Genomic Imprinting

One of the basic tenets of Mendelian genetics is that the parental origin of a gene does not affect its expression— reciprocal crosses give identical results. We have seen that there are some genetic characteristics—those encoded by X-linked genes and cytoplasmic genes—for which reciprocal crosses do not give the same results. In these cases, males and females do not contribute the same genetic material to the offspring. With regard to autosomal genes, males and females contribute the same number of genes, and paternal and maternal genes have long been assumed to have equal effects. The results of recent studies, however, have identified several mammalian genes whose expression is significantly affected by their parental origin. This phenomenon, the differential expression of genetic material depending on whether it is inherited from the male or female parent, is called genomic imprinting.

Genomic imprinting has been observed in mice in which a particular gene has been artificially inserted into a mouse's DNA (to create a transgenic mouse). In these mice, the inserted gene is faithfully passed from generation to generation, but its expression may depend on which parent transmitted the gene. For example, when a transgenic male passes an imprinted gene to his offspring, they express the gene; but, when his daughter transmits the same gene to her offspring, they don't express it. In turn, her son's offspring express it, but her daughter's offspring don't. Both male and female offspring possess the gene for the trait; the key to whether the gene is expressed is the sex of the parent transmitting the gene. In the present example, the gene is expressed only when it is transmitted by a male parent. The reverse situation, expression of a trait when the gene is transmitted by the female parent, also occurs.

Genomic imprinting has been implicated in several human disorders, including Prader-Willi and Angelman syndromes. Children with Prader-Willi syndrome have small hands and feet, short stature, poor sexual development, and mental retardation; they develop voracious appetites and frequently become obese. Many persons with Prader-Willi syndrome are missing a small region of chromosome 15 called q11—13. The deletion of this region is always inherited from the father in persons with Prader-Willi syndrome.

The deletions of q11—13 on chromosome 15 can also be inherited from the mother, but this inheritance results in a completely different set of symptoms, producing Angelman ss

|Tab|e 5.4 Sex influences on heredity syndrome. Children with Angelman syndrome exhibit frequent laughter, uncontrolled muscle movement, a large mouth, and unusual seizures. The deletion of segment q11—13 from chromosome 15 has severe effects on the human phenotype, but the specific effects depend on which parent contributes the deletion. For normal development to take place, copies of segment q 11-13 of chromosome 15 from both male and female parents are apparently required.

Several other human diseases also appear to exhibit genomic imprinting. Although the precise mechanism of this phenomenon is unknown, methylation of DNA — the addition of methyl (CH3) groups to DNA nucleotides (see Chapters 10 and 16) — is essential to the process of genomic imprinting, as demonstrated by the observation that mice deficient in DNA methylation do not exhibit imprinting. Some of the ways in which sex interacts with heredity are summarized in Table 5.4.

Concepts 9

In genomic imprinting, the expression of a gene is influenced by the sex of the parent who transmits the gene to the offspring. Additional information about genomic imprinting, Prader-Willi syndrome, and Angelman syndrome

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