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GENE INHERITANCE AND TRANSMISSION | 

Lead Editor: 
Terry McGuire

Mendelian Ratios and Lethal Genes

By: Ingrid Lobo, Ph.D. (Write Science Right) © 2008 Nature Education 
Citation: Lobo, I. (2008) Mendelian ratios and lethal genes. Nature
Education 1(1):138

What happens when good genes go bad? What kinds of mutations create "lethal genes," and how are they passed on?
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In 1905, Lucien Cuénot observed unusual patterns when studying inheritance of a coat color gene in mice. After mating
two yellow mice, he observed that the offspring never showed a normal 3:1 phenotypic ratio. Instead, Cuénot always
observed a 2:1 ratio, with two yellow mice for every one non-yellow mouse (Cuénot, 1905; Paigen, 2003). Cuénot thus
determined that yellow coat color was the dominant phenotypic trait, and by using test crosses, he showed that all his
yellow mice were heterozygotes. However, from his many crosses, Cuénot never produced a single homozygous yellow
mouse. How could this be?

Shortly thereafter, in 1910, W. E. Castle and C. C. Little confirmed Cuénot's unusual segregation ratios (Figure 1).
Moreover, they demonstrated that Cuénot's crosses resulted in what appeared to be non-Mendelian ratios because he
had discovered a lethal gene. Castle and Little did this by showing that one-quarter of the offspring from crosses
between heterozygotes died during embryonic development (Castle & Little, 1910; Paigen, 2003). This was why Cuénot
never observed homozygous yellow mice! Thus, by considering embryonic lethality, or death, as a new phenotypic class,
the classic 1:2:1 Mendelian ratio of genotypes could be reestablished (Figure 2).

Figure 1: Castle's experimental results.

As these examples illustrate, lethal genes cause the death of the organisms that carry them. Sometimes, death is not These results suggest that some alleles are lethal.

immediate; it may even take years, depending on the gene. In any case, if a mutation results in lethality, then this is © 1910 American Association for the Advancement of
indicative that the affected gene has a fundamental function in the growth, development, and survival of an organism. Science Castle, W. E. & Little, C. C. On a modified mendelian
ratio among yellow mice. Science 32, 868–870 (1910). All rights
Lethal genes can be recessive, as in the aforementioned mouse experiments. Lethal genes can also be dominant,
reserved.
conditional, semilethal, or synthetic, depending on the gene or genes involved. The following sections explore these
variations in detail. Figure Detail

Recessive Lethal Genes

In 1907, Edwin Baur began his work with the snapdragon plant Antirrhinum and characterized the condition aurea, in which plants had golden instead of green
leaves (Baur, 1907; Castle & Little, 1910). When two aurea snapdragon plants were crossed, Baur observed a 2:1 ratio of green seedlings to yellow seedlings.
Homozygous aurea plants lacked normal chlorophyll development and died either during the embryonic stage or when the plant seedlings were two to three days
old. In other words, like Cuénot's homozygous mice, the homozygous aurea plants could not fully develop, so an entire class of progeny died (Castle & Little,

Figure 2
1910).

Figure Detail
Cuénot and Baur discovered these first recessive lethal genes because they altered Mendelian inheritance ratios. Recessive lethal genes can code for either
dominant or recessive traits, but they do not actually cause death unless an organism carries two copies of the lethal allele. Examples of human diseases caused
by recessive lethal alleles include cystic fibrosis, sickle-cell anemia, and achondroplasia. Achondroplasia is an autosomal dominant bone disorder that causes
dwarfism. While the inheritance of one achondroplasia allele can cause the disease, the inheritance of two recessive lethal alleles is fatal.

Dominant Lethal Genes

Dominant lethal genes are expressed in both homozygotes and heterozygotes. But how can alleles like this be passed from one generation to the next if they cause death? Dominant lethal genes
are rarely detected due to their rapid elimination from populations. One example of a disease caused by a dominant lethal allele is Huntington's disease, a neurological disorder in humans, which
reduces life expectancy. Because the onset of Huntington's disease is slow, individuals carrying the allele can pass it on to their offspring. This allows the allele to be maintained in the population.
Dominant traits can also be maintained in the population through recurrent mutations or if the penetrance of the gene is less than 100%.

Conditional Lethal Genes

Favism is a sex-linked, inherited condition
that results from deficiency in an enzyme called glucose-6-phosphate
dehydrogenase. It is most common among people of Mediterranean, African,
Southeast
Asian, and Sephardic Jewish descent (Allison, 1960). The disease was named because when affected
individuals eat fava beans, they develop hemolytic anemia, a condition in which
red blood cells break apart and block blood vessels. Blockage can cause kidney
failure and result in death (Bowman & Walker, 1961). Affected individuals may also develop
anemia when
administered therapeutic doses of antimalarial medications and
other drugs (Allison, 1960). Note,
however, that the defective glucose-6-phosphate dehydrogenase allele only causes
death under
certain conditions, which makes it a conditional lethal gene. But why would this allele be so common?
The interesting thing about individuals with the favism allele is that they are
resistant to
malaria, because it is more difficult for malaria parasites to multiply
in cells with deficient amounts of glucose-6-phosphate dehydrogenase.
Therefore, carrying the allele for favism confers an
intrinsic genetic or
adaptive advantage by protecting individuals from contracting malaria.

Conditional lethal genes can also be

expressed due to specific circumstances, such as temperature. For example, a
mutant protein may be genetically engineered to be fully functional at 30°C
and
completely inactive at 37°C. Meanwhile, the wild-type protein is fully
functional at both temperatures. The condition in which the mutant phenotype is
expressed is termed nonpermissive.
Meanwhile, the condition in which the wild-type phenotype is expressed is
called permissive. In order to
study a conditional lethal mutant, the organism must be maintained under
permissive
conditions and then switched to the nonpermissive condition during
the course of a specific experiment. By developing a conditional lethal version
of a dominant lethal gene, scientists can study
and maintain organisms carrying
dominant lethal alleles.

Semilethal or Sublethal Genes

Hemophilia is a hereditary disease caused by
deficiencies in clotting factors, which results in impaired blood clotting and
coagulation. Because the allele responsible for hemophilia is carried on
the X
chromosome, affected individuals are predominantly males, and they inherit the
allele from their mothers. Normally, clotting factors help form a temporary
scab after a blood vessel is injured
to prevent bleeding, but hemophiliacs
cannot heal properly after injuries because of their low levels of blood
clotting factors. Therefore, affected individuals bleed for a longer period of
time until
clotting occurs. This means that normally minor wounds can be fatal
in a person with hemophilia. The alleles responsible for hemophilia are thus called
semilethal or sublethal genes,
because they
cause the death of only some of the individuals or
organisms with the affected genotype.

Synthetic Lethal Genes

Scientists studying the fruit fly observed
that pairwise combinations of some mutant alleles were not viable, whereas
singly, the same mutant alleles did not cause death (Boone et al., 2007). In
other words, some mutations are only
lethal when paired with a second mutation. These genes are called synthetic lethal genes. When the
functions of the two affected genes are not fully
understood, scientists can
create and study synthetic lethal mutants and their phenotypes to identify a gene's
function. Mechanisms can also be hypothesized from the known functions of pairs
of
mutated alleles.

For instance, if both mutations occur in

nonessential genes, a scientist could hypothesize that the two genes function
in parallel pathways that share information with one another. Each of the two
pathways could compensate for a defect in the other, but when both pathways
have a mutation, the combination results in synthetic lethality. Synthetic
lethality can also indicate that two affected
genes have the same role, and therefore,
lethality only results when both copies are nonfunctional and one gene cannot
substitute for the other. Additionally, both genes may function in the same
essential pathway, and the pathway's function may be diminished by each
mutation.

When an allele causes lethality, this is evidence that the gene must have
a critical function in an organism. The discoveries of many lethal alleles have
provided information on the functions of
genes during development.
Additionally, scientists can use conditional and synthetic lethal alleles to
study the physiological functions and relationships of genes under specific
conditions.

Exploring Genetic Interactions and Networks with Yeast

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References and Recommended Reading

Allison, A. C.
Glucose-6-phosphate dehydrogenase deficiency in red blood cells of East
Africans. Nature 186, 531–532 (1960) doi:10.1038/186531a0 (link to article)

Baur, E. Untersuchungen über die Erblichkeitsverhältnisse einer nur in Bastardform

lebensfähigen Sippe von Antirrhinum majus.
Berichte der Deutschen Botanischen Gesellschaft 25, 442–454
(1907)

Boone, C., et al. Exploring genetic interactions and networks with

yeast. Nature Reviews Genetics 8, 437–449 (2007) doi:10.1038/nrg2085 (link to article)

Bowman, J. E., &

Walker, D. G. Action of Vicia faba on erythrocytes: Possible relationship
to favism. Nature 189, 555–556 (1961) doi:10.1038/189555a0 (link to article)

Castle, W. E., &

Little, C. C. On a modified Mendelian ratio among yellow mice. Science 32, 868–870 (1910)