LETHAL GENE ACTION

For a few years after the rediscovery of Mendel’s principles, geneticists believed that mutations only
changed the appearance of a living organism. But then they discovered that a mutant allele could
cause death. In a sense, this mutation is still a change in phenotype, with the new phenotype being
lethality. Perhaps the most serious effect a gene can have on an organism is to cause death.

An allele that results in the death of an organism is called a lethal allele, and the gene involved is
called an essential gene.

Essential genes are genes that, when mutated, can result in a lethal phenotype.

If the mutation is caused by a dominant lethal allele, both homozygotes and heterozygotes for
that allele show the lethal phenotype.

If the mutation is caused by a recessive lethal allele, only homozygotes for that allele have the
lethal phenotype.
A lethal gene causes death of all the individuals carrying this gene in the appropriate genotype before these individuals
reach adulthood.

The appropriate genotype for an allele would depend on its dominance relationship with its other allele(s).

For an allele producing a recessive effect on survival, the appropriate genotype would be the homozygous state,
while for an allele having dominant effect on survival, both homozygous and heterozygous states would be the
appropriate genotype.

Lethal genes may be grouped into the following five categories:

Recessive lethals
Dominant lethals
Conditional lethals
Balanced lethals, and
Gametic lethals
 Recessive Lethals
An example of a recessive lethal gene is the allele for
yellow body color in mice.
No true-breeding yellow mice exist.

From a yellow X yellow cross, progeny are produced

with a phenotypic ratio of 2 yellow : 1 nonyellow (the
nonyellow color depends on which other coat color
genes are present).

The living yellow mice are all heterozygotes for a yellow

allele; homozygotes for the yellow allele die at the
embryo stage. In other words, the yellow allele(Y or AY)
has a dominant effects on morphology (with regard to
coat color), but a recessive effect with respect to
lethality—that is, individuals homozygous for it die.

In other words,

the yellow allele in mice is unusual in that it acts as a

recessive allele in its effect on development but acts as
a dominant allele in its effect on coat colour.
 The recessive lethal yellow allele is an allele of the agouti locus
(a) and has been given the symbol AY.
The yellow x yellow cross genotypically is
AY/A x AY/A
The expected genotypic ratio in the progeny is
¼ AY /AY : 2/4 AY/A : ¼ AA
The AY /AY mice die before birth, giving a birth ratio of
2/3 AY/A (yellow) : 1/3 : A/A (nonyellow).

Characteristically, recessive lethal alleles are recognized by a

2:1 ratio of progeny types from crosses of two heterozygotes.

This 2: 1 ratio is the typical ratio obtained due to segregation

The 2 : 1 ratio produced by a cross for a recessive lethal gene.
between two yellow mice
results from a lethal allele.
 Characteristic Features of Recessive Lethals:

❖ They are always present in the heterozygous state since their

homozygotes do not survive

❖ Recessive lethals carried in the heterozygous condition have no effect,

but they may come to expression when matings between carriers occur.

❖ A cross between the heterozygotes for a recessive lethal gene yields a

2 : 1 ratio ( instead of the typical 3: 1 ratio).
The agouti gene of mouse has been molecularly cloned, permitting analysis of the lethal yellow
allele.

In wild-type agouti mice, the agouti gene is expressed in skin samples taken a few days after birth, when the
yellow band in the hair is being produced, in skin during regeneration of hair after plucking, and in no other tissues
and at no other time.

Y
In heterozygous A /A mice, the yellow allele is expressed at high levels in all tissues and at all developmental
stages, indicating that tissue-specific regulation of expression has been lost.

Y
The explanation is that the A allele has resulted from the deletion of a large DNA segment between the agouti
gene and an upstream gene called Raly, such that the Raly promoter and the first part of that gene are now
fused to the agouti gene.

The Raly promoter thus controls the expression of the attached agouti gene.

The expression in all tissues is caused by regulatory signals in the Raly promoter. The embryonic lethality of yellow
homozygotes probably results from the absence of Raly gene activity rather than a defective agouti gene.
 Recessive lethals
Since Cuenot’s discovery numerous other factors have been found that are lethal in homozygous condition. Such genes may
cause visible phenotypic effect when present in heterozygous condition (eg. Yellow in mice and freckling caused by the gene for
Xeroderma pigmentosa in humans, aurea gene producing yellow leaved plants in heterozygous state in Antirrhinum majus;
Dexter gene in cattle; Achondroplastic dwarfness in man),
or
may show no easily observable phenotypes in heterozygotes
( eg. neurologically degenerated Tay-Sachs disease in humans,
albina seedlings in plants, such as, barley) i.e. such genes are
recessive both in their phenotypic as well as lethal effects. In such
cases, heterozygous individuals have normal phenotype as well as
normal survival and they cannot be differentiated from normal
homozygotes.
In both instances, whether the lethal gene has a dominant or
recessive phenotypic effect, it is called a recessive lethal as long as
its lethality depends upon its presence in homozygous conditions i.
e. to say,

recessive lethals carried in the heterozygous condition have no

effect but may come to expression when mating between carriers
occur.
 Dominant lethals

Dominant lethals, on the other hand, are genes whose lethal effects occur in heterozygous
individuals.
A single dose of the gene for epiloia in humans, for instance, causes abnormal skin growths,
severe mental defects, multiple tumors, so that most heterozygotes for this gene die quite
young.

Dominant lethals, therefore, cannot be maintained in the population, while recessive

lethals are maintained in the heterozygous state.

Thus dominant lethals have to be produced in every generation through mutation.

 Balanced Lethals
In 1918 Muller reported an unusual stock of Drosophila flies which were always
heterozygous for a particular lethal gene, Beaded. The Beaded gene had a dominant
effect on the shape of the wings but had been shown to be lethal in homozygous
condition. Thus Beaded flies were always heterozygotes.

A cross of Beaded x Beaded, therefore, should result in 2/3 beaded and 1/3 normal
wings, or a 2 : 1 ratio, as for the Yellow X Yellow cross among mice.
In one of Muller’s stocks, however, only Beaded flies were produced and normal-winged flies never appeared.
Since the Beaded survivors were heterozygous ( Beaded / Beaded+), the question became what had happened to the
Beaded+ / Beaded+ flies that should have been produced in a Beaded / Beaded+ X Beaded / Beaded + cross.

After detailed analysis, Muller found that the homologous chromosome carrying the normal allele for Beaded ( Bd+) also
carried a gene that was lethal in homozygous condition, i.e. , le, but which was not an allele of Beaded. Thus, in addition to
Beaded heterozygotes, the Beaded X Beaded cross produced two types of homozygous lethals,
Beaded/ Beaded and le / le as shown in the figure below.
Since Beaded and le are recessive lethals, and are not
allelic, it is only the Bd le+ / Bd+ le individuals that
are viable, because each of these homologous
chromosomes carries the wild-type allele for the
recessive lethal on the other homologue.

The Beaded heterozygotes are therefore self

–perpetuating as long as the homologous
chromosome also contains a different recessive lethal
factor.

This balancing effect between two different lethals in

a self-perpetuating stock was named a balanced
Thus in a balanced lethal system all the surviving progeny are heterozygous for the lethal genes, and the homozygotes for
lethal system by Muller.
their normal alleles are not obtained. In such a system, two non-allelic recessive lethals are linked in the repulsion phase.
 Two requirements are therefore necessary for the maintenance of a balanced lethal system:

❖ That each member of a pair of homologous chromosomes carry a different non-allelic

recessive lethal, and

❖ That each of these two different recessive lethals always remain on separate homologous
chromosomes. The second requirement is fulfilled when transfer of a non-allelic lethal
from one homologous chromosome to the other is prevented by ‘crossover suppressor’.