Genetic Analysis of Complex Disease. Группа авторов

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the proportion of individuals with a specific genotype that exhibit a particular phenotype. Examples of applications of the Hardy–Weinberg theorem are shown in Table 2.1.

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Recall that p + q = 1 and p2 + 2pq + q2 = 1 Example 1. Cystic fibrosis (CF), an autosomal recessive disease, has an incidence of 1 in 3200. What is the frequency of CF carriers in the general population?The population frequency of the disease (1 in 3200) is represented by q2In order to calculate the frequency of the carrier state (2pq), one must first determine q q = √(1/3200) = 1/57 Since p + q = 1, p = 56/57 The frequency of CF carriers is calculated as 2pq = 2(1/57)(56/57) = 1/29, or 0.0344. Example 2. The frequency of the allele (q) for an autosomal dominant disorder in 1/100. What is the frequency of the disease itself in the population?Since the frequency of the disease allele in 1/100, the frequency of the normal allele (p) = 1 − 1/100 = 99/100.Since the disease is dominant, both heterozygous carriers and homozygous individuals are affected with the disease: 2pq + q2 = 2(99/100)(1/100) + (1/100)2 = 0.0199 Example 3. An autosomal dominant disorder with incomplete penetrance (f) has a population prevalence of 16/1000. If the allele frequency for the normal allele (p) is 0.99, what is the estimated penetrance of the disease allele?Since p = 0.99, then q = 0.01As in Example 2, both heterozygous and homozygous gene carriers are affected (assuming no difference in penetrance) between homozygotes and heterozygotes. Therefore, f(q2) + f(2pq) = 0.016 f(q2 + 2pq) = 0.016 f((0.01)2 + 2(0.99)(0.01)) = 0.016 f(0.0199) = 0.016 f = 0.804

      Structure of DNA

      When Mendel described the unit of inheritance, he did not know the underlying biological factor. It was 90 years later when the actual genetic molecule was identified. The fundamental unit of inheritance that Mendel’s work uncovered was later termed “the gene.” A gene contains the information for synthesizing proteins necessary for human development, cellular and organ structure, and biological function. DNA is the molecule that comprises the gene and encodes information for synthesizing both proteins and ribonucleic acid (RNA). DNA is present in the nucleus of virtually every cell in the body. It is made up of three components: a sugar, a phosphate, and a base. In DNA, the sugar is deoxyribose, whereas in RNA, the sugar is ribose. The four bases in DNA are the pyrimidines adenine (A) and guanine (G) and the purines cytosine (C) and thymine (T). A DNA sequence is often described as an ordered list of bases, each represented by the first letter of its name (e.g. ACTGAAACTTGATT). A nucleoside is a molecule made of a base and a sugar; a nucleotide is made by adding a phosphate to a nucleoside.

      A single strand of DNA is a polynucleotide, consisting of nucleotides bonded together. A single strand of DNA is, however, unstable. The double‐helical nature of DNA, which confers stability to the molecule, was hypothesized in 1953 by J. D. Watson and F. H.C. Crick. Their cohesive theory of the structure of DNA accounted for some of the previously identified properties of DNA (Watson and Crick 1953).

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      (Source: Reprinted by permission from Thompson et al. (1991).)

      While some of the DNA in a cell codes for a protein product, the vast majority of the DNA sequence does not carry information for the formation of a protein. Within a gene, exons are the portions utilized to make proteins. Introns are the sequences between exons that do not code for the final protein product. The size and number of introns and exons vary dramatically between genes.

      Genes and Alleles

      The physical site or location of a gene is called its locus. At any particular gene locus, there exist different forms of the gene, called alleles. These alleles are unique from each other due to variations of the nucleotides or structure in the gene, which may result in altered function of the gene and/or gene product. These alleles are analogous to the factors of inheritance and variation identified in the 1800s by Mendel. Except on the sex chromosomes of males, an individual has two alleles at each locus. In some instances, a gene may exhibit homozygosity in its two alleles, meaning that both alleles are indistinguishable from each other. Such an example is the presence of two specific disease‐causing alleles of the HBB gene that together cause sickle cell anemia. In the heterozygous state, the two alleles can be distinguished from each other. Males with a normal chromosome complement represent an exception to this convention as they are “hemizygous” for loci on the X chromosome for which they do not have a Y chromosome complement.


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