Genetic Determinants of Pulmonary Disease

S. D. Litwin

• Publisher: CRC Press
• Year: 2020
• ISBN:
  9781000146295
• Edition: 1
• Topic: Medicina
• Subtopic: Medicina polmonare e toracica

This book provides a current and integrated approach to the subject of genetic determinants of pulmonary disease with emphasis on physiologic derangements and genetic mechanisms. It describes the epidemiologic-genetic approach to chronic pulmonary disease.

1
An Approach to Inherited Pulmonary Disease

ROBERT A. NORUM
Cornell University Medical College New York, New York

I. Introduction

Genetic analysis has proven a powerful tool for exposing the etiology and sources of variation in many biologic phenomena. Because we cannot arrange informative matings in the human species we must be prepared to recognize the genetic information available in matings that do occur.

In the 100 years since Mendel recognized patterns of inheritance produced by single factors which have major importance in the determination of a phenotype, the same patterns of inheritance have been recognized in thousands of human conditions [1]. The basic mechanism of inheritance is now well understood in the light of the Watson-Crick model of DNA structure. This synthesis explains the chemistry underlying Mendel's observations and the reader is referred to biochemistry texts for a description of the way in which genes beget proteins and other gene products. This chapter describes some of the ways in which genetic analysis can be useful to investigation of the etiology and pathogenesis of lung disease.

The term phenotype can be applied to any property observable in an organism or in specimens obtained from an organism. By genetic analysis phenotypes can be attributed to the action of certain genes whose presence in an individual organism is inferred from the phenotype and the pedigree. The complement of genes present in an organism is called the genotype. In diploid organisms such as humans there are two complete sets of the genes carried on the autosomes, those chromosomes other than the X and Y. A pair of genes occupies a specific place in the genome called a locus. Commonly the term genotype is used in reference to only the two genes at the one locus relevant to a specific phenotype. Alternative forms of a gene which can occupy the same locus are called alleles. An individual who has two different genes at one locus is said to be heterozygous at that locus, or a heterozygote. An individual who has two copies of the same gene at one locus is said to be homozygous at that locus, or a homozygote.

II. Genetic Inference

When a single or double dose of a particular gene at one locus has a major effect in producing an unusual phenotype, pedigrees of individuals manifesting that phenotype commonly show distinctive patterns of inheritance. The mode of transmission is a property of the phenotype rather than the genotype, since the phenotype and the mode of inheritance produced by a given genotype can change depending on how the phenotype is examined.

A. Autosomal Dominant

In humans the 22 pairs of chromosomes which are not X or Y chromosomes are called the autosomes. Genes on these chromosomes occur with equal frequency in males and females. Mendel's first law states that alleles segregate; an offspring inherits one and only one of the pair in one parent. An offspring is equally likely to inherit one or the other gene of each pair. When a phenotype is produced by a gene in a single dose, that is, in a heterozygote, the phenotype is said to be dominant. When a mating occurs between an individual who is heterozygous and has the dominant phenotype, and an individual who does not have the phenotype, each of the offspring is equally likely to inherit from the first parent either the gene for dominant phenotype or the other gene. The distinctive feature of pedigrees illustrating this mode of inheritance is the occurrence of the phenotype in successive generations. If the phenotype is expressed whenever the responsible gene is present, the phenotype is said to be fully penetrant. In pedigrees of fully penetrant dominant phenotypes, individuals who do not show the phenotype do not pass it on to their descendants (Fig. la).

FIGURE 1 (a) A pedigree showing autosomal dominant transmission of a fully penetrant phenotype; (b) a pedigree showing autosomal recessive inheritance of a phenotype; (c) a pedigree showing X-linked dominant inheritance of a phenotype; (d) a pedigree showing X-linked recessive inheritance of a phenotype. The letters indicate inferred genotypes.

Occasionally dominant phenotypes are not fully penetrant. In some phenotypes expression depends on factors such as the age of the individual, as in Huntington's chorea, or on the influence of other genetic or environmental factors. Several cases of impenetrance of the phenotype osteogenesis imperfecta are well documented. Penetrance, like other properties of phenotypes, is often heavily dependent on the methods used to assess it. (For further discussion of penetrance see Section II.G.)

Vertical inheritance of a recessive phenotype in successive generations can be produced by inbreeding or by genes of high frequency in the population as detailed below. When the phenotype is rare and inbreeding not present, vertical inheritance patterns and a 50% frequency of affected individuals among the progeny of affected persons establish a dominant mode of inheritance. Autosomal dominant phenotypes occur in males and females with equal frequency, X-linked dominant phenotypes show highly distinctive pedigree patterns as discussed later.

The vertical pedigree pattern of a dominant can also be simulated by slow virus as illustrated by Creutzfeldt-Jakob disease [2]. It remains to be seen whether the ratio of affected to unaffected progeny of slow virus disease victims also simulates the inheritance of a gene. Hereditary susceptibility to the virus may also be a factor.

In some rare human dominant phenotypes the parents of some affected individuals are themselves unaffected. The absence of any affected ancestors or other relatives of the parents argues against nonpenetrance. The children of affected individuals show the phenotype in the frequency expected of a dominant. The most plausible explanation is that the phenotype in affected individuals with unaffected parents represents the effects of a new mutation, that is, the new creation of a gene causing the phenotype. The demonstration that fathers of the new cases are on the average older than fathers in the whole population supports this argument.

B. Autosomal Recessive

Some phenotypes occur in groups of siblings (brothers and sisters) but not in their parents or children. The familial grouping of cases suggests a genetic factor but the mode of inheritance is clearly not the vertical pattern of dominant phenotypes. The model from Mendel's work that can explain this pattern of inheritance postulates that both parents are heterozygous for a gene which when present in double dose causes the phenotype. The individuals manifesting the phenotype have inherited the gene from both of their parents such that they are homozygous for the responsible gene. The phenotype is said to be recessive because heterozygotes who have only one copy of the relevant gene do not show the phenotype (Fig. lb). Autosomal recessive phenotypes, like autosomal dominants, occur with equal frequency in males and females.

Autosomal recessive inheritance of a phenotype is often harder to distinguish from polygenic or nongenetic mechanisms than is autosomal dominant inheritance. The gene contributed to a child by a heterozygous parent is equally likely to be either the gene for the recessive phenotype or its allele; for each child the probability of inheriting from one parent the gene for the recessive phenotype is 1/2. For each child of two heterozygous parents the probability of inheriting the gene for the recessive phenotype from both parents is: 1/2 X 1/2 = 1/4. When sibship sizes are small most persons with the phenotype will have no affected sibs. Furthermore, some sibships who are the offspring of two heterozygous parents will by chance include no individuals who are homozygous for the relevant gene and thus no individuals who manifest the phenotype.

To test the recessive hypothesis as an explanation for the familial grouping of some cases of a phenotype, we can count the affected and unaffected offspring of parents who are both heterozygous. A problem arises because in most cases the only means of identifying the parents as carriers is by the occurrence of the phenotype in at least one of their children. To correct for this bias of ascertainment mathematical models have been developed which yield the proportions of affected individuals expected in sibships of various sizes. The simplest example of such a model is the simple sib method of ascertainment correction. In this method the affected individual through whom the pedigree came to attention, called the proband, is ignored in the count of affected individuals. The autosomal recessive hypothesis predicts that among the sibs of these probands the phenotype will have a frequency of 1 in 4. Statistical tests can determine if the observed frequency does not fit that hypothesis. On occasion more complicated artifacts of ascertainment occur such as the tendency for sibships containing more than one affected individual to be more likely to come to investigators' attention. Corrections for more complicated biases of ascertainment have been developed, although it is sometimes difficult to know which method is appropriate for the data.

For a few rare autosomal recessive phenotypes the mode of inheritance is not In doubt despite a paucity of pedigree data. Most of these phenotypes are caused by severe deficiencies of an enzyme. The parents of an affected individual show no clinical manifestations of the phenotype, but each has an amount of the relevant enzyme which is intermediate between normal levels and severe deficiency. The genetic inference that each parent is heterozygous for a defective gene is supported by the finding of similar intermediate levels in some of their unaffected children, who are presumed to be heterozygous like the parents.

A high degree of consanguinity in the parents of individuals manifesting a rare phenotype can be an indication of autosomal recessive inheritance. Consanguinity is an estimate of the fraction of the genome in two mates that is identical because they have inherited it from the ancestors they have in common. For example, in a brother and sister about one-half of the autosomal genes are identical by descent, and in first cousins about one-eighth of the autosomal genes are identical. The offspring of such matings would be homozygous at a correspondingly large number of loci; copies of genes that are identical by descent would be "meeting" each other in these offspring. If one of the ancestors that the mates have in common was heterozygous for a gene for a rare recessive phenotype the probability of homozygosity for that gene in the children of a consanguineous mating is greatly increased, just as the probability for homozygosity for any gene present in the common ancestors is increased in those children. When the frequency of heterozygous carriers of the gene for a phenotype is low in the population a high proportion of individuals affected with the phenotype are the products of consanguineous matings. In the latter case consanguinity becomes more probable than random chance as a mechanism for copies of a rare gene to "meet" each other forming a homozygote.

Most autosomal recessive phenotypes discovered to date are fully penetrant in people who are homozygous for the gene, in contrast to the variable penetrance common among the dominant traits. This difference may largely reflect our inability to recognize autosomal recessive inheritance of a phenotype when it is not fully penetrant. One example of impenetrance in an autosomal recessive is the phenotype of chronic obstructive pulmonary disease which occurs in about 80% of people who are homozygous for the alpha₁-anti-trypsin PiZ. In this case both the inheritance and reduced penetrance can be proven because genotypes at this locus can be inferred from another phenotype, the electrophoretic mobility of serum alpha₁-antitrypsin.

C. X-Linkage

Dominant and recessive phenotypes caused by genes on the X chromosome show distinctive patterns of inheritance that are often easily recognized. Human males are described as hemizygous with respect to the loci on the X chromosome, since they have only one chromosome, and thus only one gene at each locus on the X. X-linked phenotypes which are usually recessive in females who are heterozygous for the causative gene are expressed in hemizygous males who carry a single dose of the same gene because that is the only gene present that codes for that function. The resulting pedigrees of rare X-linked phenotypes show affected males whose sisters have affected sons (Fig. Id). Expression of the phenotype in a female could be due to homozygosity for the causative gene or to an unusual proportion of inactivated X chromosomes (see Lyon phenomenon described below).

A single normal sperm contains either an X chromosome or a Y chromosome but not both. Males give their X chromosome to all their daughters. Perhaps it is more accurate to say that all the ova fertilized by sperm containing an X chromosome become females. Except in the case of mutation, which is rare, all the daughters of a man who manifests an unusual X-linked phenotype will inherit from their father the gene causing that phenotype. Since in most cases the affected male's mate will not be a heterozygote or homozygote for that gene, his daughters are most likely to be heterozygotes for the gene.

Since males give to their sons their Y chromosome and not their X chromosome, the observation of male-to-male transmission excludes the hypothesis of X-linkage of a phenotype. Male-to-male transmission could be simulated if an affected son's mother is a heterozygote for the gene and his father is also affected. The gene causing the son's phenotype came from his mother.

The Lyon hypothesis states: (1) in each mammalian female somatic cell one of the two X chromosomes is genetically inactive, (2) the choice of which of the two is inactivated is random in each cell and occurs early in embryonic development, and (3) the same X is inactive in all the cellular progeny of the embryonic cell in which the inactivation originally occurred. The hypothesis has been proven for all of the several X-chromosome loci that have been examined.

One result of the Lyon phenomenon is that each human female is a mosaic of two kinds of cells that are different because they h...