Patterns of Inheritance
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P112-113
2025-12-11
42
The patterns of inheritance shown by single-gene disorders in families depend chiefly on two factors:
• Whether the chromosomal location of the gene locus is on an autosome (chromosomes 1–22), on a sex chromosome (X and Y chromosomes), or in the mitochondrial genome
• Whether the phenotype is dominant (expressed when only one chromosome carries the pathogenic allele) or recessive (expressed only when both chromosomes of a pair carry pathogenic alleles at a locus)
The different patterns of transmission of the autosomes, sex chromosomes, and mitochondria during meiosis result in distinctive inheritance patterns of pathogenic alleles on these different types of chromosome. Because only one of the two copies of each autosome passes into a single gamete during meiosis, males and females heterozygous for a pathogenic allele on an autosome have a 50% chance of passing that allele on to any offspring, regardless of the child’s sex. Pathogenic alleles on the X chromo some, however, are not distributed equally to sons and daughters. Males pass their Y chromosome to their sons and their X to their daughters; they therefore cannot pass an allele on the X chromosome to their sons and always pass the allele to their daughters (unless it is at one of the pseudoautosomal loci). Because mitochondria are inherited from the mother only, regardless of the sex of the offspring, variants in the mitochondrial genome are not inherited according to a mendelian pattern. Autosomal, X-linked, and mitochondrial inheritance will be discussed in the rest of the chapter that follows.
Dominant and Recessive Traits
Autosomal Loci
As classically defined, a phenotype is recessive if it is expressed only in homozygotes or compound heterozygotes, all of whom lack a wild-type allele, and never in heterozygotes, who do have a wild-type allele. In contrast, a dominant inheritance pattern occurs when a phenotype is expressed in heterozygotes as well as in homozygotes (or compound heterozygotes). For the vast majority of inherited dominant diseases, homozygotes or compound heterozygotes for pathogenic alleles at autosomal loci are more severely affected than are heterozygotes, an inheritance pattern known as incompletely dominant (or semidominant). Very few diseases are known in which homozygotes (or compound heterozygotes) show the same phenotype as heterozygotes; such a disorder is referred to as a pure dominant dis ease. Finally, if phenotypic expression of both alleles at a locus occurs in a compound heterozygote, inheritance is termed codominant.
ABO Blood Group. One medically important trait that demonstrates codominant expression is the ABO blood group system important in blood transfusion and tis sue transplantation. The A, B, and O alleles at the ABO locus form a three-allele system in which two alleles (A and B) govern expression of either the A or B carbohydrate antigen on the surface of red cells as a codominant trait; a third allele (O) results in expression of neither the A nor the B antigen and is recessive. The difference between the A and B antigen is which of two different sugar molecules makes up the terminal sugar on a cell surface glycoprotein called H. Whether the A or B form of the glycoprotein is made is specified by an enzyme encoded by the ABO gene that adds one or the other sugar molecule to the H antigen, depending on which version of the enzyme is encoded by alleles at the ABO locus. There are, therefore, four phenotypes possible: O, A, B, and AB (Table 1). Type A individuals have anti gen A on their red blood cells, type B individuals have antigen B, type AB individuals have both antigens, and type O individuals have neither.
Table1. ABO Genotypes and Serum Reactivity
A feature of the ABO groups not shared by other blood group systems is the reciprocal relationship, in an individual, between the antigens present on the red blood cells and the antibodies in the serum. When the red blood cells lack antigen A, the serum contains anti-A antibodies; when the cells lack antigen B, the serum contains anti-B. Formation of anti-A and anti-B antibodies in the absence of prior blood transfusion is believed to be a response to the natural occurrence of A-like and B-like antigens in the environment (e.g., in bacteria).
X-Linked Loci
For X-linked disorders, a condition expressed only in hemizygotes and never in heterozygotes has tradition ally been referred to as an X-linked recessive, whereas a phenotype that is always expressed in heterozygotes as well as in hemizygotes has been called X-linked dominant. Because of epigenetic regulation of X-linked gene expression in carrier females, due to X chromosome inactivation, it can be difficult to determine phenotypically whether a disease with an X-linked inheritance pattern is dominant or recessive. Some geneticists have, therefore, chosen not to use these terms when describing the inheritance of X-linked disease.
Strictly speaking, the terms dominant and recessive refer to the inheritance pattern of a phenotype rather than to the alleles responsible for that phenotype. Similarly, a gene is not dominant or recessive; it is the phenotype produced by a particular pathogenic allele in that gene that shows dominant or recessive inheritance.
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