Page 145 - Genetics_From_Genes_to_Genomes_6th_FULL_Part2

304 Chapter 8 Gene Expression: The Flow of Information from DNA to RNA to Protein

TABLE 8.2 Mutations Classified by Their Effects on Protein Function

Loss-of-Function Gain-of-Function
Mutation Amorphic (null) Hypomorphic (leaky) Hypermorphic Neomorphic Antimorphic (dominant
Type negative)

Occurrence Common Common Rare Rare Rare
Usually recessive Usually dominant Usually dominant Usually dominant
Possible Can be incompletely dominant if phenotype or incompletely or incompletely
Dominance varies continuously with gene product dominant dominant
Relations
Can be dominant in cases of haploinsufficiency

The Effects of a Mutation Can proteins or rRNAs, are often lethal in homozygotes because
Be Difficult to Predict such mutations adversely affect the synthesis of all proteins
in a cell. Even a 50% reduction in the amount of some of
As noted previously, most mutations constitute loss­of­ the proteins or RNAs required for gene expression can have
function alleles. The reason is that many changes in amino severe repercussions. In Drosophila, for example, null mu­
acid sequence are likely to disrupt a protein’s function, and tations in many of the genes encoding the various ribo­
because most alterations in gene regulatory sites, such as somal proteins are lethal when homozygous. Due to
promoters, will make those sites less efficient. Nonethe­ haploinsufficiency, the same mutations in heterozygotes
less, rare mutations at almost any location in a gene can cause a dominant Minute phenotype, in which the slow
result in a gain of function. growth of cells delays the fly’s development.
Even when you know how a mutation affects gene
function, you cannot always predict whether the mutant
allele will be dominant or recessive to a wild­type allele Suppressor mutations in tRNA genes
(Table 8.2). Although most loss­of­function mutations If more than one gene encoded the same molecule with a
are recessive and almost all gain­of­function mutations role in gene expression, a mutation in one of these genes
are dominant, exceptions to these generalizations do exist. would not necessarily be lethal and might even be advan­
The reason is that dominance relations between the wild­ tageous. Bacterial geneticists have found, for example,
type and mutant alleles of genes in diploid organisms that mutations in certain tRNA genes can suppress the ef­
depend on how drastically a mutation influences protein fects of nonsense mutations in other genes. The tRNA­
production or activity, and how thoroughly phenotype gene mutations that have this effect give rise to nonsense
depends on the normal wild­type level of the protein. suppressor tRNAs.
Consider, for instance, an otherwise wild­type E. coli
population with an in­frame UAG nonsense mutation in
Mutations in Genes Encoding the the tryptophan synthase gene. All cells in this population
Molecules that Implement Expression make a truncated, nonfunctional form of the tryptophan
May Have Global Effects synthase enzyme and are thus tryptophan auxotrophs
−
(Trp ) unable to synthesize tryptophan (Fig. 8.34a). Sub­
Gene expression depends on an astonishing number and vari­ sequent exposure of these auxotrophs to mutagens, how­
+
ety of proteins and RNAs, each encoded by a separate gene. ever, generates some Trp cells that carry two mutations:
The genes for all the proteins (RNA polymerases, ribosomal One is the original tryptophan synthase nonsense muta­
protein subunits, aminoacyl­tRNA synthetases, etc.) are tran­ tion, and the second is a mutation in the gene that encodes
scribed and translated the same as any other gene. The genes a tRNA for the amino acid tyrosine. Evidently, the muta­
for all the rRNAs, tRNAs, and snRNAs are noncoding genes tion in the tRNA gene suppresses the effect of the non­
that are transcribed but not translated. Mutations in almost sense mutation, restoring the function of the tryptophan
any of these genes, whether protein­coding or noncoding, can synthase gene.
have a dramatic effect on phenotype. As Fig. 8.34b illustrates, the basis of this nonsense
Tyr
suppression is that the tRNA mutation changes an anti­
codon that recognizes the codon for tyrosine to an antico­
Lethal mutations affecting the machinery don complementary to the UAG stop codon. The mutant
of gene expression tRNA can therefore insert tyrosine into the polypeptide at
Loss­of­function mutations in the genes encoding mole­ the position of the in­frame UAG nonsense mutation, al­
cules that implement gene expression, such as ribosomal lowing the cell to make at least some full­length enzyme.