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:
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 flow.
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The criteria for defining a trait as endophenotype include all of the following except:
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 satisfied by an identified disease marker. These are as follows:
Must be associated with a candidate gene or region
Must be present with a high relative risk in relatives, thus co-segregating with the actual illness
Must be a parameter associated with the disease with biological plausibility
Must be expressed independently of clinical state (i.e. must not be a state but a trait marker)
Must be heritable
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. 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?
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 neurofibromatosis 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 influenced 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 influence of this less than 100% penetrance rate on the likelihood that their children will be affected?
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.
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