Psychiatric genetics Flashcards
It has been demonstrated that the levels of monoamine metabolites in
CSF varies with polymorphism of serotonin transporter protein. Which
of the following components of genetic apparatus is responsible for such
polymorphisms?
A. Non-coding sequences
B. RNA
C. Exons
D. Ribosomes
E. Chromosomal count
A. Polymorphism refers to variations in the genome at a particular locus noted in a
general, apparently healthy population. Polymorphisms occur at a fairly high frequency in the
general population. When the polymorphism occurs in more than 1% of a population, it can
be considered as useful for genetic linkage analysis. ABO blood groups are a good example
of polymorphism expressed in the protein products of genes. Restriction fragment length
polymorphisms are those variations that create or destroy the sites at which restriction
enzymes act on a DNA molecule, rendering differences in the fi nal ‘restricted’ or cleaved DNA
when these enzymes are applied in vitro. If these polymorphisms are due to changes in a single
nucleotide in a sequence, they are called SNPs or single nucleotide polymorphisms. SNPs
seem to be one of the most common genetic variations and various SNP genotyping methods
are being increasingly employed to study polymorphisms. Polymorphisms arise originally out
of mutations but are maintained in populations due to factors such as founder effect, genetic
drift, and natural selection. Note that most polymorphisms occur in non-coding regions (that
is introns), as coding sequences (or exons) on mutation often produce disease phenotypes.
Serotonin transporter polymorphisms have been identifi ed in the promoter region, which is a
non-coding part of DNA (5HTTLPR–5HT transporter linked promoter region). 5HTTLPR can
be a short or long variant. In those with a short variant, the serotonin transporter expression is
low; the short variant is speculated to be associated with a higher incidence of affective disorders,
anxiety, and PTSD. But the evidence is inconclusive as most studies are case–control design with
signifi cant heterogeneity. In addition, structural brain changes in the form of gray matter volume
reduction in areas important for emotional processing, such as the amygdala, have been noted in
subjects with the short variant of the promoter region.
An altered number of chromosomes is termed aneuploidy.
In the diagnosis of HIV, following a positive ELISA test, western blotting
could be used to confi rm the diagnosis. Which of the following cellular
components is separated by electrophoresis for western blotting?
A. Proteins
B. RNA
C. DNA
D. Cell membrane lipids
E. Free amino acids
A. Molecular analysis techniques include Southern, northern, and western blotting. Western
blotting is used in protein analysis, for example to detect HIV antibodies. Northern blotting
is used in RNA analysis, while Southern blotting is used in the analysis of DNA. Southern
blotting was named after its founder, Professor Edwin Southern; the other names were given to
differentiate among the various blotting techniques.
Genetic information in an organism is inherited equally from parents of
both sexes. An exception to this is seen in
A. Ribosomal RNA
B. Small arms of chromosomes
C. Mitochondrial DNA
D. Coding sequences of nuclear DNA
E. Non-coding sequences of nuclear DNA
C. Mitochondrial DNA is wholly inherited from the ovum. The sperm has no mitochondria
in its ‘head’; the ‘head’ is made of nuclear material and the acrosomal cap. The ‘body’ of sperm
have many mitochondria which provide energy to propel the ‘tail’. The ‘body’ and ‘tail’ are shed on
entry of sperm into the ovum. Hence the mitochondria of an embryo are completely maternally
derived. This is important in clinical genetics as mitochondrial DNA abnormalities result in
various diseases, such as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and
recurrent stroke syndrome) and Leber hereditary optic neuropathy. These diseases are purely
maternally inherited. Mitochondrial DNA codes for 13 proteins involved in the respiratory chain
in addition to 22 tRNAs and two ribosomal RNAs.
Microtubule-associated protein tau undergoes several post-translational
modifi cations and aggregates into paired helical fi laments in Alzheimer’s
disease. These modifi cations of tau include all of the following except
A. Hyperphosphorylation
B. Protein glycosylation
C. Ubiquitination
D. Polyamination
E. Amino acid activation
E. Amino acid activation is an important step in the translation of mRNA to proteins. As
tRNAs enter the cytoplasm after release from the nucleus where they are synthesized, they are
attached to specifi c amino acids according to the codon sequences. This is an energy-dependent
process called amino acid activation. The energy stored in such activated amino acids is used
in making peptide bonds during protein translation. Translation takes place in the cytoplasm
on ribosomes, where specifi c mRNAs are involved. Translation includes three steps—initiation,
elongation, and termination. The ribosome contains two sites—peptidyl P site where methioninecontaining
tRNA initially binds and aminoacyl A site where each new incoming tRNAs with
activated amino acids can bind. In the elongation step amino acids are added one by one in a
string-like fashion to produce proteins. Chain termination is signalled by one of three codons—
UAA, UGA, or UAG. Following this protein synthesis (or sometimes simultaneously at one end of
long proteins), post-translational modifi cations take place to transport the synthesized proteins
to appropriate cellular sites. These modifi cations take place in endoplasmic reticulum and golgi
bodies. This includes covalent modifi cations, protein folding, and tagging with signal peptides to
dispatch to appropriate cellular destinations. Glycosylation, proteolysis, phosphorylation, gamma
carboxylation, prenylation, ubiquitation, polyamination, and nitration are some of the recognized
post-translational modifi cations. This process is essential in tagging wrongly folded or aberrant
proteins to enter lysosomes for destruction.
Which one of the following refers to the synthesis of RNA molecules from DNA? A. Replication B. Translation C. Transcription D. Splicing E. Modifi cation
C. Transcription refers to the synthesis of RNA from DNA. Translation refers to the
production of proteins from RNA. Replication refers to the production of new DNA copies
from template copies of DNA. Splicing refers to the removal of non-coding sequences of RNA
following transcription. DNA contains both coding and non-coding sequences. To synthesize
proteins, the code contained in exons (coding sequences) are required. The heterogeneous
nuclear RNA, which contains both coding exons and non-coding introns, undergoes splicing by
spliceosomes within the nucleus to produce mature mRNA. Modifi cation refers to the posttranslational
changes in a protein molecule before it becomes functionally active.
Newly synthesized RNA molecules undergo splicing to produce mRNA.
Which one of the following best describes the process of splicing?
A. Introns are removed, exons are joined together.
B. Introns and exons are randomly spliced and pasted.
C. Both introns and exons are spliced out to make the RNA compact.
D. Splicing takes place in cytoplasm.
E. Splicing is a reversible process.
A. In splicing, the non-coding introns (intervening codons) are removed and exons are
pasted together, producing a compact mRNA. This takes place in the nucleus. The splicing
is carried out by small nuclear RNAs and protein complexes, which together constitute
spliceosomes. This is an irreversible process as normally hnRNAs (heterogeneous nuclear RNAs)
cannot be reassembled from mRNAs.
Which one of the following stages of the cell cycle is dominant in nondividing cells such as neurones? A. Synthetic phase (S) B. Gap phase 1 (G1) C. Gap phase 0 (G0) D. Gap phase 2 (G2) E. Mitotic phase (M)
C. Each cell undergoes a natural cycle in terms of its replication and nucleic acid synthesis
activity. The cell cycle consists of four separate phases: G1, S, G2, and M. G1 stands for growth
phase 1, S for synthetic phase, G2 for growth phase 2 and M for mitosis phase. In mitosis the
cellular material, including chromosomes, is divided between two daughter cells. Cells can leave
G1 phase to enter a G0 phase, also called the quiescent phase as no replicatory activity takes
place here. Most of these cells have temporarily or reversibly stopped dividing, for example liver
parenchyma, in which case they enter G1 phase on stimulation. Cells such as neurones enter
G0 phase indefi nitely, but note that this dogma of absolute neuronal cell cycle dormancy is
increasingly being challenged. A number of neurodegenerative diseases in humans, such as Pick’s
disease, intractable temporal lobe epilepsy, progressive supranuclear palsy, Lewy body disease,
and Parkinson’s disease, are thought to be associated with a few neurones retaining the ability to
re-enter mitosis, thus disrupting the normal cell cycle
Which one of the following nitrogenous bases is present in RNA but not DNA? A. Adenine B. Guanine C. Cytosine D. Thymidine E. Uracil
E. DNA and RNA are the most important nucleic acids in the cellular machinery. These
nucleic acids are composed of many nucleotides. Nucleotides are phosphorylated versions of
nucleosides. Each nucleoside consists of two components: a nitrogenous base and a pentose
sugar. There are two types of nitrogenous bases that can constitute a nucleoside—purines
and pyrimidines. Purines include adenine and guanine. Pyrimidines include cytosine, uracil, and
thymine. Thymine is usually found only in DNA while uracil is specifi c to RNA. DNA is double
stranded with hydrogen-bonded base pairs. In DNA adenine always bonds with thymine (two
hydrogen bonds) while cytosine bonds with guanine (three hydrogen bonds). As a result of this
specifi c pairing, the amount of total purines is always equal to the total pyrimidines in normal
DNA (Chargaff ’s rule).
Gene cloning is the process of insertion of foreign DNA into a replicating sequence such as a plasmid. Which of the following is essential for successful cloning? A. Restriction enzyme B. Actively meiotic cell C. RNA ligase D. Stem cell E. Ovum
A. Cloning is the process of copying; cloning laboratory animals refers to making identical
genetic copies of the organisms while cloning a gene refers to producing identical copies of the
gene. Gene cloning involves the insertion of foreign DNA into vectors such as bacterial plasmids
or phages. Replication of these vectors then produces numerous identical copies of the cloned
gene. In order to carry out successful cloning, a method of cutting DNA at specifi c sites to
obtain the necessary genetic element is crucial. This is possible using restriction enzymes. DNA
ligase (not RNA ligase) is used to paste the cut genetic element with plasmid DNA. A stem cell
or ovum is not necessary for gene cloning. Active mitosis is suffi cient to carry out cloning, thus
meiosis is not necessary for gene cloning
Polymerase chain reaction (PCR) was used in a study to search for various
viruses in hippocampal tissue and CSF of patients with schizophrenia. PCR
is the preferred method for the above study due to which of the following
properties?
A. A small sample of DNA is suffi cient to be detected by PCR.
B. PCR is useful even if viral sequences are not known previously.
C. PCR is not altered by contamination from other viruses in the lab.
D. Each amplifi cation procedure using PCR can be completed within a few months.
E. The DNA replication process using PCR is relatively error free
A. PCR stands for polymerase chain reaction. It is an amplifi cation process wherein a small
amount of DNA sample is amplifi ed many times to provide a supply for diagnostic analyses. The
polymerization requires heat-stable DNA polymerase, obtained from Thermus aquaticus. Just one
copy of a DNA sequence is suffi cient to undertake PCR (at least theoretically). As it is extremely
sensitive, contamination from other DNA present in the lab. environment (from bacteria, viruses,
and DNA of lab. personnel) presents signifi cant diffi culties. As PCR requires the hybridization
of primers to known sequences at either side of the region of interest (i.e. fl anking regions),
completely unknown sequences cannot be polymerized. DNA cloning by PCR can be performed
in a few hours, using relatively unsophisticated equipment. Typically, a PCR reaction consists of 30
cycles containing a denaturation, synthesis and reannealing step, with an individual cycle typically
taking 3–5 min in an automated thermal cycler. This compares favourably with the time required
for cell-based DNA cloning, which may take weeks. PCR is not error free. The DNA polymerases
used for PCR usually have no error correction mechanisms such as exonuclease activity. So, if an
error is made, initially it may get amplifi ed uncorrected, but this is less of a problem now with the
availability of high-fi delity DNA polymerases.
In a child with fl at occiput, Brushfi eld spots, and simian palmar creases, the most common cause of death is A. Cardiac failure B. Leukaemia C. Hypothyroidism D. Suicide E. Accidental injury
A. The presence of low, fl at occiput, Brushfi eld spots, and simian palmar creases indicates
Down’s syndrome. The most common cause of death in children with Down’s syndrome is
cardiac failure. Though hypothyroidism is a common accompaniment, this is rarely fatal. Suicide is
not a major cause of death in this group. In adults with Down’s syndrome, most of whom obtain
surgical correction for major cardiac anomalies at a younger age, leukaemia becomes a major
killer.
A child with low-set ears, polydactyly, and coloboma of the iris is diagnosed
to have Patau’s syndrome. Which of the following chromosomal aberrations
explains this presentation?
A. Meiotic non-disjunction
B. Mitotic non-disjunction
C. Reduplication of chromosome 13
D. Amplifi cation of the long arm of chromosome 18
E. Partial deletion of chromosome 18
A. Patau syndrome results from aneuploidy of chromosome 13 where three copies are
found. This is due to non-disjunction of chromosome 13 during meiosis, mostly in the mother.
Similar to Down’s, Patau’s syndrome is associated with increasing maternal age. Patau’s syndrome
may also occur as a result of random non-disjunction during early cell division, resulting in a
mosaic cell population. Rarely, Patau’s syndrome can result from a translocation that leaves the
fetus with three copies of chromosome 13. This is often a balanced translocation where almost
no signifi cant clinical changes are seen in the carrier, but this can affect the children of the carrier.
In non-translocation-related Patau’s syndrome, the chances of a couple having another child
with trisomy 13 is less than 1%. Most fetuses with trisomy 13 die in uterus. If survived, the clinical
features include mental retardation, microcephaly and holoprosencephaly, structural eye defects,
and congenital cardiac anomalies.
Heritability is often used to express the genetic contribution in a
multifactorial disease. Which of the following best describes heritability?
A. It refers to the share of genes contributing to a phenotype in an individual patient.
B. Heritability is disease specifi c and is always a fi xed measure for a population.
C. Zero heritability excludes the possibility of fi nding a genetic locus underlying causation.
D. Identifi cation of a genetic locus is necessary to estimate heritability.
E. Heritability cannot be measured for polygenic disorders.
C. Heritability is the proportion of variation in a trait that can be attributed to genetic
factors. It does not apply to a specifi c trait in an individual patient; it refers to the variation in the
population as a whole. It is not immutable for a specifi c disease in a population; it will vary with
the epidemiological changes in risk and environmental infl uences in a population, but it can be
fi xed at a specifi c time and for a given set of circumstances. Heritability is related to the feasibility
of fi nding a candidate gene for a disease or trait; if a disease has zero heritability in a population,
there is no chance of fi nding a gene. But this does not mean that ‘the higher the heritability, the
greater the feasibility of locating the genetic cause’. Heritability can be measured for polygenic
disorders even when candidate genes are not known.
The phenotypic variation seen in the general population for a particular trait, say height of a
person, can be explained by:
1. Total environmental effects—includes both shared and non-shared environmental effects
2. Total genetic effects—includes both additive genetic effects and dominance effects.
Narrow-sense heritability refers to the proportion of total phenotypic variation that can
be attributed to additive genetic variance. The proportion of the total phenotypic variation
attributed to total genetic variance is called broad-sense heritability
The risk of severe affective disorder in relatives of probands with bipolar affective disorder is A. 40% B. 55% C. 78% D. 19% E. 5%
D. The risk of severe affective disorder in fi rst-degree relatives of probands with bipolar
disorder is 19%. The average morbid risk of bipolar disorder itself is 8%, while unipolar
depression is around 11% in the fi rst-degree relatives of probands with a bipolar disorder. The
risk of severe affective disorders in fi rst-degree relatives of probands with unipolar depression is
estimated to be around 10%. Note that the lifetime risk of severe affective illness is about 3 to
5% for unipolar and 1% for bipolar disorders in the general population.
Which of the following chromosomal abnormalities results in a phenotype
with a cat-like cry and facial dysmorphism?
A. Partial deletion chromosome 5
B. Partial deletion chromosome 15
C. Trisomy chromosome 5
D. Trisomy chromosome 15
E. Non-disjunction chromosome 1
A. The clinical description in the question fi ts with cri-du-chat syndrome. This is a result
of partial deletion of small arm of chromosome 5. Cri-du-chat syndrome was fi rst described
by a French paediatrician, Lejeune, in 1963; he coined the term ‘cri-du-chat’ (cry of the cat). The
commonly associated clinical features of cri-du-chat syndrome are:
1. Cat-like cry
2. Dysmorphic facies
3. Profound global learning disability.
It is now recognized that this triad does not present in all patients. Restrictive language skills and
severely delayed psychomotor development are other notable features.
Which of the following polymorphism has been linked to performance on
working memory tasks in patients with schizophrenia?
A. MAO-A polymorphism
B. COMT polymorphism
C. 5-HT transporter promoter region
D. Apolipoprotein E polymorphism
E. MAO-B polymorphism
B. COMT polymorphism has been widely studied in schizophrenia. COMT stands for
catechol-o-methyl transferase. It is an important enzyme in the breakdown of dopamine in
prefrontal area of the brain. Though monoamine oxidase is the major enzyme in dopamine
metabolism in most other brain regions, COMT assumes special signifi cance in the prefrontal
brain area, at least in primates; the dopamine (reuptake) transporter is present at a low
density in the prefrontal area compared to the striatum. The gene for COMT is located on
chromosome 22q11. The deletion of 22q11 results in velo cardio facial syndrome (VCFS) or di
George syndrome. As many as 30% of affected individuals with VCFS meet diagnostic criteria for
schizophrenia. The existence of a valine-to-methionine (Val/Met) polymorphism has been noted,
stimulating more interest in COMT. Val/Val genotype results in a higher activity form, while Met/
Met is associated with lower activity of the enzyme. The higher activity variant leads to faster
breakdown and reduced availability of prefrontal dopamine. This may be associated with poorer
working memory function or ineffi cient prefrontal activity in such tasks.
Findings implicating GABA in working memory have been reported. Decreased expression
of the GABA biosynthetic enzyme glutamic acid decarboxylase 67 (GAD67), encoded by GAD1,
is found in the post-mortem brain tissue of schizophrenia patients. It has been shown that
the variation in GAD1 infl uences multiple domains of cognition, including declarative memory,
attention, and working memory. There may be epistasis between SNPs in COMT and GAD1,
suggesting a potential biological synergism, leading to increased risk. These coincident results
implicate GAD1 in the aetiology of schizophrenia and suggest that the mechanism involves altered
cortical GABA inhibitory activity in addition to COMT changes (Straub et al. 2007).
Which one of the following processes can inactivate a gene? A. Methylation B. Crossing over C. Uncoiling of a chromosome D. Unwinding of DNA strands E. Condensation
A. Chemical modifi cation of DNA is one method by which gene expression is controlled.
This can be achieved by adding methyl groups to some of the amino acids in DNA. In females,
randomly picked X chromosomes undergo methylation (Lyon’s hypothesis) resulting in Barr
bodies. In fragile-X syndrome, the fragile X site undergoes methylation, resulting in reduced
expression of the FMR1 gene on X chromosomes. This produces the phenotype of fragile-X
syndrome. Unwinding of DNA is an important step that precedes DNA synthesis (replication
from the template). Crossing over, condensation, and uncoiling are seen in the normal cell cycle.
Genes do not become inactivated during such processes and subsequent cellular synthetic
processes are intact.
Expression of genes depending upon the parent of origin is a phenomenon seen in A. Genomic imprinting B. Genetic anticipation C. Genetic amplifi cation D. Autosomal aneuploidy E. Fragmented penetrance
A. In genomic imprinting, the disease phenotype expressed depends on whether the
allele is of maternal or paternal lineage. This parent-of-origin phenomenon is an important
exception to Mendelian inheritance patterns. An often-quoted example is Angelman’s syndrome
and Prader–Willi syndrome. These are two clinically distinct, genetic diseases associated with
genomic imprinting on chromosome 15q11-q13. Major diagnostic criteria for Prader–Willi
syndrome include mental retardation, hypotonia, hyperphagia and obesity, hypogonadism, and
maturational delay. In Angelman’s syndrome ataxia, tremors, seizures, hyperactivity, and profound
mental retardation are accompanied by outbreaks of laughter (gelastic attacks). Approximately
70% of patients with Prader–Willi syndrome have a deletion in their paternally derived 15q11-
q13. Maternal uniparental disomy (inheriting both copies from the mother when the embryo
is formed) occurs in most of the remaining patients (25%). Most patients with Angelman’s
syndrome have a deletion in their maternally derived 15q11-q13. Paternal uniparental disomy
occurs in about 4% of Angelman’s syndrome. This parent-of-origin effect is thought to be due to
DNA methylation defects.
Genetic anticipation refers to the phenomenon wherein phenotypic expression of a
mutation occurs earlier in successive generations. This is seen in Huntington’s disease and other
trinucleotide repeat diseases. Autosomal aneuploidy, such as Down’s syndrome, are not ‘inherited’
diseases but show a correlation with maternal age, as an ageing ovum is prone to more cell
division errors. This is not the same as the parent-of-origin effect.
Which of the following clinical scenarios is most likely to be a result of
genetic anticipation?
A. Advanced maternal age increases the risk of Down’s syndrome.
B. Mitochondrial disorders are transmitted only from mothers.
C. Successive generations display the phenotype of Huntington’s chorea at an earlier age.
D. An autosomal recessive disorder presents with a mild dysfunction in heterozygous
individuals.
E. Male fetuses with one copy of a mutant X chromosome often die in utero.
C. The anticipation phenomenon refers to an aspect of several genetic disorders in which
the age at onset decreases and the severity of illness increases in successive generations.
The classical example is Huntington’s disease. This is also noted in other trinucleotide repeat
syndromes. Trinucleotide repeats undergo expansion during germ cell division, which further
destabilizes the mutant trinucleotide loci and the probability of the phenotypic expression
thus increases with every gametogenesis. This occurs more frequently with oogenesis than
spermatogenesis, leading to pronounced anticipation in maternally transmitted trinucleotide
diseases. Carriers of a heterozygous recessive mutation may show cellular level abnormalities
lifelong without overt disease manifestation; this is not genetic anticipation.
A large pedigree is observed for the occurrence of a rare form of recurrent
strokes. All affected females in the pedigree produce affected children of
both sexes. But none of the affected males pass the disease on to the next
generation. The most likely mode of inheritance is
A. X-linked dominant
B. X-linked recessive
C. Mitochondrial
D. Autosomal recessive
E. Spontaneous mutations
C. This description refers to MELAS, which shows mitochondrial inheritance. In
mitochondrial inheritance, the disease is transmitted from females to males but not from males
to females. MELAS stands for mitochondrial myopathy, encephalopathy, lactic acidosis, and
recurrent stroke. MELAS is a progressive neurodegenerative disorder. Patients may present with
seizures, diabetes mellitus, hearing loss, short stature, and exercise intolerance.
Which of the following conditions will produce more than one Barr body in
cells of affected patients?
A. Testicular feminization syndrome
B. Sexual infantilism due to Turner’s syndrome
C. Bilateral gynaecomastia due to Kleinfelter’s syndrome (47 XXY)
D. Triple-X syndrome with normal fertility
E. Fragile-X syndrome
D. In testicular feminization syndrome, the karyotype is usually 46 XY. Due to insensitivity
of androgen receptors, female sexual characteristics develop in such individuals. They will not
have Barr bodies. In those with Kleinfelter’s syndrome, the karyotype is usually 47 XXY. Here,
the individuals will have one Barr body in spite of being phenotypical males. Patients with
Turner’s syndrome have no Barr bodies as they have only one X chromosome, in spite of being
phenotypical females. Patients with triple-X syndrome show two Barr bodies in each cell. These
individuals are also called metafemales. In fragile-X syndrome the number of Barr bodies will not
be altered.
Mrs Smith is a 32-year-old woman with normal IQ scores whose son
has been recently diagnosed to have fragile-X syndrome. There is no
family history of fragile-X syndrome in her husband’s lineage, but Mrs
Smith’s maternal uncle had mental retardation, suspected to be fragile X
retrospectively. Which of the following best describes Mrs Smith’s genotype?
A. She has a premutation.
B. She has a complete mutation which is unexpressed.
C. She is completely normal in terms of her genotype.
D. She does not have a mutation due to variable penetrance of fragile-X syndrome.
E. She has a fragile-X chromosome whose expression will occur only after age 40.
A. Premutation is a term used in trinucleotide repeat diseases to suggest that someone is
harbouring the trinucleotide expansion but the expansion is not long enough to produce the
disease. But premutants will produce further expansion of the loci during gametogenesis and
thus their children will express the mutation if inherited. In this question the mother has no
phenotypic expression, which is rare to occur after age 32. Her genotype cannot be normal
as her uncle and son are both affected by fragile-X syndrome. Fragile-X syndrome has nearly
complete penetration falsifying the fourth option
If a mother has alleles ‘pp’ while a father has alleles ‘Pp’ at the same locus, then which of the following distributions can be expected in the next generation? A. 1/2 Pp, 1/2 pp B. 1/3 Pp, 2/3 pp C. 1/2 PP, 1/2 pp D. 1/2 Pp, 1/2 PP E. 1/4 Pp, 3/4 pp
A. The mother has genotype pp. Her gametes can both have p only. The father has Pp.
His gametes may be either p or P. If these gametes combine in the children four possible
combinations—pp, pp, pP, and pP—will be produced. Hence there will be 1/2 pp and 1/2 Pp
variants in the children.
Which of the following genetic abnormalities is associated with rocker
bottom feet, protrusion of bowel through the umbilical cord, and low-set
ears in a male child, newly born to both healthy parents with no history of
genetic disorders in the family?
A. Deletion
B. Insertion
C. Nonsense mutation
D. Translocation
E. Aneuploidy
E. This question refers to Edwards’ syndrome, which is 18 trisomy. This is an aneuploidy.
Euploidy refers to the presence of chromosomal numbers in multiples of 23. Haploid refers to
the presence of 23 chromosomes, as normally seen in gametes. Most somatic cells are diploid,
possessing 46 chromosomes. Aneuploidy refers to any aberrations in chromosomal numbers, for
example monosomy, trisomy, etc. Edward’s syndrome is characterized by 47XX +18 or 47XY +18
constitutions. It is seen in around 1 in 6000 live births; 90% of infants die in the fi rst year of life.
The common clinical features are small size, small mouth and low-set ears, clenched fi st with
overlapping fi ngers, congenital heart defects, and omphalocele.
Which of the following genetic mechanisms can explain the occurrence of
Angelman’s syndrome?
A. Maternal disomy of chromosome 15
B. Paternal disomy of chromosome 15
C. Spontaneous deletion of one copy of an allele at a certain locus, derived from the father
D. Spontaneous deletion of both copies of alleles from the father and mother
E. All of the above
B. Angelman’s syndrome is an example of genomic imprinting. Deletion of maternally
inherited 15q11-13 (70%) or uniparental disomy where both 15q11-13 come from the father
(4%) leads to Angelman’s syndrome. This is because certain genetic loci in 15q11-13 are
selectively imprinted (that is inactivated via methylation) according to the parent of origin. When
the maternally derived chromosome is absent due to deletion or paternal disomy this produces
the phenotype. Similarly, maternally derived disomy or deletion of the paternally derived
chromosome can produce Prader–Willi syndrome at the same locus.
If p is the frequency of allele A and q is the frequency of allele B of the same
gene, then the frequency of the heterozygous combination AB is
A. p2
B. q2
C. pq
D. 2pq
E. 4pq
D. This question tests one’s knowledge of the Hardy–Weinberg equilibrium. In a large
population where random mating occurs between individuals, a constant and predictable
relationship exists between various genotype and allele frequencies. If the frequency of an allele,
A, is given by p, then at the same locus a second allele, B, has a frequency q = 1 − p. The
frequency of AA individuals is given by p × p = p2. The frequency of BB is thus q2. The frequency
of heterozygosity is given by 2pq as the heterozygosity can be AB or BA, both denoting the same
constitution. According to the Hardy–Weinberg equilibrium p2 + 2pq + q2 = 1. This is true because
(p + q)2 = (p + 1 − p)2 = 12 = 1. Note that deviations from the Hardy–Weinberg equilibrium can
occur due to assortative non-random mating, natural selection, genetic drift, or gene fl ow
The criteria for defi ning a trait as endophenotype include all of the
following except
A. Association with a candidate gene.
B. Cosegregation with increased relative risk of the trait in relatives.
C. The expression is dependent on the clinical state of the patient.
D. The endophenotype is more common in the patient’s relatives than the general
population.
E. The trait and disease have a biologically plausible association
C. An endophenotype is an unseen but measurable phenomenon that is present in the distal
genotype to disease pathway. It can be a biochemical, neuroimaging, electrophysiological, pathological,
neuropsychological, or sociofunctional marker. To be termed an endophenotype, Gottesman
suggested certain criteria to be satisfi ed by an identifi ed disease marker. These are as follows:
1. Must be associated with a candidate gene or region
2. Must be present with a high relative risk in relatives, thus co-segregating with the actual illness
3. Must be a parameter associated with the disease with biological plausibility
4. Must be expressed independently of clinical state (i.e. must not be a state but a trait marker)
5. Must be heritable
6. Must be present in relatives more often than the general population.
The fusion of two different chromosomes at a common centromere results from which of the following? A. Robertsonian translocation B. Reciprocal translocation C. Inversion D. Duplication E. Iso-chromosome formation
A. Reciprocal translocation refers to exchange of genetic material between two
chromosomes. An individual who carries a reciprocal translocation will not be affected clinically
as he or she will have the normal complement of all essential genetic material. However, the
children of such an individual can inherit partial trisomy or partial monosomy of the translocated
chromosomes. Robertsonian translocations occur in approximately 1 in 1000 individuals. This
refers to the loss of short arms of two acrocentric chromosomes (which do not have much
genetic material) and subsequent fusion of the two chromosomes at ‘sticky’ centromeres.
Again there is no effect in the individuals who suffer such a translocation but their children can
inherit the effects. Five per cent of Down’s syndrome children have inherited a Robertsonian
translocation between chromosome 14 and 21, leading to triple copies of chromosome 21. In
a mother with a 14:21 translocation, the risk of subsequent children having Down’s syndrome
is elevated to 10–15%, irrespective of maternal age. The risk is around 1–2% if the father
carries such a translocation. Note that in a mother less than 30 without a translocation who
has given birth to a Down’s syndrome baby, the chances of recurrence is only 1%. Inversion
refers to a segment of chromosome between two breaks undergoing reinsertion into the same
chromosome but in a reverse order. If these breaks occur on either side of a centromere, it is
called pericentric inversion. If not, it is termed paracentric inversion. Duplication occurs during
formation of chromatids, where more than two sister chromatids are created. Isochromosomes
occur when chromosomes divide at a horizontal instead of vertical axis during cell division.
Hence daughter chromatids will have two copies of the same arm of a chromosome. This is
usually lethal for most chromosomes except the X chromosome, whose isochromosomes can
result in Turner’s syndrome in individuals who inherit isochromosome Xq (long arm).
This indicates that most determinants of Turner’s syndrome reside in the short arm of the
X chromosome.
Which of the following best describes multifactorial diseases?
A. Diseases caused by multiple environmental factors
B. Diseases caused by multiple genetic factors
C. Disease caused by non-genetic, non-environmental causes
D. Diseases caused by the interaction of multiple genes and environmental factors
E. None of the above
D. Monogenic diseases follow single gene–single disease inheritance, as for example in
phenylketonuria. However, the most common cause of genetic disorders is thought to be
multifactorial or polygenic inheritance. Polygenic diseases are genetic disorders caused by
mutations or changes in more than one genetic locus, for example neurofi bromatosis can
be caused by NF-1 or NF-2 mutations. When environmental factors also play a role in the
development of a disease or trait, the term multifactorial is used to refer to the additive effects of
many genetic and environmental factors. Multifactorial illnesses, for example diabetes, coronary
heart disease, and possibly most psychiatric illnesses, are simultaneously infl uenced by multiple
genes and by environmental factors
A husband and wife are both affected by an autosomal dominant disorder
with 75% penetrance. Provided that they are both heterozygous for the
mutation, what will be the infl uence of this less than 100% penetrance rate
on the likelihood that their children will be affected?
A. Likelihood of having unaffected offspring remains unchanged
B. Likelihood of having unaffected offspring increases
C. Likelihood of having unaffected offspring decreases
D. Likelihood of having unaffected offspring depends on the sex of the offspring
E. Likelihood of having unaffected offspring depends on the birth order of the offspring
B. If both parents are heterozygous the chance that the child inherits an autosomal
dominant disease is 3/4, that is 75% (out of four children, one may have both normal alleles,
one may have both abnormal alleles, and two may have heterozygous make-up). With 75%
penetrance, the chances of a child being affected reduces to 75% of the original chance. So 75%
× 75% = nearly 57% will be affected. This means that the likelihood of having an unaffected child
increases from 25 to nearly 40%. Hence, the lower the penetrance, the higher the likelihood of
having an unaffected child. This does not depend on the sex or birth order.
Which one of the following statement is false with respect to Mendelian
inheritance?
A. The law of independent assortment is a Mendelian principle.
B. Segregation of genetic traits is explained by Mendelian principles.
C. Mendelian principles are based on continuous variables.
D. Mendelian principles are applicable to human genetics.
E. The law of uniformity is a Mendelian principle.
C. Gregor Johann Mendel was a monk who was interested in horticulture and botany. He
studied garden peas and proposed ‘laws’ of inheritance. The fi rst law is the law of uniformity.
According to this law, if two plants that differ in just one trait (black and white) are crossed,
then the resulting hybrids will be uniform in the chosen trait (either black or white, not blue).
This is not entirely true as later geneticists demonstrated intermediate phenotypes resulting
from codominant heterozygous expression. The second law is the principle of segregation. It
states that for any particular trait, the pair of alleles of each parent separate and only one allele
passes from each parent to an offspring. Which allele in a parent’s pair of alleles is inherited is a
matter of pure chance. For example if there are two alleles with one determining white colour
and one determining black colour in the fi rst generation, then these two alleles segregate and
only one of them from each parent could be passed on to the second generation. This was
later proved to be true by studying chromosomes during cell division. The third principle is the
principle of independent assortment. It states that different pairs of alleles are passed to offspring
independently of each other. The result is that new combinations of genes present in neither
parent are possible. As a very simplistic example, if a man with blue eyes and brown hair fathers
a child with a woman with brown eyes and black hair, their offspring can have blue eyes and black
hair. The inheritance of blue eyes does not take brown hair ‘with it’; these traits are independently
assorted. Thus Mendelian principles are applicable to human genetics as well. Note that all traits
studied using Mendelian genetics refer to categorical, all-or-none, traits, that is black vs. brown,
blue vs. brown, tall vs. short, etc. It does not apply with the same simplicity to dimensional traits
such as IQ or blood pressure.
Which of the following patterns of inheritance can skip generations and can
affect individuals with unaffected parents?
A. Autosomal dominant with complete penetrance
B. Autosomal recessive
C. X-linked dominant
D. Mitochondrial inheritance
E. None of the above
B. Autosomal recessive traits skip generations and may ‘catch families unaware’. Assuming a
good degree of penetrance, an autosomal dominant pattern affects all generations. Mitochondrial
diseases will affect all generations but via maternal inheritance. X-linked recessive disorders can
skip generations but not X-linked dominant. Autosomal recessive diseases are clinically expressed
only in homozygous states. Most commonly, the homozygote is produced by the union of two
heterozygous parents (carriers) who themselves will be unaware of harbouring such an allele.
The recurrence risk in children born to such parents is 25%. If an affected homozygote marries a
heterozygote the recurrence risk is 50%. Consanguinity (union between relatives) increases the
likelihood of inheriting autosomal recessive diseases as related parents may have both inherited
carrier status for the same disease from their common ancestor.
