Chapter 4:Gene Function

Principal Points

There is a specific relationship between protein coding genes and the production of polypeptides (one gene-one polypeptide)

Many human genetic diseases are caused by deficiencies in enzyme activities (learn the ones reviewed in the chapter)

Genetic counseling consists of an analysis of the risk that prospective parents may produce a child with a genetic defect and what are the available options for avoiding or minimizing those risks. As part of this analysis a pedigree analysis- the study of a family tree- is performed.

Garrod’s HypothesisOf Inborn Errors of Metabolism: He studiedPatients with Alkaptonuria(urine that turns the colorBlack because of HA accumulation)

He also studied otherGenetic diseases thatWere the result of blocksIn a metabolic pathway

You may not “care” about bread mold BUT it is an excellent organism to figure out biochemical pathways—

Question: To isolate auxotrophs in this manner, would a scientist have to have some idea what the intermediates are in the biochemical pathway? Answer this question after reading about Beadle and Tatum’s experiment

Understand Beadle & Tatum’s experiment and the use of auxotrophic mutants to figure out an enzymatic pathway

From this table could you determine the metabolic pathway for theProduction of methionine?

Genetic Defects in Humans

What is the enzyme defect, location of the defect, symptoms, and treatments for the following genetic diseases:

Phenylketonuria AlbinismLesch-Nyhan syndromeTay-Sachs diseaseSickle Cell Cystic Fibrosis

What is OMIM?

Tay-Sachs

What is the specific mutation found in the most common form of sickle-cell anemia (Hb-S), and how does this defect affect the structure and function of the resulting polypeptide (primary, secondary, tertiary, and quantanary structure)

What are some of the different types of hemoglobin mutants have been discovered in human populations, and how do they differ from the Hb-S mutation?

It is a change in the 6th amino acid from Glu (polar) to Val (nonpolar) amino acid. This is a change in primary structure. Affects tertiary structure since polar amino acids form hydrogen bonds and ionic bonds and nonpolar do not. And definitely affects quantanary structure since mutated beta subunits can only associate with mutated subunits and not with normal beta subunits; both associate with normal alpha subunits.

Figure 4.8 Colorized scanning electron micrographs of (left) normal and (right) sickled red blood cells.

Why is Hb-S more positivelyCharged compared to Hb-A?

Figure 4.9 Electrophoresis of hemoglobin variants. Hemoglobin found (left) in normal subjects, (center) in subjects with sickle-cell trait, and (right) in subjects who exhibit sickle-cell anemia. The two hemoglobins migrate to different positions in an electric field and therefore must differ in electric charge. (WHY?)

The normal Hbmolecule

Figure 4.10 The hemoglobin molecule. The diagram shows the two polypeptides and two polypeptides, each of which is associated with a heme group.

Figure 4.11 The first seven N-terminal amino acids in normal and sickled hemoglobin polypeptides. There is a single amino acid change from glutamic acid to valine at the sixth position in the sickled hemoglobin polypeptide.

Figure 4.12 Examples of amino acid substitutions found in (a) and (b) polypeptides of various human hemoglobin variants; not all variants cause disease.

Discuss the genetic defect and its pleiotropic effects in cystic fibrosis.

What is the frequency of cyctic fibrosis defect birth rates in these populations: Caucasian, African-American, and Asian.

How did scientists deduce the function of the 1480-amino acid protein involved in cystic fibrosis?

What is the specific defect of the most common form of cystic fibrosis: F508. (Explain the annotation.)

The defective gene product in CF patients was identified, not by biochemical analysis, but by a combination of genetic and modern biology techniques. It was localized to chromosome 7 and then it was molecularly cloned from a normal subject and from patients with CF. The serious form is deletion of three consecutive base pairs in the ATP-binding region.

Figure 4.13 Child with cystic fibrosis having the back pounded to dislodge accumulated mucus in the lungs. Presently these children have an average life

Span of 35 years.

Figure 4.14 Proposed structure for cystic fibrosis transmembrane conductance regulator (CFTR). The protein has two hydrophobic segments that span the plasma membrane, and after each segment is a nucleotide-binding fold (NBF) region that binds ATP. The site of the amino acid deletion resulting from the threenucleotide- pair deletion in the CF gene most commonly seen in patients with severe cystic fibrosis is in the first (toward the amino end) NBF; this is the mutation. The central portion of the molecule contains sites that can be phosphorylated by the enzymes protein kinase A and protein kinase C.

Since carriers are heterozygotes that most often have a normal phenotype, what must be done in order to detect a carrier?

How can amniocentesis determine whether a fetus is normal?

Why is amniocentesis avoided and only resorted to in high-risk cases?

What allows chorionic villus sampling to test a fetus at an earlier stage of development?

What are two drawbacks to chorionic villus sampling, compared to amniocentesis?

Figure 4.15 Amniocentesis, a procedure used for prenatal diagnosis of genetic defects. It is done after the 12th week of gestation. Because it is complicated and costly, it is used primarily in high-risk cases, such as when a mother is over 35.

Done between the 8th and 12th weeks of pregnancy. Disadvantages are thePossibilities of fetal death and inaccurate diagnoses caused by the presenceOf maternal cells.

Google cystic fibrosis gene therapy and find out what has been did in this area of research—know this for the test!