Question

1. (11 points) Defects in collagen genes are responsible for several inherited diseases, including osteogenesis imperfecta, a disease characterized by brittle bones, and Ehlers-Danlos syndrome, which can lead to sudden death due to ruptured internal organs or blood vessels. In both diseases, the medical problems arise because the defective gene in some way compromises the function of collagen fibrils. For example, homozygous deletions of the type l collagen α1(I) gene eliminates α 1(1) collagen entirely, thereby preventing formation of any type I collagen fibrils. Such homozygous mutations are usually lethal in early development. The more common situation is for an individual to be heterozygous for the mutant gene, having one normal gene and one defective gene. Here the c less severe. onsequences are a (6 points) Type I collagen molecules are composed of two copies of the α 1(1) chain and one copy of the a2(1) chain. Calculate the fraction of type I collagen molecules, [al(ho2I), that will be normal in an individual who is heterozygous for a deletion of the entire al(I) gene (3 points, show all work). Repeat the calculation for an individual heterozygous for a point mutation in the al(l) gene (3 points, show all work) b. (5 points) Which kind of collagen gene defect- deletion or point mutation- is more likely to be dominant (that is, to cause the heterozygote to display a mutant phenotype) (L point, deletion or point mutation)? Explain your reasoning (4 points, 1-2 sentences).

Answer 1

Answer a.

The composition of the gene for collagen type I is [α1]₂[α2]₁. If a heterozygous deletion mutation exists in the α1 gene, then there are four different possibilities of collagen fibrils that can exist.

1. α1-α1*-α2 2. α1*-α1-α2 3. α1*-α1*-α2 4. α1-α1-α2.

Out of all four, three of them contain at least one defective α1 chain. Hence, only 25% (or 0.25) of collagen molecules will be normal.

For an individual that shows a heterozygous point mutation in the α1 gene, the fraction of normal collagen molecules will be 0.25 (as above). However, the severity of a point mutation may be less compared to deletion mutation, depending on the position of the point mutation.

Answer b.

A deletion mutation is more likely to be dominant in a heterozygous mutant phenotype, since it leads to total loss of a functional gene. A point mutation may produce a less efficient or abnormal gene product which may still functional whereas a deletion mutation causes total loss of the gene product. Hence, the phenotype of the heterozygous point mutation may not be as severe as compared to a heterozygous deletion mutation.