Psychiatric genetics Flashcards

Question

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

Answer 1

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.

Answer 2

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

Answer 3

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.

Answer 4

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.

Answer 5

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

Answer 6

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.

Answer 7

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.

Answer 8

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.

Answer 9

B. Mutation is a sudden, permanent, and heritable change in the DNA sequence. Changes in DNA may be transcribed to mRNA and translated to proteins, leading to disease expression. Point mutation refers to a single base change in DNA. Point mutations are usually substitutions, where one base is replaced by another. It is termed a transition if a purine is replaced by another purine or a pyrimidine replaced by another pyrimidine (e.g. A to G). It is called a transversion if a purine is replaced by a pyrimidine or vice versa (e.g. A to T). According to the effect on the triplet code, mutations could be a frame shift or in-frame. In frame-shift mutations, the deletion or insertion is not in multiples of three codons, for example a fi ve-base deletion mutation. This leads to a shift in the triplet reading frame with variable results. In-frame mutation refers to changes occurring in multiples of three bases, with no disturbances in the reading frame. According to the effect of a mutation on the protein product, mutations could be silent, mis-sense, or nonsense. A silent mutation causes no change in the protein product—this is possible because a single amino acid is often coded by more than one triplet sequence. In a silent mutation one triplet sequence is replaced by a different sequence but without changing the amino acid sequence. In a mis-sense mutation, the new mutant codon specifi es a different amino acid with variable effects on the fi nal protein product, for example in haemophilia and sickle cell anaemia. In a nonsense mutation the new codon is UUA, UGA, or UAG, which signal ‘stop’ to the amino acid sequence, resulting in a non-functional protein. Point substitutions do not shift the reading frame; they often occur in non-coding regions and go unnoticed. Even in coding regions they are often silent or mis-sense mutations.

Answer 10

A. Thymidine and folate deprivation are used in the demonstration of fragile sites in chromosomes. Cytogenetic techniques now available for the direct molecular identifi cation of such fragile sites. Fragile-X syndrome, Huntington’s disease, spinal muscular disease, and myotonic dystrophy are some of the disorders associated with fragile, trinucleotide expansions in chromosomes.

Answer 11

E. Duration of untreated psychosis (DUP) is not an endophenotype. Working memory defects, information processing defects such as prepulse inhibition, smooth pursuit defects, glial cell changes, and certain other putative neurocognitive markers are termed probable endophenotypes for schizophrenia. To be an endophenotype, a characteristic must be observable independent of clinical state and must be measurable in relatives at a higher degree than in the general population. By defi nition, DUP cannot be measured in those who are not having psychosis.

Answer 12

B. Locus heterogeneity refers to the existence of mutations in different chromosomal loci resulting in the same disease phenotype. It is an important clinical phenomenon when attempting to test for the presence of a carrier state or mutation for a specifi c disease. For example, early-onset Alzheimer’s disease could be caused by presenilin 1 or 2 mutations or by β amyloid precursor mutations. These mutations occur in chromosomes 14, 1, and 21, respectively. (Pleiotropy and allelic heterogeneity are explained below.)

Answer 13

A. When ascertaining cases for genetic family studies it is possible to miss certain cases as the disease has not occurred as yet in some members of the family. For example if a disease presents at age 40 on average, and if the studied family has three ‘normal’ members aged 50, 30, and 18, there is still the possibility that the latter two may become ‘cases’ in the future. Various methods of age correction have been employed to ascertain the morbid risk precisely in such cases. Weinberger’s weighted age method is a popular approach. Life tables can also be used for age correction. In most genetic disorders, birth order does not play a role in disease expression as each birth is an independent genetic event. Duration or severity of illness does not complicate the issues in most family studies.

Answer 14

A. Epistasis is the term used to describe gene interactions. Epistasis specifi cally refers to interaction between alleles at different genetic loci. This interaction is evident in the protein production and function of the involved genes. It can occur at the same step or at different stages of the same biochemical pathway. Variable expression refers to the variation in the degree of phenotypic expression seen in certain genetic disorders. Some individuals carrying the phenotype may be severely affected while others will only be mildly affected. This may be due to the effect of environment on a phenotype, allelic heterogeneity (different mutations causing a phenotype, leading to variation in expressed severity), or epistatic infl uences (another genetic loci conferring protection against severe expression by modifying the biochemical pathway at a distant site). Incomplete penetrance refers to the phenomenon where some individuals with the disease genotype do not display any signs of the disease at all. If the number of obligate carriers of a genotype (individuals who possess a genotype) is 100, and the number showing disease expression is 80, then the penetrance rate is 80%. Codominance refers to simultaneous expression of two alleles at a chromosomal locus, for example AB blood group when one chromosome has genotype A and the other has genotype B.

Answer 15

A. Multifactorial diseases could be defi ned by a threshold model. Considering psychiatric disorders, the families of affected individual often show substantially higher risk than the general population. These disorders can be described as quasicontinuous as the affected portion (defi ned categorically) of the population can be differentiated as mild to severe in the spectrum (continuous dimensions). This could be described as having a continuously distributed liability to develop the disease that is inherited, while the actual expression is multifactorial. If the liability crosses a particular threshold then disease expression could occur. This liability distribution curve is shifted to the right if relatives of a patient are considered, as, for the given threshold, more affected individuals are found in the families than in the general population.

Answer 16

B. The odds ratio in most psychiatric genetic association studies are in the order of 1 to 2, the median being 1.3. This is insuffi cient to prove a genetic cause for most disorders. To demonstrate a more signifi cant odds ratio, very large sample sizes are required; this methodological problem is being surmounted, at least partially, by meta-analyses that are providing evidence for the role of certain genes in psychiatric disorders. Non-contingent gene–disorder association refers to the fact that the relationship is not infl uenced by other factors such as environment or presence of other genes, that is not polygenic or multifactorial. But most psychiatric disorders do not follow non-contingent association models. The causal pathway from an identifi ed genetic abnormality to actual disease expression is too complex and not fully explored in most known genetic markers of psychiatric diseases. For example it is unclear how a mutant dysbindin gene can lead to a belief that aliens are invading earth. There are few notable exceptions to this; for example the role of the serotonin transporter polymorphism in mediating the effects of life events on the risk of depression. For a long time, much genetic research was guided by the assumption that genes cause diseases, but the expectation that direct paths will be found from gene to disease has not proven fruitful for complex psychiatric disorders. Gene × environment interaction models of disease causation appear promising, as in Caspi’s work, and may possibly throw more light on the causal chains from gene to disease.

Answer 17

A. It has been demonstrated that the ‘short’ polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) is associated with impaired effi cacy of fl uvoxamine and paroxetine. The long form is associated with better SSRI effi cacy. This can be understood by studying the mechanism of action of SSRIs. SSRIs produce antidepressant action by reducing the activity of serotonin transporter protein. In patients with the short polymorphism of the promoter region, the number of serotonin transporter molecules is reduced, leaving less substrate on which SSRIs can act. Hence the short form is associated with poorer response than the longer form, but this might be confounded by an ethnicity effect as Korean and Japanese patients show the opposite effect (the short version is associated with better SSRI response).

Answer 18

C. The name tuberous sclerosis comes from the characteristic tuber or potato-like nodules in the brain, which calcify and become sclerotic. The disorder is also known as epiloia or Bourneville’s disease. Though most infants show signs in the fi rst year of life, clinical features can be subtle initially, leading to misdiagnosis for years. The disease-causing mutations are present in either of two genes, TSC1 and TSC2. TSC1 is present on chromosome 9 and produces a protein hamartin. The TSC2 gene is on chromosome 16 and produces a protein tuberin. The natural course is very variable, ranging from mild to severe illness. In addition to the benign tumours of kidney (cysts, angiomyolipomas), phakomas of eyes, cardiac tumours, and brain tumours (tubers, subependymal nodules, and astrocytomas) that frequently occur in tuberous sclerosis, other common symptoms include seizures, mental retardation, behaviour problems, and skin abnormalities. Malignant tumours are rare and occur primarily in the kidneys. An often quoted dermatological triad consists of adenoma sebaceum (facial angiofi bromas), ash-leaf macules (hypomelanotic macules), and shagreen patches (pebbly skin on the nape of the neck). Café-au-lait patches and ungual fi bromata are other manifestations of tuberous sclerosis. In most patients, tuberous sclerosis is due to a spontaneous new mutation but in those who inherit tuberous sclerosis, the pattern of inheritance is autosomal dominant.

Answer 19

A. This description fi ts best with fragile-X syndrome. Fragile-X syndrome is also known as Martin–Bell syndrome. It is the most common cause of inherited mental retardation and is the second most common cause of genetically associated mental defi ciencies after trisomy 21. Clinical features include mild-to-moderate autism-like behaviour, especially hand fl apping and gaze avoidance, attention defi cits, and learning disability with an IQ often in the range 35 to 70. Delays in reaching early milestones for speech and language developmental are also noted. Normally, unaffected individuals have 5 to 55 CGG repeats at the 5’ end of locus Xq27.3. A span of 65–200 repeats is known as a premutation, whereas more than 200 repeats is a full mutation. Hypermethylation of cysteine bases takes place at the fully mutant locus, leading to gene inactivation. In trinucleotide expansion diseases, CAG expansion is seen in Huntington’s disease (chromosome 4); CTG expansion is seen in myotonic dystrophy (chromosome 19).

Answer 20

A. Allelic heterogeneity is said to be present if different alleles at the same locus produce the same trait or disease expression. Consider sickle cell disease. In this condition all affected individuals carry the same mutation at the same locus. This is called genetic homogeneity. But in cystic fi brosis, at the same site on chromosome 7, 600 various mutations have been identifi ed that result in the same disease phenotype. This is called allelic heterogeneity. Locus heterogeneity refers to a single disorder, trait, or pattern of traits that is caused by mutations in genes at different chromosomal loci.

Answer 21

C. Pleiotropy is a very common phenomenon among genetic diseases. It refers to a single genetic defect producing a variety of defects, in multiple organs in the body, for example Marfan’s syndrome. Here, an autosomal dominant mutation of a gene encoding fi brillin protein leads to a variety of defects, such as lens dislocation, skeletal deformities, and cardiac defects, especially aortic vessel disease.

Answer 22

A. This refers to a frame-shift mutation. When a mutation results in misreading of a single triplet while other consecutive triplets are read correctly, it is called an in-frame mutation. If a mutation (usually a deletion or insertion) results misreading of all subsequent codons, then it is termed a frame-shift mutation

Answer 23

B. According to the law of segregation, inheritance of one trait occurs independently of another trait, but this is not always the case. This is due to random crossing over during meiosis, which allows the exchange of genetic segments that are signifi cantly longer than a single gene. Such a crossing over results in the recombination of distant genetic loci. When two loci are close together, recombination is very unlikely and they are inherited as a single genetic element at a frequency signifi cantly more than chance. This is called cosegregation, and the loci are said to be linked. Note that an essential condition for linkage is that the two loci must be on the same chromosome, called as syntenic loci; but not all syntenic loci are linked. Study of such linked loci is called linkage analysis. Restriction fragment length polymorphism is a method of genotyping single nucleotide polymorphisms using restriction endonucleases. Fluorescent in situ hybridization (FISH) involves denaturation of DNA on microscope slides and binding of sequence-specifi c DNA probes to the regions of interest on the exposed DNA strands. It is often used to study areas of deletion in chromosomes.

Answer 24

D. The distance between two loci can be measured in terms of the frequency with which they undergo recombination. For linked loci the frequency of recombination is less than 50%. Genetic distances are often expressed in centiMorgans (cM). One cM is equal to 1% recombination frequency between two loci, which can occur if nearly one million base pairs separate the two loci. LOD scores (log of odds) are used to estimate the likelihood that an observed recombination frequency is truly due to the loci being linked. It is given by the log of the ratio between the probabilities of the recombination frequency being the observed value (θ) to the expected value of 50% if they are not linked. A LOD of more than 3 indicates a linkage; less than −2 indicates no linkage. The value of θ at which LOD scores are greatest is the most likely estimate of recombination frequency

Answer 25

C. LOD scores were fi rst used by Morton in 1955. It is a statistical method to establish linkage disequilibrium. A LOD (or log of odds) score is the common log of the likelihood that the recombination fraction has a certain value, θ, divided by the likelihood that it is 1/2. Conventionally, a LOD of 3, representing an odds of linkage of 1000: 1, is the accepted level for concluding linkage.

Answer 26

C. Genotype frequency measures the proportion of each genotype, AA or AB or BB, in a population. Gene frequency measures the frequency of each allele at a particular locus in the population. Here, the frequency of allele A is (40 × 2) + 54 = 134% or 1.34. The frequency of B is (6 × 2) + 54 = 66% or 0.66.

Answer 27

A. Consider an epileptic disease with generalized tonic–clonic seizures which could be caused by a genetic alteration. An identical generalized seizure could be a result of head injury that someone sustained. This is called as phenocopy. Here, phenotypic expression occurs in the absence of a genotype, due to a non-genetic reason. The term pleiotropy and the two types of heterogeneity—allelic and locus—are explained elsewhere in this chapter.

Answer 28

E. Gene frequencies and genotype ratios in a randomly breeding population remain constant from generation to generation. This is known as the Hardy–Weinberg law. This holds true only if the population is randomly breeding. If mutations are occurring in two genes at different frequencies, then this does not hold true as gene frequencies would change. In addition, if members of one population breed with occasional immigrants from an adjacent population this will introduce new genes or alter existing gene frequencies in the population. This is called gene fl ow. Similarly, strong interbreeding can happen within members of local populations. If the population is small, the Hardy–Weinberg equilibrium may be violated. As random mating can be assured only if suffi cient numbers of matings occur, this is not possible in a small population. In such cases, the frequency of an allele may begin to drift toward higher or lower values. This is called genetic drift; it is accidental and aimless and is not an adaptive genetic change as it does not guarantee that the new generations will be more fi t than the predecessors. In natural selection, certain alleles are positively selected and so their frequencies increase compared to other genes. This will result in failure of the Hardy–Weinberg equilibrium.

Answer 29

C. RNA is produced from DNA via transcription in most eukaryotic cells. A reverse procedure, where DNA is produced from RNA, takes place in certain viruses, especially retroviruses, including HIV. This procedure is mediated by a reverse transcriptase enzyme. DNA ligase acts in sealing DNA ends together during DNA replication. RNA polymerase acts in transcription of RNA from DNA. Primase acts in the initiation of DNA synthesis by catalysing the synthesis of RNA primers; this is necessary because DNA polymerases cannot initiate DNA synthesis without the help of RNA primers. When DNA replication is complete, DNA polymerase 1 destroys the RNA primers. DNA polymerase 1 contains an exonuclease which helps in proof-reading activity during DNA synthesis.

Answer 30

C. Mitosis takes place in six identifi able phases. During interphase a cell is at rest. The individual chromosomes are not visible and active growth takes place. During prophase, which is the fi rst phase of mitosis, the chromosomal material doubles and the nuclear membrane is broken down. Centrioles and spindle fi bres become visible. During metaphase the chromosomes are equatorially aligned. Each centromere is now attached to two spindle fi bres coming from opposite poles. During anaphase, the chromosomes separate and travel to opposite poles. During telophase an indentation appears in the cellular membrane and cytokinesis is then completed.

Answer 31

D. This can be calculated using the Hardy–Weinberg equilibrium. If p and q are the allele frequencies of recessive copy ‘a’ and dominant copy ‘A’, respectively, then p2 gives the frequency of homozygous aa and q2 gives the frequency of homozygous AA. 2pq gives the frequency of the heterozygous aA. 1/1600 is the frequency of homozygous individuals, that is p2. Hence, p = 1/40. If p = 1/40, then q will be 1 − p = 39/40. The number of heterozygous carries is given by 2 × 1/40 × 39/40 = 1/20 approximately. As one can see easily from this calculation, at any given time in a population there are more heterozygous carriers than diseased individuals. So negative eugenics, that is elimination of all diseased individuals, cannot eliminate an autosomal recessive disease.

Answer 32

E. Arachidonic acid is a fatty acid often found in membrane phospholipids. It is not a component of nucleic acids. Nucleic acids are made up of a purine or pyrimidine base, a pentose sugar moiety, and a phosphate group. Depending on whether the sugar is deoxyribose or ribose sugar, nucleic acids are either DNA or RNA.

Answer 33

A. Association studies simply compare the frequency of a particular marker, for example a polymorphism, in diseased and normal populations. These are usually case–control studies and are comparatively easy to carry out. Linkage studies investigate the cosegregation of a disease and a set of genetic markers. Here, the aims are to determine linkage among candidate loci and determine the genetic distance between loci in an attempt to narrow down the site of the genetic abnormality. Linkage study is possible only if at least one parent has a double heterozygote make-up, that is heterozygous at both marker and disease loci. Family study refers to a genetic study whereby cases are ascertained by interviewing all available relatives of an identifi ed proband. Age correction must be applied in such family-based case ascertainments. Adoption study investigates shared traits or phenotypes among adoptees, adopting families, and biological families in various combinations. Ecological study is not a specifi c genetic study.

Answer 34

A. In twin studies, case ascertainment and zygosity assignment is done initially. Later, concordance or discordance is measured to determine the heritability. This could be done by counting the proportion of the total number of concordantly affected twins among all pairs studied (pair-wise concordance) or by calculating the proportion of the number of affected twins among all cotwins studies (probands-wise concordance). The latter is possible if there is a twin register maintained with systematic ascertainment. Zygosity does not infl uence selection of the methods. Multifactorial diseases are commonly studied using twin studies by both methods.

Answer 35

B. Autosomal recessive diseases often skip generations. The usual pattern of inheritance is from two heterozygous carriers, who are often unaware of their carrier status until their child is born homozygous with the disease. The chance of having an offspring with homozygous inheritance is 1 in 4; in other words, one affected child for every three unaffected children born (1: 3). This ratio becomes 1: 1 (50%) if one of the parents is homozygous and suffering from the disease

Answer 36

E. Increased death rate will not affect the number of genes or genotype distribution in a population directly. All the other options given can alter the Hardy–Weinberg equilibrium.

Answer 37

A. For continuous traits such as IQ, path analysis could be used in measuring heritability from concordance rates. The heritability h2 = 2(RMZ − RDZ). Here monozygotic concordance is 0.86 and dizygotic concordance is 0.61. Hence, heritability is given by 2 (0.86 − 0.61) = 2(0.25) = 0.5.

Answer 38

E. Cystic fi brosis follows an autosomal recessive inheritance pattern. It is one of the most frequently occurring recessive gene mutation in Caucasian populations, with an estimated frequency of 1 in 30 carriers in the general population. Single-gene disorders usually follow the Mendelian pattern of inheritance; notable exceptions are mitochondrial diseases, trinucleotide expansion diseases, and genomic imprinting.

Answer 39

C. Path analysis provides a diagrammatic approach to estimate the contribution of genetic and environmental factors in inheritance of a trait. The shared environment and shared genetic make-up are drawn to demonstrate the sources of resemblance between two siblings. Path coeffi cients are calculated for each connecting path between the sources and the siblings, and sum of these coeffi cients can provide a genetic correlation between the siblings.

Answer 40

B. The relative infl uence of genetic factors in defi ning the variance in a trait is expressed as heritability. If this is defi ned as the proportion of the total phenotypic variance attributable to additive genetic variance, then it is known as narrow-sense heritability. Heritability is also sometimes used to describe the proportion of variance explained by the total genetic variance (additive and non-additive genetic variance); here it is called broad-sense heritability. Non-additive genetic infl uences include phenomena such as epistasis (gene–gene interaction) and dominance effects, where presence of one gene mitigates the expression of other gene. A twin pair is said to be concordant when both cotwins have the same disease expression (or both are disease free). The pair can be discordant if one of them harbours a disease while the other does not. Due to the higher degree of genetic similarity among monozygotic twins, one would expect higher concordance between monozygotic twins compared to dizygotic twins if the disease being studied has a signifi cant genetic component.

Answer 41

C. A linkage to chromosome 17 has been shown for a specifi c variant of frontotemporal dementing syndrome. This syndrome is now referred to as frontotemporal dementia with parkinsonism-17 (FTDP-17). The linkage region contains the gene for tau protein. tau pathology is noted in various other dementing syndromes, including Alzheimer’s disease, where inappropriate hyperphosphorylation of tau is implicated in the production of neurofi bril tangles.

Answer 42

A. In prophase, condensation of the replicated chromosomal material leads to the formation of sister chromatids, still attached at the centromeres. Each chromosome has two short and two long chromatids, corresponding to the short and long arms of the chromosomes

Answer 43

D. HLA stands for human leukocyte antigens. These molecules are expressed on the surface of white blood cells to coordinate the immune response. DR and DQ are two different types of HLA molecules. Many different HLA ‘subtypes’ (DR1, DR2, DQ1, DQB1*0602) exist normally. HLA DR2 subtype has been linked to narcolepsy–cataplexy syndrome. African-American narcoleptic patients are frequently DR2 negative but they have a stronger association with another HLA gene allele, HLA-DQB1*0602.

Answer 44

D. The gene for the MAO-A enzyme is located on chromosome X. In males a single X chromosome yields two dissimilar MAOA genotype variations: a high and a low activity variant. Females have two copies of the X chromosome, hence they can have three different levels of MAO-A activity: a high–high activity group (homozygous high), a low–low activity group (homozygous low), and a third, heterozygous group with low–high (mixed pattern). Caspi et al. (2002) studied MAO-A related genetic infl uences on the outcome of childhood maltreatment. They found out that high MAO-A activity exerts a protective infl uence against the development of antisocial outcomes (such as adolescent conduct disorder, violent episodes, etc.), especially in maltreated boys and to some extent in girls.

Answer 45

D. Milder forms of mania respond better to lithium than severe mania. Patients with classical features of mania respond better than those with schizoaffective presentation. On a similar note, dysphoric mania, mixed affective episodes, and rapid-cycling mania respond poorly to lithium treatment. Having a family history of bipolar illness is suggestive of good prophylactic response of lithium in relapse prevention; such an effect is not clearly demonstrated for the effects of lithium in treating acute mania.

Answer 46

E. Friedreich ataxia (FRDA1) is caused by mutation in the gene encoding a protein called frataxin. The locus of the frataxin gene has been mapped to chromosome 9q. The most common molecular abnormality that affects the site of this gene is a trinucleotide repeat expansion of the triplet codon GAA in intron 1 of the frataxin gene. Another locus for Fredreich’s ataxia has been mapped to chromosome 9p; it is called FRDA2.

Answer 47

C. First-degree relatives share 50% of their genes in common. This genetic relatedness reduces to 25% among second-degree relatives and 12.5% among third-degree relatives. The possible contribution of genetic factors for a disorder can be studied using the resemblance of disease risk across successive generations. A strong genetic contribution is suggested by a 50% decrement in disease risk with successive generations. If the risk decreases by more than 50% this suggests that the disease is either multifactorial with the possibility of signifi cant gene– environment interaction or a more complex mode of genetic transmission. The ratio of the rate of the disorder in relatives to the population-based rate is commonly denoted by λ. This does not refer to linkage equilibrium. For diseases that are autosomal dominant in inheritance, λ tends to exceed 20; for complex multifactorial disorders, λ derived from family studies tends to range from 2 to 5.

Answer 48

D. The proportion of phenotypic variation attributable to genetic causes is referred to as heritability in the broad sense. The proportion attributable to non-genetic causes includes shared and non-shared environmental variance, gene–environment covariance, and interaction. The estimate of heritability for major depression from twin studies is around 0.37. The relative risks based on the existing adoption studies suggest that the familial recurrence cannot be attributed solely to shared environmental factors. The remaining 63% of variance is almost wholly attributed to environmental factors unique to the individual.

Answer 49

C. The apolipoprotein-E ε4 (APOE e4) allele increases the risk of Alzheimer’s disease in a dose-dependent fashion. The odds of developing Alzheimer’s disease are 2.6−3.2 times greater in those with one copy, and nearly 15 times higher in those with two copies of the APOE e4. A signifi cant protective effect has been noted in those with e2/ e3 genotype. The population attributable risk due to APOE e4 allele for Alzheimer’s dementia is very high due to its high frequency of occurrence in the general population. APOE e4 can also increase the risk of vascular dementia.

Answer 50

C. A gene on locus 13q34, called G72, codes for D-amino acid oxidase activator (DAOA). A series of initial studies have identifi ed this genetic locus as potentially contributing to schizophrenia susceptibility. The D-amino acid oxidase is the only enzyme oxidizing D-serine. D-serine is an important coagonist for the NMDA glutamate receptor. Hence it is posited that the variations in the G72 gene may infl uence the effi ciency of glutamate gating at N-methyl-Daspartate- type (NMDA) receptors, but some later studies have failed to replicate the earlier fi ndings. G72 has also been associated with depression in psychotic patients and also with bipolar disorder.

Answer 51

B. Only a very small percentage (nearly 1.5%) of the human genetic code carried in DNA encodes proteins. This is because a large proportion of human DNA consists of long intron sequences, which are non-coding portions that get spliced out when transcription takes place. Hence, even when the complete sequence of a genome is known, mapping the functional genetic code will be diffi cult. A transcriptome is defi ned as all messenger RNA (mRNA) molecules transcribed from the DNA in a cell. The mRNA molecules act as ‘mediators’ between DNA codes and actual protein products. A transcriptome is not unique for a species or even for an individual; this is because what genes are transcribed in a cell depends on the kind of cell (e.g. WBCs, hepatocytes, epithelial cells) and what function is being carried out by the cell at that time. Hence, environmental infl uences or physiological needs will modify the transcriptome.

Answer 52

B. The monozygotic concordance for simple Mendelian disorders is approximately 100%. This is because the penetrance is usually complete (though it may vary) in simple Mendelian disorders. In contrast, penetrance is incomplete in schizophrenia. Phenocopies of schizophrenia are very common; multiple organic and drug-induced states resemble schizophrenia. Locus heterogeneity in the same family is not a feature of simple Mendelian disorders affecting single loci. As the exact genetic localization of schizophrenia is still not certain, locus heterogeneity cannot be determined for schizophrenia, but given the multifactorial nature of schizophrenia, signifi cant locus heterogeneity is very likely. Mendelian disorders need not necessarily present in childhood; many autosomal dominant disorders present clinically only in adulthood

Answer 53

A. The human genome is comprised of two sets of 23 chromosomes, one set inherited from each parent, and the DNA encodes 30 000 genes. Formerly, it was believed that genes were almost always present in two copies in a genome, but recently large segments of DNA of various sizes have been found to differ in copy number. Such copy-number variations (or CNVs) can lead to dosage imbalances in both functional (exons) and non-coding (introns) regions. As a result, many genes that were thought to occur in two copies per genome have now been found to be present in one, three, or even more copies.

Answer 54

D. Fragile-X patients have more than 200 CGG repeats in the 5’ untranslated region of the fragile-X mental retardation 1 gene (FXMR-1). As in other trinucleotide repeat diseases, these expansions originate from phenotypically normal individuals who carry an intermediate number of unstable repeats (60 to 200). Normal individuals have 6 to 60 repeats. Even in carriers with premutation, longer repeats are observed to be more toxic than shorter, near normal ones. These carriers may show evidence of a neurodegenerative condition distinct from fragile X. The degree of toxicity increases with abundance of the transcript. CAG repeats are seen in Huntington’s chorea.

Answer 55

A. Genetic testing for Huntington’s disease involves testing the person at risk for the presence of excessive DNA repeats that predict development of clinical features. The test cannot predict the age at which the onset of such symptoms could occur. Almost all patients carry a specifi c mutant gene at chromosome 4 and the inheritance has complete penetrance. Earlier genetic testing involved linkage analysis with only probabilistic estimates given to at-risk individuals. The tested individuals were given a risk estimate of less than 5% or greater than 95%, based on the results. Since 1993, direct identifi cation of the trinucleotide expansion has been made possible, greatly increasing the accuracy of the test to nearly 100%. Being an autosomal dominant condition, the disease exhibits an all-or-none phenomenon; homozygotes are no more severely affected than heterozygotes. Prenatal testing is possible even when the at-risk parent has not had a test him/ herself. In this case, only the proportion of the parent’s risk that is passed on to the fetus can be estimated; often this may not give suffi cient information to decide on termination of pregnancies. The disease can occur in persons with apparently no positive family history, though this is extremely rare nowadays.

Answer 56

A. This patient presents with neurofi bromatosis type 1. Patients with neurofi bromatosis can present with light-brown spots on the skin (café-au-lait spots), neurofi bromas, freckling in the area of the armpit or the groin, hamartoma of the iris (Lisch nodules), optic glioma, and scoliosis. Many children with NF1 have larger than normal head circumference and may have congenital heart defects. They may have poor linguistic and visual–spatial skills, in addition to attention defi cit hyperactivity disorder (ADHD). Most symptoms are notable before the age of 10. The genetic localization of NF1 points to chromosome 17. The NF1 gene codes for a protein called neurofi bromin, which acts as a regulator of cell division in the CNS. A second type of neurofi bromatosis is called NF2; the clinical presentation and genetic abnormality seen in NF2 are different from NF1. The gene responsible for NF2 has been identifi ed on chromosome 22. The NF2 gene product codes a tumour-suppressor protein called merlin.