Human genetics – An Introduction to Genetic Analysis …

In the study of rare disorders, four general patterns of inheritance are distinguishable by pedigree analysis: autosomal recessive, autosomal dominant, X-linked recessive, and X-linked dominant.

The affected phenotype of an autosomal recessive disorder is determined by a recessive allele, and the corresponding unaffected phenotype is determined by a dominant allele. For example, the human disease phenylketonuria is inherited in a simple Mendelian manner as a recessive phenotype, with PKU determined by the allele p and the normal condition by P . Therefore, sufferers from this disease are of genotype p /p , and people who do not have the disease are either P /P or P /p . What patterns in a pedigree would reveal such an inheritance? The two key points are that (1) generally the disease appears in the progeny of unaffected parents and (2) the affected progeny include both males and females. When we know that both male and female progeny are affected, we can assume that we are dealing with simple Mendelian inheritance, not sex-linked inheritance. The following typical pedigree illustrates the key point that affected children are born to unaffected parents:

From this pattern, we can immediately deduce simple Mendelian inheritance of the recessive allele responsible for the exceptional phenotype (indicated in black). Furthermore, we can deduce that the parents are both heterozygotes, say A /a ; both must have an a allele because each contributed an a allele to each affected child, and both must have an A allele because they are phenotypically normal. We can identify the genotypes of the children (in the order shown) as A /, a /a , a /a , and A /. Hence, the pedigree can be rewritten as follows:

Note that this pedigree does not support the hypothesis of X-linked recessive inheritance, because, under that hypothesis, an affected daughter must have a heterozygous mother (possible) and a hemizygous father, which is clearly impossible, because he would have expressed the phenotype of the disorder.

Notice another interesting feature of pedigree analysis: even though Mendelian rules are at work, Mendelian ratios are rarely observed in families, because the sample size is too small. In the preceding example, we see a 1:1 phenotypic ratio in the progeny of a monohybrid cross. If the couple were to have, say, 20 children, the ratio would be something like 15 unaffected children and 5 with PKU (a 3:1 ratio); but, in a sample of 4 children, any ratio is possible, and all ratios are commonly found.

The pedigrees of autosomal recessive disorders tend to look rather bare, with few black symbols. A recessive condition shows up in groups of affected siblings, and the people in earlier and later generations tend not to be affected. To understand why this is so, it is important to have some understanding of the genetic structure of populations underlying such rare conditions. By definition, if the condition is rare, most people do not carry the abnormal allele. Furthermore, most of those people who do carry the abnormal allele are heterozygous for it rather than homozygous. The basic reason that heterozygotes are much more common than recessive homozygotes is that, to be a recessive homozygote, both parents must have had the a allele, but, to be a heterozygote, only one parent must carry the a allele.

Geneticists have a quantitative way of connecting the rareness of an allele with the commonness or rarity of heterozygotes and homozygotes in a population. They obtain the relative frequencies of genotypes in a population by assuming that the population is in Hardy-Weinberg equilibrium, to be fully discussed in Chapter 24 . Under this simplifying assumption, if the relative proportions of two alleles A and a in a population are p and q , respectively, then the frequencies of the three possible genotypes are given by p 2 for A /A , 2pq for A /a , and q 2 for a /a . A numerical example illustrates this concept. If we assume that the frequency q of a recessive, disease-causing allele is 1/50, then p is 49/50, the frequency of homozygotes with the disease is q 2 =(1/50)2 =1/250, and the frequency of heterozygotes is 2pq =249/501/50 , or approximately 1/25. Hence, for this example, we see that heterozygotes are 100 times as frequent as disease sufferers, and, as this ratio increases, the rarer the allele becomes. The relation between heterozygotes and homozygotes recessive for a rare allele is shown in the following illustration. Note that the allele frequencies p and q can be used as the gamete frequencies in both sexes.

The formation of an affected person usually depends on the chance union of unrelated heterozygotes. However, inbreeding (mating between relatives) increases the chance that a mating will be between two heterozygotes. An example of a marriage between cousins is shown in . Individuals III-5 and III-6 are first cousins and produce two homozygotes for the rare allele. You can see from that an ancestor who is a heterozygote may produce many descendants who also are heterozygotes. Hence two cousins can carry the same rare recessive allele inherited from a common ancestor. For two unrelated persons to be heterozygous, they would have to inherit the rare allele from both their families. Thus matings between relatives generally run a higher risk of producing abnormal phenotypes caused by homozygosity for recessive alleles than do matings between nonrelatives. For this reason, first-cousin marriages contribute a large proportion of the sufferers of recessive diseases in the population.

Pedigree of a rare recessive phenotype determined by a recessive allele a . Gene symbols are normally not included in pedigree charts, but genotypes are inserted here for reference. Note that individuals II-1 and II-5 marry into the family; they are assumed (more...)

What are some examples of human recessive disorders? PKU has already served as an example of pedigree analysis, but what kind of phenotype is it? PKU is a disease of processing of the amino acid phenylalanine, a component of all proteins in the food that we eat. Phenylalanine is normally converted into tyrosine by the enzyme phenylalanine hydroxylase:

However, if a mutation in the gene encoding this enzyme alters the amino acid sequence in the vicinity of the enzymes active site, the enzyme cannot bind or convert phenylalanine (its substrate). Therefore phenylalanine builds up in the body and is converted instead into phenylpyruvic acid, a compound that interferes with the development of the nervous system, leading to mental retardation.

Babies are now routinely tested for this processing deficiency at birth. If the deficiency is detected, phenylalanine can be withheld by use of a special diet, and the development of the disease can be arrested.

Cystic fibrosis is another disease inherited according to Mendelian rules as a recessive phenotype. The allele that causes cystic fibrosis was isolated in 1989, and the sequence of its DNA was determined. This has led to an understanding of gene function in affected and unaffected persons, giving hope for more effective treatment. Cystic fibrosis is a disease whose most important symptom is the secretion of large amounts of mucus into the lungs, resulting in death from a combination of effects but usually precipitated by upper respiratory infection. The mucus can be dislodged by mechanical chest thumpers, and pulmonary infection can be prevented by antibiotics; so, with treatment, cystic fibrosis patients can live to adulthood. The disorder is caused by a defective protein that transports chloride ions across the cell membrane. The resultant alteration of the salt balance changes the constitution of the lung mucus.

Albinism, which served as a model of allelic determination of contrasting phenotypes in Chapter 1 , also is inherited in the standard autosomal recessive manner. The molecular nature of an albino allele and its inheritance are diagrammed in . This diagram shows a simple autosomal recessive inheritance in a pedigree and shows the molecular nature of the alleles involved. In this example, the recessive allele a is caused by a base pair change that introduces a stop codon into the middle of the gene, resulting in a truncated polypeptide. The mutation, by chance, also introduces a new target site for a restriction enzyme. Hence, a probe for the gene detects two fragments in the case of a and only one in A . (Other types of mutations would produce different effects at the level detected by Southern, Northern, and Western analyses.)

The molecular basis of Mendelian inheritance in a pedigree.

In all the examples heretofore considered, the disorder is caused by an allele for a defective protein. In heterozygotes, the single functional allele provides enough active protein for the cells needs. This situation is called haplosufficiency.

In human pedigrees, an autosomal recessive disorder is revealed by the appearance of the disorder in the male and female progeny of unaffected persons.

Here the normal allele is recessive, and the abnormal allele is dominant. It may seem paradoxical that a rare disorder can be dominant, but remember that dominance and recessiveness are simply properties of how alleles act and are not defined in terms of how common they are in the population. A good example of a rare dominant phenotype with Mendelian inheritance is pseudo-achondroplasia, a type of dwarfism ( ). In regard to this gene, people with normal stature are genotypically d /d , and the dwarf phenotype in principle could be D /d or D /D . However, it is believed that the two doses of the D allele in the D /D genotype produce such a severe effect that this is a lethal genotype. If this is true, all the dwarf individuals are heterozygotes.

The human pseudoachondroplasia phenotype, illustrated by a family of five sisters and two brothers. The phenotype is determined by a dominant allele, which we can call D , that interferes with bone growth during development. Most members of the human population (more...)

In pedigree analysis, the main clues for identifying a dominant disorder with Mendelian inheritance are that the phenotype tends to appear in every generation of the pedigree and that affected fathers and mothers transmit the phenotype to both sons and daughters. Again, the equal representation of both sexes among the affected offspring rules out sex-linked inheritance. The phenotype appears in every generation because generally the abnormal allele carried by a person must have come from a parent in the preceding generation. Abnormal alleles can arise de novo by the process of mutation. This event is relatively rare but must be kept in mind as a possibility. A typical pedigree for a dominant disorder is shown in . Once again, notice that Mendelian ratios are not necessarily observed in families. As with recessive disorders, persons bearing one copy of the rare A allele (A /a ) are much more common than those bearing two copies (A /A ), so most affected people are heterozygotes, and virtually all matings concerning dominant disorders are A /a a /a . Therefore, when the progeny of such matings are totaled, a 1:1 ratio is expected of unaffected (a /a ) to affected (A /a ) persons.

Pedigree of a dominant phenotype determined by a dominant allele A . In this pedigree, all the genotypes have been deduced.

Huntington disease is an example of a disease inherited as a dominant phenotype determined by an allele of a single gene. The phenotype is one of neural degeneration, leading to convulsions and premature death. However, it is a late-onset disease, the symptoms generally not appearing until after the person has begun to have children ( ). Each child of a carrier of the abnormal allele stands a 50 percent chance of inheriting the allele and the associated disease. This tragic pattern has led to a great effort to find ways of identifying people who carry the abnormal allele before they experience the onset of the disease. The application of molecular techniques has resulted in a promising screening procedure.

The age of onset of Huntington disease. The graph shows that people carrying the allele generally do not express the disease until after child-bearing age.

Some other rare dominant conditions are polydactyly (extra digits) and brachydactyly (short digits), shown in , and piebald spotting, shown in .

Some rare dominant phenotypes of the human hand. (a) (right) Polydactyly, a dominant phenotype characterized by extra fingers, toes, or both, determined by an allele P . The numbers in the accompanying pedigree (left) give the number of fingers in the (more...)

Piebald spotting, a rare dominant human phenotype. Although the phenotype is encountered sporadically in all races, the patterns show up best in those with dark skin. (a) The photographs show front and back views of affected persons IV-1, IV-3, III-5, (more...)

Pedigrees of Mendelian autosomal dominant disorders show affected males and females in each generation; they also show that affected men and women transmit the condition to equal proportions of their sons and daughters.

Phenotypes with X-linked recessive inheritance typically show the following patterns in pedigrees:

Many more males than females show the phenotype under study. This is because a female showing the phenotype can result only from a mating in which both the mother and the father bear the allele (for example, XA Xa Xa Y), whereas a male with the phenotype can be produced when only the mother carries the allele. If the recessive allele is very rare, almost all persons showing the phenotype are male.

None of the offspring of an affected male are affected, but all his daughters are carriers, bearing the recessive allele masked in the heterozygous condition. Half of the sons of these carrier daughters are affected ( ). Note that, in common X-linked phenotypes, this pattern might be obscured by inheritance of the recessive allele from a heterozygous mother as well as the father.

None of the sons of an affected male show the phenotype under study, nor will they pass the condition to their offspring. The reason behind this lack of male-to-male transmission is that a son obtains his Y chromosome from his father, so he cannot normally inherit the fathers X chromosome too.

Pedigree showing that X-linked recessive alleles expressed in males are then carried unexpressed by their daughters in the next generation, to be expressed again in their sons. Note that III-3 and III-4 cannot be distinguished phenotypically.

In the pedigree analysis of rare X-linked recessives, a normal female of unknown genotype is assumed to be homo-zygous unless there is evidence to the contrary.

Perhaps the most familiar example of X-linked recessive inheritance is red-green colorblindness. People with this condition are unable to distinguish red from green and see them as the same. The genes for color vision have been characterized at the molecular level. Color vision is based on three different kinds of cone cells in the retina, each sensitive to red, green, or blue wavelengths. The genetic determinants for the red and green cone cells are on the X chromosome. As with any X-linked recessive, there are many more males with the phenotype than females.

Another familiar example is hemophilia, the failure of blood to clot. Many proteins must interact in sequence to make blood clot. The most common type of hemophilia is caused by the absence or malfunction of one of these proteins, called Factor VIII. The most well known cases of hemophilia are found in the pedigree of interrelated royal families in Europe ( ). The original hemophilia allele in the pedigree arose spontaneously (as a mutation) either in the reproductive cells of Queen Victorias parents or of Queen Victoria herself. The son of the last czar of Russia, Alexis, inherited the allele ultimately from Queen Victoria, who was the grandmother of his mother Alexandra. Nowadays, hemophilia can be treated medically, but it was formerly a potentially fatal condition. It is interesting to note that, in the Jewish Talmud, there are rules about exemptions to male circumcision that show clearly that the mode of transmission of the disease through unaffected carrier females was well understood in ancient times. For example, one exemption was for the sons of women whose sisters sons had bled profusely when they were circumcised.

The inheritance of the X-linked recessive condition hemophilia in the royal families of Europe. A recessive allele causing hemophilia (failure of blood clotting) arose in the reproductive cells of Queen Victoria, or one of her parents, through mutation. (more...)

Duchenne muscular dystrophy is a fatal X-linked recessive disease. The phenotype is a wasting and atrophy of muscles. Generally the onset is before the age of 6, with confinement to a wheelchair by 12, and death by 20. The gene for Duchenne muscular dystrophy has now been isolated and shown to encode the muscle protein dystrophin. This discovery holds out hope for a better understanding of the physiology of this condition and, ultimately, a therapy.

A rare X-linked recessive phenotype that is interesting from the point of view of sexual differentiation is a condition called testicular feminization syndrome, which has a frequency of about 1 in 65,000 male births. People afflicted with this syndrome are chromosomally males, having 44 autosomes plus an X and a Y, but they develop as females ( ). They have female external genitalia, a blind vagina, and no uterus. Testes may be present either in the labia or in the abdomen. Although many such persons marry, they are sterile. The condition is not reversed by treatment with the male hormone androgen, so it is sometimes called androgen insensitivity syndrome. The reason for the insensitivity is that the androgen receptor malfunctions, so the male hormone can have no effect on the target organs that contribute to maleness. In humans, femaleness results when the male-determining system is not functional.

Four siblings with testicular feminization syndrome (congenital insensitivity to androgens). All four subjects in this photograph have 44 autosomes plus an X and a Y chromosome, but they have inherited the recessive X-linked allele conferring insensitivity to (more...)

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Human genetics - An Introduction to Genetic Analysis ...