Mendelian Inheritance

Mendelian Patterns of Inheritance

In order to understand the concept of Mendelian inheritance, several essential terms must first be defined. A genetic locus is a specific position or location on a chromosome. Frequently, the term locus is used to refer to a specific gene.

Alleles are alternative forms of a gene Opens in new window, or of a DNA sequence, at a given locus. If both alleles at a locus are identical, the individual is homozygous at that locus; if they are different, s/he is heterozygous. Such individuals are called homozygotes or heterozygotes, respectively.

An individual with two different mutant alleles at a given locus is a compound heterozygote, whereas an individual with one mutant allele at each of two different loci is a double heterozygote.

A genotype Opens in new window comprises an individual’s set of alleles and constitutes the genetic factors that create a phenotype. A phenotype Opens in new window is the visible or measurable properties resulting from a genotype, such as coronary artery disease or obesity. Phenotype can also be defined as the effect of gene action, whether caused by a single gene or the entire genotype.

Following Mendel, Mendelian diseases are diseases that are the result of a single mutant gene that has a large effect on phenotype and that are inherited in simple patterns similar to or identical with those describe by Mendel for certain discrete characteristics in garden peas.

Mendelian diseases are autosomal if they are encoded by genes on one of the 22 pairs of autosomes, or non-sex chromosomes, and X-linked if encoded by a mutant allele on the X chromosome. According Mendel, dominant is defined as those conditions that are expressed in heterozygotes, i.e., individuals who have one copy of a mutant allele and one copy of a normal, or wild-type, allele, and recessive those conditions that are clinically manifest only in individuals homozygous for the mutant allele (or compound heterozygotes for two different mutant alleles), i.e., carrying a double dose of an abnormal gene.

It should be stressed that dominance and recessivity refer to traits, or phenotypes, and not to genes. Although we sometimes speak of dominant and recessive genes, this is a shorthand and should be understood to refer to traits.

By now more than 5000 human phenotypes known to be inherited in a Mendelian fashion have been catalogued.

More than half are autosomal dominant traits, 36% are autosomal recessive Opens in new window, and less than 10% are X-linked Opens in new window. Of these 5000 traits, approximately 4000 are associated with human diseases. In almost 600 of these, one or more disease-causing mutations have been identified.

The pattern of inheritance of most Mendelian traits has been deduced from observing the segregation or transmission of these traits within families.

To establish the pattern of transmission, a usual first step is to obtain information about the family history of the patient and to summarize the details in the form of a pedigree Opens in new window, a graphical representation of the family tree, with use of standard symbols.

The standardized pattern and symbols used for constructing a three-generation pedigree are addressed here Opens in new window.

The patterns shown by single-gene disorders in pedigrees depend chiefly on two factors:

1. whether the phenotype Opens in new window is dominant (expressed when only one chromosome of a pair carries the mutant allele and the other chromosome has a wild-type allele at that locus) or recessive (expressed only when both chromosomes of a pair carry mutant alleles at a locus);and
2. the chromosomal location of the gene locus, which may be on an autosome (chromosomes 1 to 22) or on a sex chromosome (chromosomes X and Y).

It is pertinent, however, to distinguish between genes that are physically located on the sex chromosomes (X or Y synteny) and genes that show X-linked) inheritance.

The majority of loci on the X show X-linked inheritance Opens in new window because they participate in meiotic recombination only during female gametogenesis Opens in new window, when there are two X chromosomes Opens in new window, but cannot recombine with Y during male gametogenesis.

Autosomal and X-Linked Inheritance

Whether an abnormal gene is on an autosome or is X-linked has a profound effect on the clinical expression of the disease. First, autosomal disorders, in general, affect males and females equally. (The only exceptions are referred to as sex-limited disorder).

For X-linked disorders, the situation is quite different. Males have only a single X and are therefore hemizygous with respect to X-linked genes; 46,XYL males are never heterozygous for alleles at X-linked loci, whereas females can be heterozygous or homozygous at X-linked loci. Second, to compensate alleles for most X-linked genes are expressed from only one of the two X chromosomes in any given cell of a female.