinically recognized cases of Down
syndrome.
• Mosaicism can also exist at a molecular level if a new mutation arises in a somatic or
early germline cell division.
• The possibility of germline or gonadal mosaicism is a particular concern when
counseling the parents of a child in whom a condition such as Duchenne muscular
dystrophy is an isolated case.

Somatic mosaicism caused by mitotic non-disjunction

Chimerism
• Chimerism can be defined as the presence in an individual of two
or more genetically distinct cell lines derived from more than one
zygote; that is, they have a different genetic origin.
• The word chimera is derived from the mythological Greek monster
that had the head of a lion, the body of a goat and the tail of a
dragon.
• Chimeras are of two kinds: dispermic chimeras and blood chimeras

Dispermic Chimeras
• These are the result of double fertilization whereby two genetically
different sperm fertilize two ova and the resulting two zygotes fuse to form
one embryo (tetragametic individual)
• If the two zygotes are of different sex, the chimeric embryo can develop
into an individual with true hermaphroditism and an XX/XY karyotype.
• Mouse chimeras of this type can now be produced experimentally in the
laboratory to facilitate the study of gene transfer

Blood Chimeras
• Blood chimeras result from an exchange of hemopoietic stem cells
in utero, via the placenta, between non-identical (dizygotic twins).
• Chimerism is confirmed if a double contribution of maternal and
paternal alleles can be demonstrated in the two cell lines cells.
• For example, 90% of one twin’s cells can have an XY karyotype
with red blood cells showing predominantly blood group B, whereas
90% of the cells of the other twin can have an XX karyotype with
red blood cells showing predominantly blood group A.

Genetics dentistry part 1 2017

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