Zoo 317 Heredity, Evolution and Society
|Lecture 21||Cummings 11: pp 266-282|
II. Mutation rates.
III. Molecular consequences of mutations.
IV. Unstable genes.
I. A mutation can be defined as any heritable change.
B. Historically, point mutations are those changes in DNA that are invisible microscopically. They may involve a single nucleotide or hundreds of thousands of nucleotides. With development of methods of analyzing DNA, the term point mutation is often equated with changes in a single nucleotide. Deletion or insertion of a small number of nucleotides are described by these more informative terms.
C. Mutations can also be distinguished by the types of cells in which they occur.
2. Somatic mutations occur in somatic cells and cannot be transmitted to offspring.
E. Inherited disorders that are quite distinct phenotypically may be due to different mutations in the same gene. E.g. Lesch-Nyhan syndrome and a rare form of gout are both mutations in the HPRT locus.
2. If the mutation in HPRT permits some enzymatic activity, hemizygous males have elevated uric acid in the blood but not nearly so high as in Lesch-Nyhan syndrome. This causes a rare, mild form of gout. It is not the common cause of gout.
B. The range of known mutation rates varies from 1 in 10,000 for Duchenne muscular dystrophy and neurofibromatosis type-1 (the largest genes known) to several genes in the range of 1 in 10,000,000.
C. Mutation rate studies never measure all the possible mutations at a locus. Many of the mutations cause no obvious phenotypic effect and could only be recognized by direct analysis of DNA sequences.
D. The rate of nucleotide substitutions is on the order of 1 per 100,000,000 nucleotides. Since there are 3 billion nucleotides per genome, that means that every gamete has about 30 new mutations involving nucleotide substitutions.
2. Missense mutations involve a change of codons that cause substitution of one amino acid for another. E.g. Sickle cell hemoglobin: beta codon 6 GAG (Glu) > GTG (Val).
3. Nonsense mutations involve change from one of the 61 codons that specify amino acids to one of the three termination codons. E.g. In the form of thalassemia common in the Mediterranean region, Hb beta thal-1, codon 17 AAG (Tyr) > TAG (Ter). This causes premature termination of the protein chain.
4. Sense mutations involve change from a termination codon to one that codes for amino acids. E.g. Hemoglobin Constant Spring alpha 142 TAA (Ter) > CAA (Gln). Translation continues beyond the normal termination until another termination codon is encountered.
2. In some instances, such as a mutation that causes persistence of fetal hemoglobin beyond the fetal period, nucleotide substitution in the 5' regulatory region causes the gene to be transcribed when it should be shut off.
2. Substitutions within an intron or exon can create new splice sites.
3. Changes in the 3' direction (downstream) from the coding regions can interfere with addition of poly-A tail.
E. Many mutations that cause loss of gene function are deletions of larger numbers of nucleotides. E.g. Duchenne muscular dystrophy.
F. The mutations that occur at a particular locus may be quite heterogeneous. Some may knock out gene function completely, others may reduce the function, and still others may have no effect on the phenotype, i.e., they are normal variants. As a result of this heterogeneity, many patients described as "homozygous" for a recessive allele may actually be heterozygous for two different defective alleles. Such a person is often called a compound heterozygote.
B. Since the number of triplets (nearly) always increases, the condition is more severe in succeeding generations and also appears earlier. This phenomenon is known as anticipation.
C. Some ten diseases are known to result from trinucleotide expansion. In addition to the fragile-X syndrome, these include Huntington disease. HD is a late onset disease, usually first appearing in persons in their 30's and 40's.
D. The mechanism for trinucleotide expansion is unknown. Also, for unknown reasons, expansion occurs only in females in the case of the fragile-X site, only in males in the case of Huntington disease, and in both sexes in some other conditions.
|mutation||point mutation||germinal mutation|
|somatic mutation||Lesch-Nyhan syndrome||mutation rate|
|nucleotide substitution||synonymous/silent mutation||missense mutation|
|nonsense mutation||sense mutation||insertion|
|deletion||frameshift mutation||compound heterozygote|