Page 142 - Genetics_From_Genes_to_Genomes_6th_FULL_Part2

8.5 The Effects of Mutations on Gene Expression and Function 301

Figure 8.28 Why most loss-of-function mutant alleles are Figure 8.29 When a phenotype varies continuously with
recessive to wild-type alleles. Pink ellipses represent amounts levels of protein function, incomplete dominance results.
of an enzyme in Drosophila called xanthine dehydrogenase. Flies
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need only 10% of the enzyme produced in wild-type strains (A /A )
2
1
to have normal eye color. Null allele a and hypomorphic allele a
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1
are recessive to wild-type because A /a or A /a heterozygotes R / R +
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+
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have enough enzyme for normal eye color. + 50
R / R
+
R / R 0
50
R / R 50
50
R / R 0
0
Amount R / R 0
of
protein Enzyme 0 25 50 75 100
level
Threshold 0 + 0
for wild-type normal level of activity); and R is a null allele. R / R hetero­
eye color zygotes produce pink flowers whose color is halfway between
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A + a /a A + a 2 A +
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/A 1 /a /a /a red and white because one­half the R /R level of enzyme
+ 1 2 2
activity is not enough to generate a full red. Combining R or
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0
50
Recessive loss-of-function alleles R with the R allele produces pigmentation intermediate
Loss­of­function alleles that block the function of a protein between red and pink or between pink and white.
completely are called null mutations, or amorphic muta-
tions. For protein­encoding genes, the mutations either Unusual dominant loss-of-function alleles
prevent synthesis of the polypeptide or promote synthesis With phenotypes exquisitely sensitive to the amount of func­
of a protein incapable of carrying out any function. tional protein produced, even a relatively small change of two­
It is easy to understand why amorphic alleles are usually fold or less can cause a switch between distinct phenotypes.
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recessive to wild­type alleles. Consider an A /a heterozy­ Therefore, a heterozygote for a loss­of­function mutation that
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gote, in which the wild­type A allele generates functional generates less than the normal amount of functional gene prod­
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protein, while the null a allele does not (Fig. 8.28). If the uct may look different from the wild­type organism. Geneti­
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amount of protein produced by the single A allele (usually, cists use the term haploinsufficiency to describe relatively rare
though not always, half the amount produced in an A /A situations in which one wild­type allele does not provide
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cell) is above the threshold amount sufficient to fulfill the enough of a gene product to avoid a mutant phenotype.
normal biochemical requirements of the cell, the phenotype The number of haploinsufficient genes in humans is esti­
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of the A /a heterozygote will be wild type. The vast majority mated to be about 800. One example of a human haploinsuf­
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of genes function in this way; A /A cells actually make more ficient gene is GLI3, which encodes a transcription factor
than twice as much of the protein needed for the normal phe­ important for the specification of digits. Heterozygosity for
notype. Mendel’s alleles for green pea color or wrinkled pea loss­of­function mutations in GLI3 causes one form of
shape were likely null alleles and recessive to wild­type polydactyly—the presence of extra fingers and toes (Fig. 8.30).
alleles for this reason. (Recall Fig. 2.20.)
A hypomorphic mutation is a loss­of­function allele Unusual Gain-of-Function Alleles Are
that produces either less of the wild­type protein or a mu­ Almost Always Dominant
tant protein that functions less effectively than the wild­
type protein (a in Fig. 8.28). Hypomorphic alleles are Because there are many ways to interfere with a gene’s abil­
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usually recessive to wild­type alleles for the same reason ity to make sufficient amounts of active protein, the large
that amorphic alleles are usually recessive. majority of mutations in most genes are loss­of­function
alleles. However, rare mutations that either enhance a pro­
Incompletely dominant loss-of-function alleles tein’s function, confer a new activity on a protein, or express
Some combinations of alleles generate phenotypes that vary a protein at the wrong time or place act as gain-of-function
continuously with the amount of functional gene product, alleles. Because a single such allele by itself usually pro­
giving rise to incomplete dominance. For example, loss­of­ duces a protein that can alter phenotype even in the presence
function mutations in a single pigment­producing gene can of the normal protein, these unusual gain­of­function alleles
generate a red­to­white spectrum of flower colors, with the are almost always dominant to wild­type alleles. Many
white resulting from the absence of an enzyme in a biochem­ dominant mutant alleles are lethal when homozygous.
ical pathway (Fig. 8.29). Consider three alleles of the gene
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encoding enzyme R: R specifies the wild­type amount of the Hypermorphic alleles
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enzyme; R generates half the normal amount of the same A hypermorphic mutation is one that generates either
enzyme (or the full amount of an altered form that has half the more normal protein product than the wild­type allele, or a