Medical Genetics & Epigenetics - Ch. 9-12, 15

What are three possible mechanisms that can lead to neurodegenerative disorders?

1) Alzheimer's Disease: The lifetime risk for AD in the general population is 12.1% in men and 20.3% in women by age 85. Most of the increased risk in relatives of affected individuals is not due to mendelian inheritance; rather, as described in Chapter 8, this familial aggregation results from a complex genetic contribution involving one or more incompletely penetrant genes that act independently, from multiple interacting genes, or from some combination of genetic and environmental factors. Approximately 7% to 10% of patients, however, do have a monogenic highly penetrant form of AD that is inherited in an autosomal dominant manner. In the 1990s, four genes associated with AD were identified (Table 12-5). Mutations in three of these genes— encoding the β-amyloid precursor protein (βAPP), presenilin 1, and presenilin 2— lead to autosomal dominant AD. The fourth gene, APOE, encodes apolipoprotein E (apoE), the protein component of several plasma lipoproteins. Mutations in APOE are not associated with monogenic AD. Rather, as we saw in Chapter 8, the ε4 allele of APOE modestly increases susceptibility to nonfamilial AD and influences the age at onset of at least some of the monogenic forms. The most important pathological abnormalities of AD are the deposition in the brain of two fibrillary proteins, β-amyloid peptide (Aβ) and tau protein. The Aβ peptide is generated from the larger βAPP protein (see Table 12-5), as discussed in the next section, and is found in extracellular amyloid or senile plaques in the extracellular space of AD brains. Amyloid plaques contain other proteins besides the Aβ peptide, notably apoE (see Table 12-5). Tau is a microtubule-associated protein expressed abundantly in neurons of the brain. Hyperphosphorylated forms of tau compose the neurofibrillary tangles that, in contrast to the extracellular amyloid plaques, are found within AD neurons. The tau protein normally promotes the assembly and stability of microtubules, functions that are diminished by phosphorylation. Although the formation of tau neurofibrillary tangles appears to be one of the causes of the neuronal degeneration in AD, mutations in the tau gene are associated not with AD but with another autosomal dominant dementia, frontotemporal dementia. 2) Disorders of mitochondrial DNA: The general characteristics of the mtDNA genome and the features of the inheritance of disorders caused by mutations in this genome were first described in Chapters 2 and 7 but are reviewed briefly here. The small circular mtDNA chromosome is located inside mitochondria and contains only 37 genes (Fig. 12-26). Most cells have at least 1000 mtDNA molecules, distributed among hundreds of individual mitochondria, with multiple copies of mtDNA per mitochondrion. In addition to encoding two types of ribosomal RNA (rRNA) and 22 transfer RNAs (tRNAs), mtDNA encodes 13 proteins that are subunits of oxidative phosphorylation. Mutations in mtDNA can be inherited maternally (see Chapter 7) or acquired as somatic mutations. The diseases that result from mutations in mtDNA show distinctive patterns of inheritance due to three features of mitochondrial chromosomes: • Replicative segregation • Homoplasmy and heteroplasmy • Maternal inheritance Replicative segregation refers to the fact that the multiple copies of mtDNA in each mitochondrion replicate and sort randomly among newly synthesized mitochondria, which in turn are distributed randomly between the daughter cells (see Fig. 7-25). Homoplasmy is the situation in which a cell contains a pure population of normal mtDNA or of mutant mtDNA, whereas heteroplasmy describes the presence of a mixture of mutant and normal mtDNA molecules within a cell. Thus the phenotype associated with a mtDNA mutation will depend on the relative proportion of normal and mutant mtDNA in the cells of a particular tissue (see Fig. 7-25). As a result, mitochondrial disorders are generally characterized by reduced penetrance, variable expression, and pleiotropy. The maternal inheritance of mtDNA (discussed in greater detail in Chapter 7; see Fig. 7-24) reflects the fact that sperm mitochondria are generally eliminated from the embryo, so that mtDNA is almost always inherited entirely from the mother; paternal inheritance of mtDNA disease is highly unusual and has been well documented in only one instance. Examples of mtDNA diseases are: - Leber Hereditary Optic Neuropathy: rapid onset of blindness in young adult life due to optic nerve atrophy. Maternal inheritance. Largely homoplastic. - Leigh Syndrome: early onset progressive neurodegeneration with hypotoria, developmental delay, optic atrophy, and respiratory abnormalities. Maternal inheritance. Heteroplasmic. 3) Diseases due to expansion of unstable repeat sequences. The inheritance pattern of diseases due to unstable repeat expansions was presented in Chapter 7, with emphasis on the unusual genetics of this unique group of almost 20 disorders. These features include the unstable and dynamic nature of the mutations, which are due to the expansion, within the transcribed region of the affected gene, of repeated sequences such as the codon for glutamine (CAG) in Huntington disease (Case 24) and most of a group of neurodegenerative disorders called the spinocerebellar ataxias, or due to the expansion of trinucleotides in noncoding regions of RNAs, including CGG in fragile X syndrome (Case 17), GAA in Friedreich ataxia, and CUG in myotonic dystrophy 1 (Fig. 12-28). Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 251). Elsevier Health Sciences. Kindle Edition.

What is the definition of a genetic disease? What is the most known functional defect studied in single-gene disorders? What are exceptions?

A genetic disease occurs when an alteration in the DNA of an essential gene changes the amount or function, or both, of the gene products— typically messenger RNA (mRNA) and protein but occasionally specific noncoding RNAs (ncRNAs) with structural or regulatory functions. Although almost all known single-gene disorders result from mutations that affect the function of a protein, a few exceptions to this generalization are now known. These exceptions are diseases due to mutations in ncRNA genes, including microRNA (miRNA) genes that regulate specific target genes, and mitochondrial genes that encode transfer RNAs (tRNAs; see Chapter 12). It is essential to understand genetic disease at the molecular and biochemical levels, because this knowledge is the foundation of rational therapy. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 195). Elsevier Health Sciences. Kindle Edition.

What was the first autosomal recessive human disease recognized? Hint: Black Urine Disease

Alkaptonuria is a rare inherited genetic disorder in which the body cannot process the amino acids phenylalanine and tyrosine, which occur in protein. It is caused by a mutation in the HGD gene for the enzyme homogentisate 1,2-dioxygenase (EC 1.13.11.5); if a person inherits abnormal copies from each parent (it is a recessive condition) the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form alkapton are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over thirty years old, although the dark discoloration of the urine is present from birth.

What types of genetic markers are used in GWAS for the association approach to complex diseases?

Genetic markers are DNA sequences that serve as landmarks near genes of interest. These were used starting in 1980 in linkage mapping. Currently, they are used in genome-wide association studies.

What are three phenomena that lead to nonrandom mating in human populations - thus being an exception the Hardy Weinberg assumption of random mating?

In human populations, nonrandom mating may occur because of three distinct but related phenomena: stratification, assortative mating, and consanguinity.

What is population genetics? What types of factors can affect population genetics?

Population genetics is concerned both with genetic factors, such as mutation and reproduction, and with environmental and societal factors, such as selection and migration, which together determine the frequency and distribution of alleles and genotypes in families and communities. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 155). Elsevier Health Sciences. Kindle Edition.

What two classes can proteins be classified as based on their pattern of expression?

Proteins can be separated into two general classes on the basis of their pattern of expression: housekeeping proteins, which are present in virtually every cell and have fundamental roles in the maintenance of cell structure and function; and tissue-specific specialty proteins, which are produced in only one or a limited number of cell types and have unique functions that contribute to the individuality of the cells in which they are expressed. Most cell types in humans express 10,000 to 15,000 protein-coding genes. Knowledge of the tissues in which a protein is expressed, particularly at high levels, is often useful in understanding the pathogenesis of a disease. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 215). Elsevier Health Sciences. Kindle Edition.

What is the major practical application of the Hardy-Weinberg Law in medical genetics?

The major practical application of the Hardy-Weinberg law in medical genetics is in genetic counseling for autosomal recessive disorders. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 157). Elsevier Health Sciences. Kindle Edition.

How do mutations disrupt the formation of biologically normal proteins? What are the eight steps in which mutations can disrupt the production of a normal protein?

To form a biologically active protein (such as the hemoglobin molecule), information must be transcribed from the nucleotide sequence of the gene to the mRNA and then translated into the polypeptide, which then undergoes progressive stages of maturation (see Chapter 3). Mutations can disrupt any of these steps (Table 11-1). As we shall see next, abnormalities in five of these stages are illustrated by various hemoglobinopathies; the others are exemplified by diseases to be presented in Chapter 12. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 197). Elsevier Health Sciences. Kindle Edition.

What is the genetic basis for linkage analysis and association analysis?

A fundamental feature of human biology is that each generation reproduces by combining haploid gametes containing 23 chromosomes, resulting from independent assortment and recombination of homologous chromosomes (see Chapter 2). To understand fully the concepts underlying genetic linkage analysis and tests for association, it is necessary to review briefly the behavior of chromosomes and genes during meiosis as they are passed from one generation to the next. During meiosis I, homologous chromosomes line up in pairs along the meiotic spindle. The paternal and maternal homologues exchange homologous segments by crossing over and creating new chromosomes that are a "patchwork" consisting of alternating portions of the grandmother's chromosomes and the grandfather's chromosomes (see Fig. 2-15). In the family illustrated in Figure 10-1, examples of recombined chromosomes are shown in the offspring (generation II) of the couple in generation I. Also shown is that the individual in generation III inherits a maternal chromosome that contains segments derived from all four of his maternal grandparents' chromosomes. The creation of such patchwork chromosomes emphasizes the notion of human genetic individuality: each chromosome inherited by a child from a parent is never exactly the same as either of the two copies of that chromosome in the parent. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 172). Elsevier Health Sciences. Kindle Edition.

What are ancestry informative markers (AIMs)? Why are AIMs useful to study?

Alleles that show large differences in allele frequency among populations originating in different parts of the world are referred to as ancestry informative markers (AIMs). Sets of AIMs have been identified whose frequencies differ among populations derived from widely separated geographical origins (e.g., European, African, Far East Asian, Middle Eastern, Native American, and Pacific Islanders). AIMs are therefore useful as markers for: - charting human migration patterns - documenting historical admixture between or among populations - determining the degree of genetic diversity among identifiable population subgroups Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 167). Elsevier Health Sciences. Kindle Edition.

What is balanced polymorphism?

Although certain mutant alleles may be deleterious in homozygotes, there may be environmental conditions in which heterozygotes for some diseases have increased fitness not only over homozygotes for the mutant allele but even over homozygotes for the normal allele. This situation is termed heterozygote advantage. Even a slight heterozygote advantage can lead to an increase in frequency of an allele that is severely detrimental in homozygotes, because heterozygotes greatly outnumber homozygotes in the population. A situation in which selective forces operate both to maintain a deleterious allele and to remove it from the gene pool is described as a balanced polymorphism. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 165). Elsevier Health Sciences. Kindle Edition.

Can genotyping just a few hundred or thousand SNPs in an invidual allow for the identification of the likely proportion of his or her genome contributed by ancestors?

Although there are millions of variants with different allele frequencies that can distinguish different population groups, genotyping as few as just a few hundred or a thousand SNPs in an individual is sufficient to identify the likely proportion of his or her genome contributed by ancestors from these different continental populations and to infer, therefore, the likely geographical origin( s) of that individual's ancestors. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 167). Elsevier Health Sciences. Kindle Edition.

Calculate the genotype frequencies of the population based off of the allele frequencies calculated for CCR5 earlier - assume that Hardy-Weinberg assumptions are met.

Applying the Hardy-Weinberg formula to the CCR5 example given earlier, with relative frequencies of the two alleles in the population of 0.906 (for the wild-type allele CCR5) and 0.094 (for ΔCCR5), then the Hardy-Weinberg law states that the relative proportions of the three combinations of alleles (genotypes) are p2 = 0.906 × 0.906 = 0.821 (for an individual having two wild-type CCR5 alleles), q2 = 0.094 × 0.094 = 0.009 (for two ΔCCR5 alleles), and 2pq = (0.906 × 0.094) + (0.094 × 0.906) = 0.170 (for one CCR5 and one ΔCCR5 allele). When these genotype frequencies (0.821 AA : 0.170 Aa: 0.009 aa), which were calculated by the Hardy-Weinberg law, are applied to a population of 788 individuals, the derived numbers of people with the three different genotypes are 647 AA: 134 Aa : 7 aa - based on a total sample population of 788. As long as the assumptions of the Hardy-Weinberg law are met in a population, we would expect these genotype frequencies (0.821 : 0.170 : 0.009) to remain constant generation after generation in that population. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 157). Elsevier Health Sciences. Kindle Edition.

What diseases was linkage analysis used in order to localize the disease-gene?

CF, Huntington Disease, Marfan Syndrome, NF1

What is the founder effect? Does it relate to genetic drift?

One special form of genetic drift is referred to as founder effect. When a small subpopulation breaks off from a larger population, the gene frequencies in the small population may be different from those of the population from which it originated because the new group contains a small, random sample of the parent group and, by chance, may not have the same gene frequencies as the parent group. If one of the original founders of a new group just happens to carry a relatively rare allele, that allele will have a far higher frequency than it had in the larger group from which the new group was derived. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 162-163). Elsevier Health Sciences. Kindle Edition.

Why are loss of protein function disorders due to impaired binding or metabolism of cofactors the most responsive of genetic disorders to specific biochemical therapies?

Some proteins acquire biological activity only after they associate with cofactors, such as BH4 in the case of PAH, as discussed earlier. Mutations that interfere with cofactor synthesis, binding, transport, or removal from a protein (when ligand binding is covalent) are also known. For many of these mutant proteins, an increase in the intracellular concentration of the cofactor is frequently capable of restoring some residual activity to the mutant enzyme, for example by increasing the stability of the mutant protein. Consequently, enzyme defects of this type are among the most responsive of genetic disorders to specific biochemical therapy because the cofactor or its precursor is often a water-soluble vitamin that can be administered safely in large amounts (see Chapter 13). Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 223). Elsevier Health Sciences. Kindle Edition.

What are the two critical components of the Hardy-Weinberg Law? What does the Hardy-Weinberg Law state? What loci does the law apply to? What loci does it not apply to?

The Hardy-Weinberg law has two critical components. The first is that under certain ideal conditions (see Box), a simple relationship exists between allele frequencies and genotype frequencies in a population. Suppose p is the frequency of allele A, and q is the frequency of allele a in the gene pool. Assume alleles combine into genotypes randomly; that is, mating in the population is completely at random with respect to the genotypes at this locus. The chance that two, A, alleles will pair up to give the AA genotype is then p^2; the chance that two, a ,alleles will come together to give the aa genotype is q^2; and the chance of having one A and one a pair, resulting in the Aa genotype, is 2pq (the factor 2 comes from the fact that the A allele could be inherited from the mother and the a allele from the father, or vice versa). A second component of the Hardy-Weinberg law is that if allele frequencies do not change from generation to generation, the proportion of the genotypes will not change either; that is, the population genotype frequencies from generation to generation will remain constant, at equilibrium, if the allele frequencies p and q remain constant. More specifically, when there is random mating in a population that is at equilibrium and genotypes AA, Aa, and aa are present in the proportions p2 : 2pq : q2, then genotype frequencies in the next generation will remain in the same relative proportions, p2 : 2pq : q2. The Hardy-Weinberg law states that the frequency of the three genotypes AA, Aa, and aa is given by the terms of the binomial expansion of (p + q) 2 = p2 + 2pq + q2. This law applies to all autosomal loci and to the X chromosome in females, but not to X-linked loci in males who have only a single X chromosome. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 156). Elsevier Health Sciences. Kindle Edition.

Why are the sizes of LD blocks encompassing alleles at a particular set of polymorphic loci not identical in all populations?

The size of an LD block encompassing alleles at a particular set of polymorphic loci is not identical in all populations. African populations have smaller blocks, averaging 7.3 kb per block across the genome, compared with 16.3 kb in Europeans; Chinese and Japanese block sizes are comparable to each other and are intermediate, averaging 13.2 kb. This difference in block size is almost certainly the result of the smaller number of generations since the founding of the non-African populations compared with populations in Africa, thereby limiting the time in which there has been opportunity for recombination to break up regions of LD. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 178). Elsevier Health Sciences. Kindle Edition.

What are six classes of LDLR mutations that alter LDL receptor function?

• Class 1 mutations are null alleles that prevent the synthesis of any detectable receptor; they are the most common type of disease-causing mutations at this locus. In the remaining five classes, the receptor is synthesized normally, but its function is impaired. • Mutations in class 2 (like those in classes 4 and 6) define features of the polypeptide critical to its subcellular localization. The relatively common class 2 mutations are designated transport-deficient because the LDL receptors accumulate at the site of their synthesis, the ER, instead of being transported to the Golgi complex. These alleles are predicted to prevent proper folding of the protein, an apparent requisite for exit from the ER. • Class 3 mutant receptors reach the cell surface but are incapable of binding LDL. • Class 4 mutations impair localization of the receptor to the coated pit, and consequently the bound LDL is not internalized. These mutations alter or remove the cytoplasmic domain at the carboxyl terminus of the receptor, demonstrating that this region normally targets the receptor to the coated pit. • Class 5 mutations are recycling-defective alleles. Receptor recycling requires the dissociation of the receptor and the bound LDL in the endosome. Mutations in the epidermal growth factor precursor homology domain prevent the release of the LDL ligand. This failure leads to degradation of the receptor, presumably because an occupied receptor cannot return to the cell surface. • Class 6 mutations lead to defective targeting of the mutant receptor to the basolateral membrane, a process that depends on a sorting signal in the cytoplasmic domain of the receptor. Mutations affecting the signal can mistarget the mutant receptor to the apical surface of hepatic cells, thereby impairing the recycling of the receptor to the basolateral membrane and leading to an overall reduction of endocytosis of the LDL receptor. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 228-229). Elsevier Health Sciences. Kindle Edition.

What factors can upset the relative frequency of various genotypes predicted by the Hardy-Weinberg Law? What magnitude of impact do we expect new mutations or natural selection to have on allele frequencies for autosomal recessive disease? What magnitude of impact do we expect mutations or selection to have on allele frequencies for autosomal dominant or X-linked disease?

1) In human populations, nonrandom mating may occur because of three distinct but related phenomena: stratification, assortative mating, and consanguinity. --> fast effect can affect allele frequencies even within a single generation. 2) Changes in allele frequency due to selection or mutation usually occur slowly, in small increments, and cause much less deviation from Hardy-Weinberg equilibrium, at least for recessive diseases. The rates of new mutations (see Chapter 4) are generally well below the frequency of heterozygotes for autosomal recessive diseases; the addition of new mutant alleles to the gene pool thus has little effect in the short term on allele frequencies for such diseases. In addition, most deleterious recessive alleles are hidden in asymptomatic heterozygotes and thus are not subject to selection. As a consequence, selection is not likely to have major short-term effects on the allele frequency of these recessive alleles. Importantly, however, for dominant or X-linked disease, mutation and selection do perturb allele frequencies from what would be expected under Hardy-Weinberg equilibrium, by substantially reducing or increasing certain genotypes. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 160). Elsevier Health Sciences. Kindle Edition.

What are some factors that contribute to ethnic differences in disease frequencies? Give an associated disease example per factor.

1) Lack of gene flow due to genetic isolation, so that a mutation in one group would not have an opportunity to be spread through matings to other groups. One extreme example of a difference in the incidence of genetic disease among different ethnic groups is the high incidence of Huntington disease (Case 24) among the indigenous inhabitants around Lake Maracaibo, Venezuela, that resulted from the introduction of a Huntington disease mutation into this genetic isolate. 2) Genetic drift - including nonrandom distribution of alleles among the individuals who founded particular subpopulations (founder effect) - hereditary type I tyrosinemia is an autosomal recessive condition that causes hepatic failure and renal tubular dysfunction due to deficiency of fumarylacetoacetase, an enzyme in the degradative pathway of tyrosine. The disease frequency is 1 in 685 in the Saguenay- Lac-Saint-Jean region of Quebec, but only 1 in 100,000 in other populations. As predicted for a founder effect, 100% of the mutant alleles in the Saguenay- Lac-Saint-Jean patients are due to the same mutation. 3) Heterozygote advantage under environmental conditions that favor the reproductive fitness of carriers of deleterious mutations (selection) - A well-known example of heterozygote advantage is resistance to malaria in heterozygotes for the mutation in sickle cell disease (Case 42). The sickle cell allele in the β-globin gene has reached its highest frequency in certain regions of West Africa, where heterozygotes are more fit than either type of homozygote because heterozygotes are relatively more resistant to the malarial organism. In regions where malaria is endemic, normal homozygotes are susceptible to malaria; many become infected and are severely, even fatally, affected, leading to reduced fitness. Sickle cell homozygotes are even more seriously disadvantaged, with a low relative fitness that approaches zero because of their severe hematological disease, discussed more fully in Chapter 11. Heterozygotes for sickle cell disease have red cells that are inhospitable to the malaria parasite but do not undergo sickling under normal environmental conditions; the heterozygotes are thus relatively more fit than homozygotes for the normal β-globin allele and reproduce at a higher rate. Thus, over time, the sickle cell mutant allele has reached a frequency as high as 0.15 in some areas of West Africa that are endemic for malaria, far higher than could be accounted for by recurrent mutation alone. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 165). Elsevier Health Sciences. Kindle Edition.

What are three approaches in which geneticists go about discovering the particular genes implicated in disease and the variants they contain that underlie or contribute to human diseases? In what situations will each analysis be most useful?

1) The first approach, linkage analysis, is family-based. Linkage analysis takes explicit advantage of family pedigrees to follow the inheritance of a disease among family members and to test for consistent, repeated coinheritance of the disease with a particular genomic region or even with a specific variant or variants, whenever the disease is passed on in a family. 2) The second approach, association analysis, is population-based. Association analysis does not depend explicitly on pedigrees but instead takes advantage of the entire history of a population to look for increased or decreased frequency of a particular allele or set of alleles in a sample of affected individuals taken from the population, compared with a control set of unaffected people from that same population. It is particularly useful for complex diseases that do not show a mendelian inheritance pattern. 3) The third approach involves direct genome sequencing of affected individuals and their parents and/ or other individuals in the family or population. This approach is particularly useful for rare mendelian disorders in which linkage analysis is not possible because there are simply not enough such families to do linkage analysis or because the disorder is a genetic lethal that always results from new mutations and is never inherited. In these situations, sequencing the genome (or just the coding exons of every gene, the exome) of an affected individual and sifting through the resulting billions (or in the case of the exome, tens of millions) of bases of DNA has been successfully used to find the gene responsible for the disorder. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 171). Elsevier Health Sciences. Kindle Edition.

What factors can disturb Hardy-Weinberg Equilibrium?

1) The first is that the population under study is large and that mating is random. However, a very small population in which random events can radically alter an allele frequency may not meet this first assumption. This first assumption is also breached when the population contains subgroups whose members choose to marry within their own subgroup rather than the population at large. 2) The second assumption is that allele frequencies do not change significantly over time. This requires that there is no migration in or out of the population by groups whose allele frequencies at a locus of interest are radically different from the allele frequencies in the population as a whole. 3) Similarly, selection for or against particular alleles, or the addition of new alleles to the gene pool due to mutations, will break the assumptions of the Hardy-Weinberg law. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 158). Elsevier Health Sciences. Kindle Edition.

What is a lysosomal storage disease example that involves altered protein function due to abnormal post-translational modification?

A Loss of Glycosylation: I-Cell Disease Some proteins have information contained in their primary amino acid sequence that directs them to their subcellular residence, whereas others are localized on the basis of post-translational modifications. This latter mechanism is true of the acid hydrolases found in lysosomes, but this form of cellular trafficking was unrecognized until the discovery of I-cell disease, a severe autosomal recessive lysosomal storage disease. The disorder has a range of phenotypic effects involving facial features, skeletal changes, growth retardation, and intellectual disability and survival of less than 10 years. The cytoplasm of cultured skin fibroblasts from I-cell patients contains numerous abnormal lysosomes, or inclusions, (hence the term inclusion cells or I cells). In I-cell disease, the cellular levels of many lysosomal acid hydrolases are greatly diminished, and instead they are found in excess in body fluids. This unusual situation arises because the hydrolases in these patients have not been properly modified post-translationally. A typical hydrolase is a glycoprotein, the sugar moiety containing mannose residues, some of which are phosphorylated. The mannose-6-phosphate residues are essential for recognition of the hydrolases by receptors on the cell and lysosomal membrane surface. In I-cell disease, there is a defect in the enzyme that transfers a phosphate group to the mannose residues. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 222). Elsevier Health Sciences. Kindle Edition.

What is a disease example involving dysregulation of a biosynthetic pathway?

Acute intermittent porphyria (AIP) is an autosomal dominant disease associated with intermittent neurological dysfunction. The primary defect is a deficiency of porphobilinogen (PBG) deaminase, an enzyme in the biosynthetic pathway of heme, required for the synthesis of both hemoglobin and hepatic cytochrome p450 drug-metabolizing enzymes (Fig. 12-11). All individuals with AIP have an approximately 50% reduction in PBG deaminase enzymatic activity, whether their disease is clinically latent (90% of patients throughout their lifetime) or clinically expressed (approximately 10%). This reduction is consistent with the autosomal dominant inheritance pattern (see Chapter 7). Homozygous deficiency of PBG deaminase, a critical enzyme in heme biosynthesis, would presumably be incompatible with life. AIP illustrates one molecular mechanism by which an autosomal dominant disease may manifest only episodically. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 225). Elsevier Health Sciences. Kindle Edition.

Do alleles at loci on the same chromosome assort independently? What does it mean to say genes are syntenic?

Alleles at Loci on the Same Chromosome Assort Independently If at Least One Crossover between Them Always Occurs. Now suppose that an individual is heterozygous at two loci 1 and 2, with alleles A and B paternally derived and a and b maternally derived, but the loci are on the same chromosome (Fig. 10-3). Genes that reside on the same chromosome are said to be syntenic (literally, "on the same thread"), regardless of how close together or how far apart they lie on that chromosome. In Figure 10.3 - crossing over between homologous chromosomes in meiosis I is shown between chromatids of two homologous chromosomes on the left. Crossovers result in new combinations of maternally and paternally derived alleles on the recombinant chromosomes present in gametes, shown on the right. If no crossing over occurs in the interval between loci 1 and 2, only parental (nonrecombinant) allele combinations, AB and ab, occur in the offspring. If one or two crossovers occur in the interval between the loci, half the gametes will contain a nonrecombinant combination of alleles and half the recombinant combination. The same is true if more than two crossovers occur between the loci (not illustrated here). NR, Nonrecombinant; R, recombinant. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 172). Elsevier Health Sciences. Kindle Edition.

What are alleles? What is a polymorphism? How do alleles and polymorphisms relate to linkage analysis?

Although any two homologous chromosomes generally look identical under the microscope, they differ substantially at the DNA sequence level. As discussed in Chapter 4, these differences at the same position (locus) on a pair of homologous chromosomes are alleles. Alleles that are common (generally considered to be those carried by approximately 2% or more of the population) constitute a polymorphism, and linkage analysis in families requires following the inheritance of specific alleles as they are passed down in a family. Allelic variants on homologous chromosomes allow geneticists to trace each segment of a chromosome inherited by a particular child to determine if and where recombination events have occurred along the homologous chromosomes. Several tens of millions of genetic markers are available to serve as genetic markers for this purpose. It is a truism now in human genetics to say that it is essentially always possible to determine with confidence, through a series of analyses outlined in this chapter, whether a given allele or segment of the genome in a patient has been inherited from his or her father or mother. This advance— a singular product of the Human Genome Project— is an essential feature of genetic analysis to determine the precise genetic basis of disease. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 172). Elsevier Health Sciences. Kindle Edition.

Do the location and order on the chromosomes for the ~ 20,000 coding genes exist in nearly identical places for humans? What factors make humans unique from one another?

Although the approximately 20,000 coding genes and their location and order on the chromosomes are nearly identical in all humans, we saw in Chapter 4 that humans as a whole have tens of millions of different alleles, ranging from changes in single base pairs (SNPs) to large genomic variants (CNVs or indels) hundreds of kilobases in size, that underlie extensive polymorphism among individuals. Many of the alleles found in one population are found in all human populations, at similar frequencies around the globe. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 166). Elsevier Health Sciences. Kindle Edition.

What is an example of ectopic expression or heterochronic expression? Is this predominantly due to a mutation that still results in normal protein structure? Or is this predominantly due to a mutation that results in abnormal protein structure?

An important class of mutations includes those that lead to inappropriate expression of the gene at an abnormal time or place. These mutations occur in the regulatory regions of the gene. Thus cancer is frequently due to the abnormal expression of a gene that normally promotes cell proliferation— an oncogene— in cells in which the gene is not normally expressed (see Chapter 15). Some mutations in hemoglobin regulatory elements lead to the continued expression in adults of the γ-globin gene, which is normally expressed at high levels only in fetal life. Such γ-globin gene mutations cause a benign phenotype called the hereditary persistence of fetal hemoglobin (Hb F). Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 197). Elsevier Health Sciences. Kindle Edition.

Based on Table 9, how would you calculate the genotype frequencies for the WT-CCR5 allele and the mutated CCR5 allele? -- this example allows us to estimate allele frequencies. In contrast, what does the Hardy-Weinberg Law allow us to estimate?

As we have just shown with the CCR5 example, we can use a sample of individuals with known genotypes in a population to derive estimates of the allele frequencies by simply counting the alleles in individuals with each genotype. How about the converse? Can we calculate the proportion of the population with various genotypes once we know the allele frequencies? Deriving genotype frequencies from allele frequencies is not as straightforward as counting because we actually do not know in advance how the alleles are distributed among homozygotes and heterozygotes. If a population meets certain assumptions, however, there is a simple mathematical equation for calculating genotype frequencies from allele frequencies. This equation is known as the Hardy-Weinberg law. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 156). Elsevier Health Sciences. Kindle Edition.

What is the HapMap and how does it relate to LD?

Association analyses on a genome scale are referred to as genome-wide association studies, known by their acronym GWAS. Such an undertaking for all known variants is impractical for many reasons but can be approximated by genotyping cases and controls for a mere 300,000 to 1 million individual variants located throughout the genome to search for association with the disease or trait in question. The success of this approach depends on exploiting LD because, as long as a variant responsible for altering disease susceptibility is in LD with one or more of the genotyped variants within an LD block, a positive association should be detectable between that disease and the alleles in the LD block. Developing such a set of markers led to the launch of the Haplotype Mapping (HapMap) Project, one of the biggest human genomics efforts to follow completion of the Human Genome Project. The HapMap Project began in four geographically distinct groups— a primarily European population, a West African population, a Han Chinese population, and a population from Japan— and included collecting and characterizing millions of SNP loci and developing methods to genotype them rapidly and inexpensively. Since that time, whole-genome sequencing has been applied to many populations in what is referred to as the 1000 Genomes Project, resulting in a massive expansion in the database of DNA variants available for GWAS with different populations around the globe. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 184). Elsevier Health Sciences. Kindle Edition.

What is assortative mating? What is the overall genetic effect of positive assortative mating on genotype frequency? What is a clinically relevant example of assortative mating?

Assortative mating is the choice of a mate because the mate possesses some particular trait. Assortative mating is usually positive; that is, people tend to choose mates who resemble themselves (e.g., in native language, intelligence, stature, skin color, musical talent, or athletic ability). To the extent that the characteristic shared by the partners is genetically determined, the overall genetic effect of positive assortative mating is an increase in the proportion of the homozygous genotypes at the expense of the heterozygous genotype. A clinically important aspect of assortative mating is the tendency to choose partners with similar medical problems, such as congenital deafness or blindness or exceptionally short stature. In such a case, the expectations of Hardy-Weinberg equilibrium do not apply because the genotype of the mate at the disease locus is not determined by the allele frequencies found in the general population. For example, consider achondroplasia (Case 2), an autosomal dominant form of skeletal dysplasia with a population incidence of 1 per 15,000 to 1 per 40,000 live births. Offspring homozygous for the achondroplasia mutation have a severe, lethal form of skeletal dysplasia that is almost never seen unless both parents have achondroplasia and are thus heterozygous for the mutation. This would be highly unlikely to occur by chance, except for assortative mating among those with achondroplasia. Although the long-term population effect of this kind of positive assortative mating on disease gene frequencies is insignificant, a specific family may find itself at very high genetic risk that would not be predicted from strict application of the Hardy-Weinberg law. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 159-160). Elsevier Health Sciences. Kindle Edition.

What causes linkage disequilibrium? How is LD quantified?

Because LD is a result not only of genetic distance but also of the amount of time during which recombination had a chance to occur and the possible effects of selection for or against particular haplotypes, different populations living in different environments and with different histories can have different values of D′ between the same two alleles at the same loci in the genome. To quantify varying degrees of LD, therefore, geneticists often use a measure derived from D, referred to as D′. D′ is designed to vary from 0, indicating linkage equilibrium, to a maximum of ± 1, indicating very strong LD. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 178). Elsevier Health Sciences. Kindle Edition.

What are the two classes of driver genes? How can these classes be further subdivided based on how they drive oncogenesis? What is a proto-oncogene? What is a tumor suppressor gene? Are proto-oncogene mutations or tumor suppressor gene mutations more common? Which one results in a gain-of-function versus a loss-of-function?

Both classes of driver genes: (1) those with specific effects on cellular proliferation or survival (2) those with global effects on genome or DNA integrity Can be further subdivided into one of two functional categories depending on how, if mutated, they drive oncogenesis. (1) The first category includes proto-oncogenes. These are normal genes that, when mutated in very particular ways, become driver genes through alterations that lead to excessive levels of activity. Once mutated in this way, driver genes of this type are referred to as activated oncogenes. Only a single mutation at one allele can be sufficient for activation, and the mutations that activate a proto-oncogene can range from highly specific point mutations causing dysregulation or hyperactivity of a protein, to chromosome translocations that drive overexpression of a gene, to gene amplification events that create an overabundance of the encoded mRNA and protein product. (2) The second, and more common, category of driver genes includes tumor suppressor genes (TSGs), mutations in which cause a loss of expression of proteins necessary to control the development of cancers. To drive oncogenesis, loss of function of a TSG typically requires mutations at both alleles. There are many ways that a cell can lose the function of TSG alleles. Loss-of-function mechanisms can range from missense, nonsense, or frame-shift mutations to gene deletions or loss of a part or even an entire chromosome. Loss of function of TSGs can also result from epigenomic transcriptional silencing due to altered chromatin conformation or promoter methylation (see Chapter 3), or from translational silencing by miRNAs or disturbances in other components of the translational machinery Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 313). Elsevier Health Sciences. Kindle Edition.

As of 2014, how many genetic disorder phenotypes for which the molecular basis is known?

By 2014, the online version of Mendelian Inheritance in Man listed over 5500 phenotypes for which the molecular basis is known, largely phenotypes with autosomal and X-linked inheritance. Although it is impressive that the basic molecular defect has been found in so many disorders, it is sobering to realize that the pathophysiology is not entirely understood for any genetic disease. Sickle cell disease (Case 42), discussed later in this chapter, is among the best characterized of all inherited disorders, but even here, knowledge is incomplete— despite its being the first molecular disease to be recognized, more than 65 years ago. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 195). Elsevier Health Sciences. Kindle Edition.

What are passenger mutations? What are drive gene mutations? What is a known gene found in the vast majority of cancers?

By analyzing many thousands of samples obtained from more than 30 types of human cancer, researchers are building The Cancer Genome Atlas, a public catalog of mutations, epigenomic modifications, and abnormal gene expression profiles found in a wide variety of cancers. Although the project is still under way, the results to date from these studies are striking. The number of mutations present in a tumor can vary from just a few to many tens of thousands. Most mutations found through sequencing of tumor tissue appear to be random, are not recurrent in particular cancer types, and probably occurred as the cancer developed, rather than directly causing the neoplasia to develop or progress. Such mutations are referred to as "passenger" mutations. However, a subset of a few hundred genes has been repeatedly found to be mutated at high frequency in many samples of the same type of cancer or even in multiple different types of cancers, mutated in fact far too frequently to simply be passenger mutations. These genes are thus presumed to be involved in the development or progression of the cancer itself and are therefore referred to as "driver" genes, that is, they harbor mutations (so-called driver gene mutations) that are likely to be causing a cancer to develop or progress. Although many driver genes are specific to particular tumor types, some, such as those in the TP53 gene encoding the p53 protein, are found in the vast majority of cancers of many different types. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 309-311). Elsevier Health Sciences. Kindle Edition.

Chapter 15: Cancer Genetics and Genomics How does genetics relate to cancer?

Cancer is one of the most common and serious diseases seen in clinical medicine. There are 14 million new cases of cancer diagnosed each year and over 8 millions deaths from the disease worldwide. Based on the most recent statistics available, cancer treatment costs $ 80 billion per year in direct health care expenditures in the United States alone. Cancer is invariably fatal if it is not treated. Identification of persons at increased risk for cancer before its development is an important objective of genetics research. And for both those with an inherited predisposition to cancer as well those in the general population, early diagnosis of cancer and its early treatment are vital, and both are increasingly reliant on advances in genome sequencing and gene expression analysis. In this chapter, we describe how genetic and genomic studies demonstrate that cancer is fundamentally a genetic disease. We describe the kinds of genes that have been implicated in initiating cancer and the mechanisms by which dysfunction of these genes can result in the disease. Second, we review a number of heritable cancer syndromes and demonstrate how insights gained into their pathogenesis have illuminated the basis of the much more common, sporadic forms of cancer. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 309). Elsevier Health Sciences. Kindle Edition.

What is neoplasia and neoplasm? What are the key characteristics for a neoplasm to be considered a cancer? What does malignant mean? What is a benign tumor?

Cancer is the name used to describe the more virulent forms of neoplasia, a disease process characterized by uncontrolled cellular proliferation leading to a mass or tumor (neoplasm). The abnormal accumulation of cells in a neoplasm occurs because of an imbalance between the normal processes of cellular proliferation and cellular attrition. Cells proliferate as they pass through the cell cycle and undergo mitosis. Attrition, due to programmed cell death (see Chapter 14), removes cells from a tissue. For a neoplasm to be a cancer, however, it must also be malignant, which means that not only is its growth uncontrolled, it is also capable of invading neighboring tissues that surround the original site (the primary site) and can spread (metastasize) to more distant sites (Fig. 15-1). Tumors that do not invade or metastasize are not cancerous but are referred to as benign tumors, although their abnormal function, size or location may make them anything but benign to the patient. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 309). Elsevier Health Sciences. Kindle Edition.

What is genetic drift? Does it impact the allele frequency of small or large populations more severely?

Chance events can have a much greater effect on allele frequencies in a small population than in a large one. For example, when a new mutation occurs in a small population, its frequency is represented by only one copy among all the copies of that gene in the population. Random effects of environment or other chance occurrences that are independent of the genotype (i.e., events that occur for reasons unrelated to whether an individual is carrying the mutant allele) can produce significant changes in the frequency of the disease allele when the population is small. Such chance occurrences disrupt Hardy-Weinberg equilibrium and cause the allele frequency to change from one generation to the next. This phenomenon, known as genetic drift, can explain how allele frequencies can change as a result of chance. During the next few generations, although the population size of the new group remains small, there may be considerable fluctuation in gene frequency until allele frequencies come to a new equilibrium as the population increases in size. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 162). Elsevier Health Sciences. Kindle Edition.

Describe how chromosome and subchromosomal mutations can also serve as driver mutations.

Chromosome and subchromosomal mutations (see Chapters 4 and 5) can also serve as driver mutations. Particular translocations are sometimes highly specific for certain types of cancer and involve specific genes (e.g., the BCR-ABL translocation in chronic myelogenous leukemia) (Case 10); in contrast, other cancers can show complex rearrangements in which chromosomes break into numerous pieces and rejoin, forming novel and complex combinations (a process known as "chromosome shattering"). Finally, large genomic alterations involving many kilobases of DNA can form the basis for loss of function or increased function of one or more driver genes. Large genomic alterations include deletions of a segment of a chromosome or multiplication of a chromosomal segment to produce regions with many copies of the same gene (gene amplification). Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 311). Elsevier Health Sciences. Kindle Edition.

What are LD blocks?

Clusters of alleles form blocks defined by linkage disequilibrium. Contiguous SNPs can be grouped into clusters of varying size in which the SNPs in any one cluster show high levels of LD with each other but not with SNPs outside that cluster (Fig. 10-9). For example, the nine polymorphic loci in cluster 1 (see Fig. 10-9A), each consisting of two alleles, have the potential to generate 29 = 512 different haplotypes; yet, only five haplotypes constitute 98% of all haplotypes seen. The absolute values of | D′ | between SNPs within the cluster are well above 0.8. Clusters of loci with alleles in high LD across segments of only a few kilobase pairs to a few dozen kilobase pairs are termed LD blocks. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 178). Elsevier Health Sciences. Kindle Edition.

What is consanguinity? What is the overall genetic effect of consanguinity on genotype frequency? What is a clinically relevant example of consanguinity?

Consanguinity, like stratification and positive assortative mating, brings about an increase in the frequency of autosomal recessive disease by increasing the frequency with which carriers of an autosomal recessive disorder mate. Unlike the disorders in stratified populations, in which each subgroup is likely to have a high frequency of a few alleles, the kinds of recessive disorders seen in the offspring of related parents may be very rare and unusual in the population as a whole because consanguineous mating allows an uncommon allele inherited from a heterozygous common ancestor to become homozygous. A similar phenomenon is seen in genetic isolates, small populations derived from a limited number of common ancestors who tended to mate only among themselves. Mating between two apparently "unrelated" individuals in a genetic isolate may have the same risk for certain recessive conditions as that observed in consanguineous marriages because the individuals are both carriers by inheritance from common ancestors of the isolate, a phenomenon known as inbreeding. For example, among Ashkenazi Jews in North America, mutant alleles for Tay-Sachs disease (GM2 gangliosidosis) (Case 43), discussed in detail in Chapter 12, are relatively more common than in other ethnic groups. The frequency of Tay-Sachs disease is 100 times higher in Ashkenazi Jews (1 per 3600) than in most other populations (1 per 360,000). Thus the Tay-Sachs carrier frequency among Ashkenazi Jews is approximately 1 in 30 (q2 = 1/ 3600, q = 1/ 60, 2pq = ≈ 1/ 30) as compared to a carrier frequency of approximately 1 in 300 in non-Ashkenazi individuals. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 160). Elsevier Health Sciences. Kindle Edition.

How many genes encode enzymes in the human genome? What are enzymopathies?

Enzymes are the catalysts that mediate the efficient conversion of a substrate to a product. The diversity of substrates on which enzymes act is huge. Accordingly, the human genome contains more than 5000 genes that encode enzymes, and there are hundreds of human diseases— the so-called enzymopathies— that involve enzyme defects. We first discuss one of the best-known groups of inborn errors of metabolism, the hyperphenylalaninemias. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 216-217). Elsevier Health Sciences. Kindle Edition.

What is familial hypercholesterolemia? What type of disease mechanism does it demonstrate?

FH is classified as a type 2 familial dyslipidemia. There are five types of familial dyslipidemia (not including subtypes), and each are classified from both the altered lipid profile and by the genetic abnormality. For example, high LDL (often due to LDL receptor defect) is type 2. Others include defects in chylomicron metabolism, triglyceride metabolism, and metabolism of other cholesterol-containing particles, such as VLDL and IDL. About 1 in 300 to 500 people have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare.[1] People who have one abnormal copy (are heterozygous) of the LDLR gene may develop cardiovascular disease prematurely at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.[2]

What is a disease example involving a defect in receptor proteins?

Familial hypercholesterolemia is one of a group of metabolic disorders called the hyperlipoproteinemias. These diseases are characterized by elevated levels of plasma lipids (cholesterol, triglycerides, or both) carried by apolipoprotein B (apoB)-containing lipoproteins. Other monogenic hyperlipoproteinemias, each with distinct biochemical and clinical phenotypes, have also been recognized. In addition to mutations in the LDL receptor gene (Table 12-2), abnormalities in three other genes can also lead to familial hypercholesterolemia (Fig. 12-12). Remarkably, all four of the genes associated with familial hypercholesterolemia disrupt the function or abundance either of the LDL receptor at the cell surface or of apoB, the major protein component of LDL and a ligand for the LDL receptor. Mutations in the LDL receptor gene (LDLR) are the most common cause of familial hypercholesterolemia (Case 16). The receptor is a cell surface protein responsible for binding LDL and delivering it to the cell interior. Elevated plasma concentrations of LDL cholesterol lead to premature atherosclerosis (accumulation of cholesterol by macrophages in the subendothelial space of major arteries) and increased risk for heart attack and stroke in both untreated heterozygote and homozygote carriers of mutant alleles. Physical stigmata of familial hypercholesterolemia include xanthomas (cholesterol deposits in skin and tendons) (Case 16) and premature arcus corneae (deposits of cholesterol around the periphery of the cornea). Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 227). Elsevier Health Sciences. Kindle Edition.

What do we expect from mutation and selection balance in X-linked recessive mutations?

For those X-linked phenotypes of medical interest that are recessive, or nearly so, selection occurs in hemizygous males and not in heterozygous females, except for the small proportion of females who are manifesting heterozygotes with reduced fitness (see Chapter 7). In this brief discussion, however, we assume that heterozygous females have normal fitness. Because males have one X chromosome and females two, the pool of X-linked alleles in the entire population's gene pool is partitioned at any given time, with one third of mutant alleles present in males and two thirds in females. As we saw in the case of autosomal dominant mutations, mutant alleles lost through selection must be replaced by recurrent new mutations to maintain the observed disease incidence. If the incidence of a serious X-linked disease is not changing and selection is operating against (and only against) hemizygous males, the mutation rate, µ, must equal the coefficient of selection, s (i.e., the proportion of mutant alleles that are not passed on), times q, the allele frequency, adjusted by a factor of 3 because selection is operating only on the third of the mutant alleles in the population that are present in males at any time. Thus, μ = sq / 3 For an X-linked genetic lethal disease, s = 1, and one third of all copies of the mutant gene responsible are lost from each generation and must, in a stable equilibrium, be replaced by de novo mutations. Therefore, in such disorders, one third of all persons who have X-linked lethal disorders are predicted to carry a new mutation, and their genetically normal mothers have a low risk for having subsequent children with the same disorder (again, assuming the absence of germline mosaicism). The remaining two thirds of the mothers of individuals with an X-linked lethal disorder would be carriers, with a 50% risk for having another affected son. However, the prediction that two thirds of the mothers of individuals with an X-linked lethal disorder are carriers of a disease-causing mutation is based on the assumption that mutation rates in males and in females are equal. It can be shown that if the mutation rate in males is much greater than in females, then the chance of a new mutation in the egg is very low, and most of the mothers of affected children will be carriers, having inherited the mutation as a new mutation from their unaffected fathers and then passing it on to their affected children. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 162). Elsevier Health Sciences. Kindle Edition.

What is race from a scientific point of view? Will racial categorization be used by medical professionals in the future?

From the scientific point of view, however, race is a fiction. Racial categories are constructed using poorly defined criteria that subdivide humankind using physical appearance (i.e., skin color, hair texture, and facial structures) combined with social characteristics that have their origins in the geographical, historical, cultural, religious, and linguistic backgrounds of the community in which an individual was born and raised. Although some of these distinguishing characteristics have a basis in the differences in the alleles carried by individuals of different ancestry, others likely have little or no basis in genetics. Racial categorization has been widely used in the past in medicine as the basis for making a number of assumptions concerning an individual's genetic makeup. Knowing the frequencies of alleles of relevance to health and disease in different populations around the globe is valuable for alerting a physician to an increased likelihood for disease based on an individual's genetic ancestry. However, with the expansion of individualized genetic medicine, it is hoped that more and more of the variants that contribute to disease will be assessed directly rather than having ethnicity or "race" used as a surrogate for an accurate genotype. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 168-169). Elsevier Health Sciences. Kindle Edition.

What is a haplotype? How do haplotype frequencies align with allele frequencies in linkage equilibrium versus linkage disequilibrium?

Haplotype = is the set of alleles located on the same chromosome. Figure 10-7 demonstrates how the same allele frequencies can result in different haplotype frequencies indicative of linkage equilibrium, strong linkage disequilibrium, or partial linkage disequilibrium. (A) - Under linkage equilibrium, haplotype frequencies are as expected from the product of the relevant allele frequencies. (B) - Loci 1 and 2 are located very close to one another, and alleles at these loci show strong linkage disequilibrium. Haplotype A-S is absent and a-s is less frequent (0.4 instead of 0.45) compared to what is expected from allele frequencies. (C) - Alleles at loci 1 and 2 show partial linkage disequilibrium. Haplotypes, A-S and a-s are underrepresented compared to what is expected from allele frequencies. ***Note that the allele frequencies for A and a at locus 1 and for S and s at locus 2 are the same in all three tables; it is the way the alleles are distributed in haplotypes, shown in the central four cells of the table, that differ. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 177). Elsevier Health Sciences. Kindle Edition.

What is a disease example involving impaired cofactor binding?

Homocystinuria due to cystathionine synthase deficiency (Fig. 12-8) was one of the first aminoacidopathies to be recognized. The clinical phenotype of this autosomal recessive condition is often dramatic. The most common features include dislocation of the lens, intellectual disability, osteoporosis, long bones, and thromboembolism of both veins and arteries, a phenotype that can be confused with Marfan syndrome, a disorder of connective tissue (Case 30). The accumulation of homocysteine is believed to be central to most, if not all, of the pathology. Homocystinuria was one of the first genetic diseases shown to be vitamin responsive; pyridoxal phosphate is the cofactor of the enzyme, and the administration of large amounts of pyridoxine, the vitamin precursor of the cofactor, often ameliorates the biochemical abnormality and the clinical disease (see Chapter 13). In many patients, the affinity of the mutant enzyme for pyridoxal phosphate is reduced, indicating that altered conformation of the protein impairs cofactor binding. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 223). Elsevier Health Sciences. Kindle Edition.

In the case of crossing-over for syntenic genes: Why is a parental chromosome considered a non-recombinant chromosome? Why is non-parental chromosome considered a recombinant chromosome? What proportions would we expect if 1, 2, or more recombinations occur between two loci? How does it relate to independent assortment?

How will these alleles behave during meiosis? We know that between one and four crossovers occur between homologous chromosomes during meiosis I when there are two chromatids per homologous chromosome. If no crossing over occurs within the segment of the chromatids between the loci 1 and 2 (and ignoring whatever happens in segments outside the interval between these loci), then the chromosomes we see in the gametes will be AB and ab, which are the same as the original parental chromosomes; a parental chromosome is therefore a non-recombinant chromosome. If crossing over occurs at least once in the segment between the loci, the resulting chromatids may be either non-recombinant or Ab and aB, which are not the same as the parental chromosomes; such a nonparental chromosome is therefore a recombinant chromosome. One, two, or more recombinations occurring between two loci at the four-chromatid stage result in gametes that are 50% nonrecombinant (parental) and 50% recombinant (nonparental), which is precisely the same proportions one sees with independent assortment of alleles at loci on different chromosomes. Thus, if two syntenic loci are sufficiently far apart on the same chromosome to ensure that there is going to be at least one crossover between them in every meiosis, the ratio of recombinant to nonrecombinant genotypes will be, on average, 1 : 1, just as if the loci were on separate chromosomes and assorting independently. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 172-174). Elsevier Health Sciences. Kindle Edition.

If a dominant disease is deleterious but not lethal, how will the fitness of those individuals be affected? What does the mutation rate per generation, u, account for in the equation u = sq ?

If a dominant disease is deleterious but not lethal, affected persons may reproduce but will nevertheless contribute fewer than the average number of offspring to the next generation; that is, their fitness, f, will be reduced. Such a mutation will be lost through selection at a rate proportional to the reduced fitness of heterozygotes. The frequency of the mutant alleles responsible for the disease in the population therefore represents a balance between loss of mutant alleles through the effects of selection and gain of mutant alleles through recurrent mutation. A stable allele frequency will be reached at whatever level balances the two opposing forces: one (selection) that removes mutant alleles from the gene pool and one (de novo mutation) that adds new ones back. The mutation rate per generation, µ, at a disease locus must be sufficient to account for that fraction of all the mutant alleles (allele frequency q) that are lost by selection from each generation. Thus, u = sq As an illustration of this relationship, in achondroplasia, the fitness of affected patients is not zero, but they have only approximately one fifth as many children as people of normal stature in the population. Thus their average fitness, f, is 0.20, and the coefficient of selection, s, is 1 − f, or 0.80. In the subsequent generation, then, only 20% of current achondroplasia alleles are passed on from the current generation to the next. Because the frequency of achondroplasia appears stable from generation to generation, new mutations must be responsible for replacing the 80% of mutant genes in the population lost through selection. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 161-162). Elsevier Health Sciences. Kindle Edition.

If medical advances improve the fitness of affected persons, what would we expect to see in the observed incidence of the disease?

If the fitness of affected persons suddenly improved (e.g., because of medical advances), the observed incidence of the disease in the population would be predicted to increase and reach a new equilibrium. Retinoblastoma (Case 39) and other dominant embryonic tumors with childhood onset are examples of conditions that now have a greatly improved prognosis, with a predicted consequence of increased disease frequency in the population. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 162). Elsevier Health Sciences. Kindle Edition.

What is an example of a novel property mutation? Is this predominantly due to a mutation that still results in normal protein structure? Or is this predominantly due to a mutation that results in abnormal protein structure?

In a few diseases, a change in the amino acid sequence confers a novel property on the protein, without necessarily altering its normal functions. The classic example of this mechanism is sickle cell disease (Case 42), which, as we will see later in this chapter, is due to an amino acid substitution that has no effect on the ability of sickle hemoglobin to transport oxygen. Rather, unlike normal hemoglobin, sickle hemoglobin chains aggregate when they are deoxygenated and form abnormal polymeric fibers that deform red blood cells. That novel property mutations are infrequent is not surprising, because most amino acid substitutions are either neutral or detrimental to the function or stability of a protein that has been finely tuned by evolution. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 197). Elsevier Health Sciences. Kindle Edition.

Why does selection have a big impact on dominant mutant alleles?

In contrast to recessive mutant alleles, dominant mutant alleles are exposed directly to selection. Consequently, the effects of selection and mutation are more obvious and can be more readily measured for dominant traits. A genetic lethal dominant allele, if fully penetrant, will be exposed to selection in heterozygotes, thus removing all alleles responsible for the disorder in a single generation. Several human diseases are thought or known to be autosomal dominant traits with zero or near-zero fitness and thus always result from new rather than inherited autosomal dominant mutations (i.e. Atelosteogenesis, Cornelia de Lange Syndrome, Osteogenesis Imperfecta Type II, and Thanatophoric Dysplasia) Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 161). Elsevier Health Sciences. Kindle Edition.

What is a disease example where gains of glycosylation caused by missense mutations cause pathogenic consequences? This is in contrast to I-cell disease where a loss of glycosylation has pathogenic consequences...

In contrast to the failure of protein glycosylation exemplified by I-cell disease, it has been shown that an unexpectedly high proportion (approximately 1.5%) of the missense mutations that cause human disease may be associated with abnormal gains of N-glycosylation due to mutations creating new consensus N-glycosylation sites in the mutant proteins. That such novel sites can actually lead to inappropriate glycosylation of the mutant protein, with pathogenic consequences, is highlighted by the rare autosomal recessive disorder, mendelian susceptibility to mycobacterial disease (MSMD). MSMD patients have defects in any one of a number of genes that regulate the defense against some infections. Consequently, they are susceptible to disseminated infections upon exposure to moderately virulent mycobacterial species, such as the bacillus Calmette-Guérin (BCG) used throughout the world as a vaccine against tuberculosis, or to nontuberculous environmental bacteria that do not normally cause illness. Some MSMD patients carry missense mutations in the gene for interferon-γ receptor 2 (IFNGR2) that generate novel N-glycosylation sites in the mutant IFNGR2 protein. These novel sites lead to the synthesis of an abnormally large, overly glycosylated receptor. The mutant receptors reach the cell surface but fail to respond to interferon-γ. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 223). Elsevier Health Sciences. Kindle Edition.

What is the central, organizing concept of population genetics?

In this chapter, we describe the central, organizing concept of population genetics, Hardy-Weinberg equilibrium; we consider its assumptions and the factors that may cause true or apparent deviation from equilibrium in real as opposed to idealized populations. Finally, we provide some insight into how differences in allelic variant or disease gene frequencies arise among members of different, more or less genetically isolated groups. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 155). Elsevier Health Sciences. Kindle Edition.

Chapter 12: The Molecular, Biochemical, and Cellular Basis of Genetic Disease What is the purpose of Chapter 12?

In this chapter, we extend our examination of the molecular and biochemical basis of genetic disease beyond the hemoglobinopathies to include other diseases and the abnormalities in gene and protein function that cause them. In Chapter 11, we presented an outline of the general mechanisms by which mutations cause disease (see Fig. 11-1) and reviewed the steps at which mutations can disrupt the synthesis or function of a protein (see Table 11-2). Those outlines provide a framework for understanding the pathogenesis of all genetic disease. However, mutations in other classes of proteins often disrupt cell and organ function by processes that differ from those illustrated by the hemoglobinopathies, and we explore them in this chapter. To illustrate these other types of disease mechanisms, we examine here well-known disorders such as phenylketonuria, cystic fibrosis, familial hypercholesterolemia, Duchenne muscular dystrophy, and Alzheimer disease. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 215). Elsevier Health Sciences. Kindle Edition.

What are the definitions of linked equilibrium and linkage disequilibrium? Is the disease-causing allele and the marker allele linked within families or between families?

Linkage Disequilibrium is non-random assortment of alleles at 2 or more loci. - The closer the markers, the stronger the LD since recombination will have occurred at a low rate.

How is linkage analysis a method of mapping genes? What two pieces of information do we rely on to determine if two loci are linked?

Linkage analysis is a method of mapping genes that uses studies of recombination in families to determine whether two genes show linkage when passed on from one generation to the next. We use information from the known or suspected mendelian inheritance pattern (dominant, recessive, X-linked) to determine which of the individuals in a family have inherited a recombinant or a nonrecombinant chromosome. To decide whether two loci are linked and, if so, how close or far apart they are, we rely on two pieces of information: (1) First, using the family data in hand, we need to estimate θ, the recombination frequency between the two loci, because that will tell us how close or far apart they are. (2) Next, we need to ascertain whether θ is statistically significantly different from 0.5, because determining whether two loci are linked is equivalent to asking whether the recombination fraction between them differs significantly from the 0.5 fraction expected for unlinked loci. Estimating θ and, at the same time, determining the statistical significance of any deviation of θ from 0.5, relies on a statistical tool called the likelihood ratio. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 180). Elsevier Health Sciences. Kindle Edition.

How is linkage analysis used in Mendelian Diseases?

Linkage analysis is used when there is a particular mode of inheritance (autosomal dominant, autosomal recessive, or X-linked) that explains the inheritance pattern. LOD score analysis allows mapping of genes in which mutations cause diseases that follow mendelian inheritance. The LOD score gives both: • A best estimate of the recombination frequency, θmax, between a marker locus and the disease locus • An assessment of how strong the evidence is for linkage at that value of θmax. Values of the LOD score Z above 3 are considered strong evidence. Linkage at a particular θmax of a disease gene locus to a marker with known physical location implies that the disease gene locus must be near the marker. The smaller the θmax is, the closer the disease locus is to the linked marker locus. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 181). Elsevier Health Sciences. Kindle Edition.

How does linkage relate to recombination frequency? What is common notation for recombination frequency? What does theta equal if two loci are linked or if they are unlinked? Do linked or unlinked loci follow independent assortment?

Linkage is the term used to describe a departure from the independent assortment of two loci, or, in other words, the tendency for alleles at loci that are close together on the same chromosome to be transmitted together, as an intact unit, through meiosis. Analysis of linkage depends on determining the frequency of recombination as a measure of how close two loci are to each other on a chromosome. A common notation for recombination frequency (as a proportion, not a percentage) is the Greek letter theta, θ, where θ varies from 0 (no recombination at all) to 0.5 (independent assortment). If two loci are so close together that θ = 0 between them they are said to be completely linked. If they are so far apart that θ = 0.5 they are assorting independently and are unlinked. In between these two extremes are various degrees of linkage. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 175). Elsevier Health Sciences. Kindle Edition.

Why are lysosomal storage diseases a unique class of enzymopathies? What is an example?

Lysosomes are membrane-bound organelles containing an array of hydrolytic enzymes involved in the degradation of a variety of biological macromolecules. Mutations in these hydrolases are unique because they lead to the accumulation of their substrates inside the lysosome, where the substrates remain trapped because their large size prevents their egress from the organelle. Their accumulation and sometimes toxicity interferes with normal cell function, eventually causing cell death. Moreover, the substrate accumulation underlies one uniform clinical feature of these diseases— their unrelenting progression. In most of these conditions, substrate storage increases the mass of the affected tissues and organs. When the brain is affected, the picture is one of neurodegeneration. The clinical phenotypes are very distinct and often make the diagnosis of a storage disease straightforward. More than 50 lysosomal hydrolase or lysosomal membrane transport deficiencies, almost all inherited as autosomal recessive conditions, have been described. Historically, these diseases were untreatable. However, bone marrow transplantation and enzyme replacement therapy have dramatically improved the prognosis of these conditions. Example: Tay-Sachs Disease - Tay-Sachs disease (Case 43) is one of a group of heterogeneous lysosomal storage diseases, the GM2 gangliosidoses, that result from the inability to degrade a sphingolipid, GM2 ganglioside (Fig. 12-5). The biochemical lesion is a marked deficiency of hexosaminidase A (hex A). Although the enzyme is ubiquitous, the disease has its clinical impact almost solely on the brain, the predominant site of GM2 ganglioside synthesis. The clinical course of Tay-Sachs disease is tragic. Affected infants appear normal until approximately 3 to 6 months of age but then gradually undergo progressive neurological deterioration until death at 2 to 4 years. The effects of neuronal death can be seen directly in the form of the so-called cherry-red spot in the retina (Case 43). Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 221-222). Elsevier Health Sciences. Kindle Edition.

What is independent assortment? When is a gamete termed parental versus non-parental?

Main concept: alleles at loci on different chromosomes assort independently. Assume there are two polymorphic loci, 1 and 2, on different chromosomes, with alleles A and a at locus 1 and alleles B and b at locus 2 (Fig. 10-2). Suppose an individual's genotype at these loci is Aa and Bb; that is, she is heterozygous at both loci, with alleles A and B inherited from her father and alleles a and b inherited from her mother. The two different chromosomes will line up on the metaphase plate at meiosis I in one of two combinations with equal likelihood. After recombination and chromosomal segregation are complete, there will be four possible combinations of alleles, AB, ab, Ab, and aB, in a gamete; each combination is as likely to occur as any other, a phenomenon known as independent assortment. Because AB gametes contain only her paternally derived alleles, and ab gametes only her maternally derived alleles, these gametes are designated parental. In contrast, Ab or aB gametes, each containing one paternally derived allele and one maternally derived allele, are termed non-parental gametes. On average, half (50%) of gametes will be parental and 50% will be non-parental. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 172). Elsevier Health Sciences. Kindle Edition.

Describe how normal cell division or environmental agents may increase the rate of mutations around the genome. How does this relate to driver genes?

Many different genome alterations can act as driver gene mutations. In some cases, a single nucleotide change or small insertion or deletion can be a driver mutation. Large numbers of cell divisions are required to produce an adult organism of an estimated 1014 cells from a single-cell zygote. Given a frequency of 10 − 10 replication errors per base of DNA per cell division, and an estimated 1015 cell divisions during the lifetime of an adult, replication errors alone result in thousands of new single nucleotide or small insertion/ deletion mutations in the genome in every cell of the organism. Some environmental agents, such as carcinogens in cigarette smoke or ultraviolet or X-irradiation, will increase the rate of mutations around the genome. If, by chance, mutations occur in critical driver genes in a particular cell, then the oncogenic process may be initiated. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 311). Elsevier Health Sciences. Kindle Edition.

What is gene flow? How does it relate to migration? Is the process slow or fast? Can it affect large populations? What is genetic admixture?

Migration can change allele frequency by the process of gene flow, defined as the slow diffusion of genes across a barrier. Gene flow usually involves a large population and a gradual change in gene frequencies. The genes of migrant populations with their own characteristic allele frequencies are gradually merged into the gene pool of the population into which they have migrated, a process referred to as genetic admixture. The term migration is used here in the broad sense of crossing a reproductive barrier, which may be racial, ethnic, or cultural and not necessarily geographical and requiring physical movement from one region to another. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 163). Elsevier Health Sciences. Kindle Edition.

What are the four ways in which mutations can affect protein function? Which pathway is the most common? What is the difference between heterochronic expression and ectopic expression?

Mutations involving protein-coding genes have been found to cause disease through one of four different effects on protein function (Fig. 11-1). (1) The most common effect by far is a loss of function of the mutant protein. Many important conditions arise, however, from other mechanisms: (2) a gain of function in the mutant protein (3) the acquisition of a novel property by the mutant protein (4a) the expression of a gene at the wrong time (heterochronic expression) (4b) the expression of a gene in the wrong place (ectopic expression). Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 195). Elsevier Health Sciences. Kindle Edition.

What are some diseases that occur due to a gain-of-function mutation? Is this predominantly due to a mutation that still results in normal protein structure? Or is this predominantly due to a mutation that results in abnormal protein structure? Or both?

Mutations may also enhance one or more of the normal functions of a protein; in a biological system, however, more is not necessarily better, and disease may result. Gain-of-function mutations fall into two broad classes: • Mutations that increase the production of a normal protein. Some mutations cause disease by increasing the synthesis of a normal protein in cells in which the protein is normally present. The most common mutations of this type are due to increased gene dosage, which generally results from duplication of part or all of a chromosome. The classic example is trisomy 21 (Down syndrome), which is due to the presence of three copies of chromosome 21. Other important diseases arise from the increased dosage of single genes, including one form of familial Alzheimer disease due to a duplication of the amyloid precursor protein (βAPP) gene (see Chapter 12), and the peripheral nerve degeneration Charcot-Marie-Tooth disease type 1A (Case 8), which generally results from duplication of only one gene, the gene for peripheral myelin protein 22 (PMP22). • Mutations that enhance one normal function of a protein. Rarely, a mutation in the coding region may increase the ability of each protein molecule to perform one or more of its normal functions, even though this increase is detrimental to the overall physiological role of the protein. For example, the missense mutation that creates hemoglobin Kempsey locks hemoglobin into its high oxygen affinity state, thereby reducing oxygen delivery to tissues. Another example of this mechanism occurs in the form of short stature called achondroplasia (Case 2). Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 196-197). Elsevier Health Sciences. Kindle Edition.

Give a disease example involving a mutation in genes that encode collagen.

Osteogenesis imperfecta (OI) is a group of inherited disorders that predispose to skeletal deformity and easy fracturing of bones, even with little trauma (Fig. 12-21). The combined incidence of all forms of the disease is approximately 1 per 10,000. Approximately 95% of affected individuals have heterozygous mutations in one of two genes, COL1A1 and COL1A2, that encode the chains of type I collagen, the major protein in bone. A remarkable degree of clinical variation has been recognized, from lethality in the perinatal period to only a mild increase in fracture frequency. The clinical heterogeneity is explained by both locus and allelic heterogeneity; the phenotypes are influenced by which chain of type I procollagen is affected and according to the type and location of the mutation at the locus. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 238). Elsevier Health Sciences. Kindle Edition.

What is an example of the Hardy-Weinberg Law used for X-linked disease?

Remember this law applies to all autosomal loci and to the X chromosome in females, but not to X-linked loci in males who have only a single X chromosome. Recall from Chapter 7 that, for X-linked genes, there are three female genotypes but only two possible male genotypes. To illustrate gene frequencies and genotype frequencies when the gene of interest is X-linked, we use the trait known as X-linked red-green color blindness, which is caused by mutations in the series of visual pigment genes on the X chromosome. We use color blindness as an example because, as far as we know, it is not a deleterious trait (except for possible difficulties with traffic lights), and color blind persons are not subject to selection. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 158). Elsevier Health Sciences. Kindle Edition.

Why does the Hardy-Weinberg law still hold in recessive disease despite selection against the recessive disease?

Selection against harmful recessive mutations has far less effect on the population frequency of the mutant allele than does selection against dominant mutations because only a small proportion of the genes are present in homozygotes and are therefore exposed to selective forces. Even if there were complete selection against homozygotes (f = 0), as in many lethal autosomal recessive conditions, it would take many generations to reduce the gene frequency appreciably because most of the mutant alleles are carried by heterozygotes with normal fitness. Even reduction or removal of selection against an autosomal recessive disorder by successful medical treatment (e.g., as in the case of PKU) would have just as slow an effect on increasing the gene frequency over many generations. Thus as long as mating is random, genotypes in autosomal recessive diseases can be considered to be in Hardy-Weinberg equilibrium, despite selection against homozygotes for the recessive allele. Thus the mathematical relationship between genotype and allele frequencies described in the Hardy-Weinberg law holds for most practical purposes in recessive disease. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 161). Elsevier Health Sciences. Kindle Edition.

What does the LOD score allow us to calculate?

Statistical theory tells us that when the value of the likelihood ratio for all values of θ between 0 and 0.5 are calculated, the value of θ that gives the greatest value of this likelihood ratio is, in fact, the best estimate of the recombination fraction you can make given the data and is referred to as θmax. By convention, the computed likelihood ratio for different values of θ is usually expressed as the log10 and is called the LOD score (Z) where LOD stands for "Logarithm of the ODds." The use of logarithms allows likelihood ratios calculated from different families to be combined by simple addition instead of having to multiply them together. The value of θ that maximizes the likelihood ratio, θmax, may be the best estimate one can make for θ given the data, but how good an estimate is it? The magnitude of the LOD score provides an assessment of how good an estimate of θmax you have made. By convention, a LOD score of + 3 or greater (equivalent to greater than 1000 : 1 odds in favor of linkage) is considered firm evidence that two loci are linked— that is, that θmax is statistically significantly different from 0.5. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 181). Elsevier Health Sciences. Kindle Edition.

What is stratification? Give an example of a disease and population subject to stratification. What is the overall genetic effect of stratification on genotype frequency? Does stratification have an effect on the frequency of autosomal dominant disease or X-linked disease or autosomal recessive disease?

Stratification describes a population in which there are a number of subgroups that have— for a variety of historical, cultural, or religious reasons— remained relatively genetically separate during modern times. Worldwide, there are numerous stratified populations; for example, the United States population is stratified into many subgroups, including whites of northern or southern European ancestry, African Americans, and numerous Native American, Asian, and Hispanic groups. Similarly stratified populations exist in other parts of the world as well, either currently or in the recent past, such as Sunni and Shia Muslims, Orthodox Jews, French-speaking Canadians, or different castes in India. When mate selection in a population is restricted for any reason to members of one particular subgroup, and that subgroup happens to have a variant allele with a higher frequency than in the population as a whole, the result will be an apparent excess of homozygotes in the overall population beyond what one would predict from allele frequencies in the population as a whole if there were truly random mating. To illustrate this point, suppose a population contains a minority group, constituting 10% of the population, in which a mutant allele for an autosomal recessive disease has a frequency qmin = 0.05 and the wild-type allele has frequency pmin = 0.95. In the remaining majority 90% of the population, the mutant allele is nearly absent (i.e., qmaj is ≈ 0 and pmaj = 1). An example of just such a situation is the African American population of the United States and the mutant allele at the β-globin locus responsible for sickle cell disease (Case 42). The overall frequency of the disease allele in the total population, qpop, is therefore equal to 0.1 × 0.05 = 0.005, and, simply applying the Hardy-Weinberg law, the frequency of the disease in the population as a whole would be predicted to be q2pop = (0.005) 2 = 2.5 × 10 − 5 if mating were perfectly random throughout the entire population. If, however, individuals belonging to the minority group were to mate exclusively with other members of that same minority group (an extreme situation that does not apply in reality), then the frequency of affected individuals in the minority group would be (q2min) = (0.05) 2 = 0.0025. Because the minority group is one tenth of the entire population, the frequency of disease in the total population is 0.0025/ 10 = 2.5 × 10 − 4, or 10-fold higher than the calculated q2pop = 2.5 × 10 − 5 obtained by naively applying the Hardy-Weinberg law to the population as a whole without consideration of stratification. Namely affects frequency of: - autosomal recessive disease - minor effect on X-linked disease No effect on frequency of: - autosomal dominant disease Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 159). Elsevier Health Sciences. Kindle Edition.

How is frequency of recombination used as a measure of distance between loci?

Suppose now that two loci are on the same chromosome but are either far apart, very close together, or somewhere in between (Fig. 10-4). As we just saw, when the loci are far apart (see Fig. 10-4A), at least one crossover will occur in the segment of the chromosome between loci 1 and 2, and there will be gametes of both the nonrecombinant genotypes AB and ab and recombinant genotypes Ab and aB, in equal proportions (on average) in the offspring. On the other hand, if two loci are so close together on the same chromosome that crossovers never occur between them, there will be no recombination; the nonrecombinant genotypes (parental chromosomes AB and ab in Fig. 10-4B) are transmitted together all of the time, and the frequency of the recombinant genotypes Ab and aB will be 0. In between these two extremes is the situation in which two loci are far enough apart that one recombination between the loci occurs in some meioses but not in others (see Fig. 10-4C). In this situation, we observe nonrecombinant combinations of alleles in the offspring when no crossover occurred and recombinant combinations when a recombination has occurred, but the frequency of recombinant chromosomes at the two loci will fall between 0% and 50%. The crucial point is that the closer together two loci are, the smaller the recombination frequency, and the fewer recombinant genotypes are seen in the offspring. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 174). Elsevier Health Sciences. Kindle Edition.

What is a disease example that results in disorders of structural proteins?

The Clinical Phenotype of Duchenne Muscular Dystrophy. Affected boys are normal for the first year or two of life but develop muscle weakness by 3 to 5 years of age (Fig. 12-16), when they begin to have difficulty climbing stairs and rising from a sitting position. The child is typically confined to a wheelchair by the age of 12 years. Although DMD is currently incurable, recent advances in the management of pulmonary and cardiac complications (which were leading causes of death in DMD boys) have changed the disease from a life-limiting to a life-threatening disorder. In the preclinical and early stages of the disease, the serum level of creatine kinase is grossly elevated (50 to 100 times the upper limit of normal) because of its release from diseased muscle. The brain is also affected; on average, there is a moderate decrease in IQ of approximately 20 points. The most common molecular defects in patients with DMD are deletions (60% of alleles) (see Figs. 12-18 and 12-19), which are not randomly distributed. Rather, they are clustered in either the 5′ half of the gene or in a central region that encompasses an apparent deletion hot spot (see Fig. 12-18). The absence of dystrophin in DMD destabilizes the myofiber membrane, increasing its fragility and allowing increased Ca + + entry into the cell, with subsequent activation of inflammatory and degenerative pathways. In addition, the chronic degeneration of myofibers eventually exhausts the pool of myogenic stem cells that are normally activated to regenerate muscle. This reduced regenerative capacity eventually leads to the replacement of muscle with fat and fibrotic tissue. The Clinical Phenotype of Becker Muscular Dystrophy. Becker muscular dystrophy (BMD) is also due to mutations in the dystrophin gene, but the BMD alleles produce a much milder phenotype. Patients are said to have BMD if they are still walking at the age of 16 years. There is significant variability in the progression of the disease, and some patients remain ambulatory for many years. In general, patients with BMD carry mutated alleles that maintain the reading frame of the protein and thus express some dystrophin, albeit often an altered product at reduced levels. Dystrophin is generally demonstrable in the muscle of patients with BMD (Fig. 12-17). In contrast, patients with DMD have little or no detectable dystrophin. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 234). Elsevier Health Sciences. Kindle Edition.

What is the concept of fitness in relation to natural selection? If either the mutation rate or the effectiveness of selection is altered, what do we also expect to change as a result? How do we measure fitness of an allele? What does a value of f =1 or f=0 represent? What is the coefficient of selection? What does a value of s=1 represent?

The concept of fitness is a chief factor that determines whether a mutation is eliminated immediately, becomes stable in the population, or even becomes, over time, the predominant allele at the locus concerned. The frequency of an allele in a population at any given time represents a balance between the rate at which mutant alleles appear through mutation and the effects of selection. If either the mutation rate or the effectiveness of selection is altered, the allele frequency is expected to change. Whether an allele is transmitted to the succeeding generation depends on its fitness, f, which is a measure of the number of offspring of affected persons who survive to reproductive age, compared with an appropriate control group. If a mutant allele is just as likely as the normal allele to be represented in the next generation, f equals 1. If an allele causes death or sterility, selection acts against it completely, and f equals 0. Values between 0 and 1 indicate transmission of the mutation, but at a rate that is less than that of individuals who do not carry the mutant allele. A related parameter is the coefficient of selection, s, which is a measure of the loss of fitness and is defined as 1 − f, that is, the proportion of mutant alleles that are not passed on and are therefore lost as a result of selection. In the genetic sense, a mutation that prevents reproduction by an adult is just as "lethal" as one that causes a very early miscarriage of an embryo, because in neither case is the mutation transmitted to the next generation. Fitness is thus the outcome of the joint effects of survival and fertility. When a genetic disorder limits reproduction so severely that the fitness is zero (i.e., s = 1), it is thus referred to as a genetic lethal. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 160). Elsevier Health Sciences. Kindle Edition.

What are some diseases that occur due to a loss-of-function mutation? Is this predominantly due to a mutation that still results in normal protein structure? Or is this predominantly due to a mutation that results in abnormal protein structure? Or both?

The loss of function of a gene may result from alteration of its coding, regulatory, or other critical sequences due to nucleotide substitutions, deletions, insertions, or rearrangements. A loss of function due to deletion, leading to a reduction in gene dosage, is exemplified by the α-thalassemias (Case 44), which are most commonly due to deletion of α-globin genes (see later discussion); by chromosome-loss diseases (Case 27), such as monosomies like Turner syndrome (see Chapter 6) (Case 47); and by acquired somatic mutations— often deletions— that occur in tumor-suppressor genes in many cancers, such as retinoblastoma (Case 39) (see Chapter 15). Many other types of mutations can also lead to a complete loss of function, and all are illustrated by the β-thalassemias (Case 44) (see later discussion), a group of hemoglobinopathies that result from a reduction in the abundance of β-globin, one of the major adult hemoglobin proteins in red blood cells. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 195). Elsevier Health Sciences. Kindle Edition.

What is map distance based on? What unit is map distance measured in? What does a recombination frequency of 50% entail?

The map distance between two loci is a theoretical concept that is based on actual data— the extent of observed recombination, θ, between the loci. Map distance is measured in units called centimorgans (cM), defined as the genetic length over which, on average, one crossover occurs in 1% of meioses. (The centimorgan is of a "morgan," named after Thomas Hunt Morgan, who first observed genetic recombination in the fruit fly Drosophila.) Therefore a recombination fraction of 1% (i.e., θ = 0.01) translates approximately into a map distance of 1 cM. As we discussed before in this chapter, the recombination frequency between two loci increases proportionately with the distance between two loci only up to a point because, once markers are far enough apart that at least one recombination will always occur, the observed recombination frequency will equal 50% (θ = 0.5), no matter how far apart physically the two loci are. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 175-176). Elsevier Health Sciences. Kindle Edition.

Describe some areas where the cellular functions of driver genes could turn oncogenic/cancerous. What are oncomirs?

The nature of some driver gene mutations comes as no surprise: the mutations directly affect specific genes that regulate processes that are readily understood to be important in oncogenesis. These processes include cell-cycle regulation, cellular proliferation, differentiation and exit from the cell cycle, growth inhibition by cell-cell contacts, and programmed cell death (apoptosis). However, the effects of other driver gene mutations are not so readily understood and include genes that act more globally and indirectly affect the expression of many other genes. Included in this group are genes encoding products that maintain genome and DNA integrity or genes that affect gene expression, either at the level of transcription by epigenomic changes, at the post-transcriptional level through effects on messenger RNA (mRNA) translation or stability, or at the post-translational level through their effects on protein turnover (Table 15-1). Other driver genes affect translation, for example, genes that encode noncoding RNAs from which regulatory microRNAs (miRNAs) are derived (see Chapter 3). Many miRNAs have been found to be either greatly overexpressed or down-regulated in various tumors, sometimes strikingly so. Because each miRNA may regulate as many as 200 different gene targets, overexpression or underexpression of miRNAs may have widespread oncogenic effects because many driver genes will be dysregulated. Noncoding miRNAs that impact gene expression and contribute to oncogenesis are referred to as oncomirs. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 311-312). Elsevier Health Sciences. Kindle Edition.

Give a summary of the Hardy-Weinberg law. What problem does the Hardy-Weinberg law not address? Give a clinically important example of marked differences in allele frequencies within different populations.

The previous discussion of the Hardy-Weinberg law explained how, at equilibrium, genotype frequencies are determined by allele frequencies and remain stable from generation to generation, assuming the allele frequencies in a large, isolated, randomly mating population remain constant. However, there is a problem of interest to human geneticists that the Hardy-Weinberg law does not address: Why are allele frequencies different in different populations in the first place? In particular, for the medical geneticist, why are some mutant alleles that are clearly deleterious more common in certain population groups than in others? One clinically important example of marked differences in allele frequencies is seen with the Rh blood group. The Rh blood group is very important clinically because of its role in hemolytic disease of the newborn and in transfusion incompatibilities. In simplest terms, the population is separated into Rh-positive individuals, who express, on their red blood cells, the antigen Rh D, a polypeptide encoded by the RHD gene, and Rh-negative individuals, who do not express this antigen. Being Rh-negative is therefore inherited as an autosomal recessive trait in which the Rh-negative phenotype occurs in individuals homozygous or compound heterozygous for nonfunctional alleles of the RHD gene. The frequency of Rh-negative individuals varies enormously in different ethnic groups. The chief significance of the Rh system is that Rh-negative persons can readily form anti-Rh antibodies after exposure to Rh-positive red blood cells. Normally, during pregnancy, small amounts of fetal blood cross the placental barrier and reach the maternal bloodstream. If the mother is Rh-negative and the fetus Rh-positive, the mother will form antibodies that return to the fetal circulation and damage the fetal red blood cells, causing hemolytic disease of the newborn with consequences that can be severe if not treated. In pregnant Rh-negative women, the risk for immunization by Rh-positive fetal red blood cells can be minimized with an injection of Rh immune globulin at 28 to 32 weeks of gestation and again after pregnancy. Rh immune globulin serves to clear any Rh-positive fetal cells from the mother's circulation before she is sensitized. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 164). Elsevier Health Sciences. Kindle Edition.

Chapter 11: The Molecular Basis of Genetic Disease What is the purpose of Chapter 11?

The term molecular disease, introduced over six decades ago, refers to disorders in which the primary disease-causing event is an alteration, either inherited or acquired, affecting a gene( s), its structure, and/ or its expression. In this chapter, we first outline the basic genetic and biochemical mechanisms underlying monogenic or single-gene disorders. We then illustrate them in the context of their molecular and clinical consequences using inherited diseases of hemoglobin— the hemoglobinopathies— as examples. This overview of mechanisms is expanded in Chapter 12 to include other genetic diseases that illustrate additional principles of genetics in medicine. In chapter 11, we focus our attention to diseases caused by defects in protein-coding genes; the study of phenotype at the level of proteins, biochemistry, and metabolism constitutes the discipline of biochemical genetics. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 195). Elsevier Health Sciences. Kindle Edition.

Chapter 10 - Identifying the genetic basis for human disease What is the purpose of this chapter?

This chapter provides an overview of how geneticists study families and populations to identify genetic contributions to disease. Whether a disease is inherited in a recognizable mendelian pattern, as illustrated in Chapter 7, or just occurs at a higher frequency in relatives of affected individuals, as explored in Chapter 8, it is the different genetic and genomic variants carried by affected family members or affected individuals in the population that either cause disease directly or influence their susceptibility to disease. Genome research has provided geneticists with a catalogue of all known human genes, knowledge of their location and structure, and an ever-growing list of tens of millions of variants in DNA sequence found among individuals in different populations. As we saw in previous chapters, some of these variants are common, others are rare, and still others differ in frequency among different ethnic groups. Whereas some variants clearly have functional consequences, others are certainly neutral. For most, their significance for human health and disease is unknown. In Chapter 4, we dealt with the effect of mutation, which alters one or more genes or loci to generate variant alleles and polymorphisms. And in Chapters 7 and 8, we examined the role of genetic factors in the pathogenesis of various mendelian or complex disorders. In this chapter, we discuss how geneticists go about discovering the particular genes implicated in disease and the variants they contain that underlie or contribute to human diseases, focusing on three approaches. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 171). Elsevier Health Sciences. Kindle Edition.

How can we accurately measure true genetic map distance between two widely spaced loci?

To accurately measure true genetic map distance between two widely spaced loci, therefore, one has to use markers spaced at short genetic distances (1 cM or less) in the interval between these two loci, and then add up the values of θ between the intervening markers, because the values of θ between pairs of closely neighboring markers will be good approximations of the genetic distances between them. Using this approach, the genetic length of an entire human genome has been measured and, interestingly, found to differ between the sexes. When measured in female meiosis, genetic length of the human genome is approximately 60% greater (≈ 4596 cM) than when it is measured in male meiosis (2868 cM), and this sex difference is consistent and uniform across each autosome. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 176). Elsevier Health Sciences. Kindle Edition.

What two broad generalizations can be made about the relationship between the site of a protein's expression and the site of disease? What does genetic redundancy refer to?

Two broad generalizations can be made about the relationship between the site of a protein's expression and the site of disease: • First (and somewhat intuitively), mutation in a tissue-specific protein most often produces a disease restricted to that tissue. However, there may be secondary effects on other tissues, and in some cases mutations in tissue-specific proteins may cause abnormalities primarily in organs that do not express the protein at all; ironically, the tissue expressing the mutant protein may be left entirely unaffected by the pathological process. This situation is exemplified by phenylketonuria. Phenylketonuria is due to the absence of phenylalanine hydroxylase (PAH) activity in the liver, but it is the brain (which expresses very little of this enzyme), and not the liver, that is damaged by the high blood levels of phenylalanine resulting from the lack of hepatic PAH. Consequently, one cannot necessarily infer that disease in an organ results from mutation in a gene expressed principally or only in that organ, or in that organ at all. • Second, although housekeeping proteins are expressed in most or all tissues, the clinical effects of mutations in housekeeping proteins are frequently limited to one or just a few tissues, for at least two reasons. In most such instances, a single or a few tissue( s) may be affected because the housekeeping protein in question is normally expressed abundantly there and serves a specialty function in that tissue. This situation is illustrated by Tay-Sachs disease; the mutant enzyme in this disorder is hexosaminidase A, which is expressed in virtually all cells, but its absence leads to a fatal neurodegeneration, leaving non-neuronal cell types unscathed. In other instances, another protein with overlapping biological activity may also be expressed in the unaffected tissue, thereby lessening the impact of the loss of function of the mutant gene, a situation known as genetic redundancy. Unexpectedly, even mutations in genes that one might consider as essential to every cell, such as actin, can result in viable offspring. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (pp. 215-216). Elsevier Health Sciences. Kindle Edition.

Chapter 9: Genetic Variation in Populations What are some methods to study the differences in the frequencies of different alleles in different populations? What is the purpose of Chapter 9?

we have alluded to differences in the frequencies of different alleles in different populations, whether assessed by examining different single nucleotide polymorphisms (SNPs), indels, or copy number variants (CNVs) in the genomes of many thousands of individuals studied worldwide (see Chapter 4) or inferred by ascertaining individuals with specific phenotypes and genetic disorders among populations around the globe (see Chapters 7 and 8). Chapter 9 purpose - Here we consider in greater detail the genetics of populations and the principles that influence the frequency of genotypes and phenotypes in those populations. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 155). Elsevier Health Sciences. Kindle Edition.

What are the three main classes of cancer? How are cancers classified?

• Sarcomas, in which the tumor has arisen in mesenchymal tissue, such as bone, muscle, or connective tissue, or in nervous system tissue; • Carcinomas, which originate in epithelial tissue, such as the cells lining the intestine, bronchi, or mammary ducts; and • Hematopoietic and lymphoid malignant neoplasms, such as leukemia and lymphoma, which spread throughout the bone marrow, lymphatic system, and peripheral blood. Within each of the major groups, tumors are classified by site, tissue type, histological appearance, degree of malignancy, chromosomal aneuploidy, and, increasingly, by which gene mutations and abnormalities in gene expression are found within the tumor. Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. Thompson & Thompson Genetics in Medicine E-Book (Thompson and Thompson Genetics in Medicine) (p. 309). Elsevier Health Sciences. Kindle Edition.