HUMAN GENETICS

for 1st YEAR STUDENTS


MENDELIAN INHERITANCE

SEX LIMITED INHERITANCE

In some X-linked recessive diseases, such as Duchenne muscular dystrophy, expression of the disease phenotype is limited exclusively to males. In some X-linked dominant traits, such as incontinentia pigmenti or orofaciodigital syndrome (OFD 1), expression is limited to females, males do not survive to term. However, the expression of a disease in only one gender does not necessarily imply that the disease is X-linked. There are autosomal diseases that are limited to expression in only one sex. Precocious puberty and beard growth are factors expressed only in males. The hereditary form of prolapsed uterus is expressed only in females. These are called sex limited traits.

MITOCHONDRIAL INHERITANCE

The DNA of mitochondria contains about ten genes involved in oxidative phosphorylation, as well as a few other genes. This DNA is capable of mutation, so it is not surprising that a few human diseases have been found to be associated with mitochondrial inheritance. Leber optic atrophy is a classic example of a disease of mitochondrial DNA. The ovum, originating in the female, has about 100,000 copies of mitochondrial DNA; the sperm, originating in the male, has fewer than 100 copies, and these are probably lost at fertilization. Virtually all of ones mitochondria come from his, or her, mother. Affected fathers produce no affected offspring, while the offspring of affected mothers are all affected. Figure 3 below shows the typical mitochondrial inheritance pattern.

Mitochondrial inheritance
pattern

Figure 3 Mitochondrial inheritance pattern.

IMPRINTING

Prader-Willi syndrome affects between 1/10,000 and 1/30,000 live births. The study of this disease led to the discovery that, for some genes, the origin of the gene may be important. For some loci the gene inherited from the father acts differently from the gene inherited from the mother, even though they may have the same DNA. This phenomenon is called imprinting. About 75% of patients with Prader-Willi syndrome have a small deletion of the long arm of chromosome 15, a small piece of one chromosome 15 is missing while the homologous chromosome remains intact. When this deletion is on the paternal chromosome (the father's genes are missing) Prader-Willi syndrome results. When this deletion is on the maternal chromosome (the mother's genes are missing) Angelman syndrome results. The two diseases have very different clinical symptoms. The other 25% of Prader-Willi syndrome patients are almost all the result of uniparental disomy, a rare chromosomal event in which both chromosomes come from a single parent. (This will be covered later under chromosomal diseases.) When both chromosomes 15 are derived from the mother, Prader-Willi syndrome results. When both chromosomes 15 are derived from the father, Angelman syndrome results. For normal development an individual must inherit one copy of this chromosomal region from his or her father and one from his or her mother. Several other regions have been found to show uniparental disomy without this effect on the phenotype. Small deletions usually affect the phenotype but they produce the same phenotype whether of maternal or paternal origin. Through some unknown mechanism, the gene, or genes, involved in Prader-Willi and Angelman syndrome know their origin and behave according to that origin. At the present time we do not know whether this is a general phenomenon or not. It might be limited to this small region of chromosome 15. It might be quite wide spread. Imprinting represents an exception to Mendel's laws and remains an important area of research.


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