High school biology
Pleiotropy and lethal alleles
Pleiotropy: where one gene affects multiple characteristics. Lethal alleles: alleles that prevent survival when homozygous or heterozygous.
From Mendel’s experiments, you might imagine that all genes control a single characteristic and affect some harmless aspect of an organism’s appearance (such as color, height, or shape). Those predictions are true for some genes, but definitely not all of them! For example:
- A human genetic disorder called Marfan syndrome is caused by a mutation in one gene, yet it affects many aspects of growth and development, including height, vision, and heart function. This is an example of pleiotropy, or one gene affecting multiple characteristics.
- A cross between two heterozygous yellow mice produces yellow and brown mice in a ratio of , not . This is an example of lethality, in which a particular genotype makes an organism unable to survive.
In this article, we’ll take a closer look at pleiotropic genes and lethal alleles, seeing how these variations on Mendel's rules fit into our modern understanding of inheritance.
When we mentioned Mendel’s experiments with purple-flowered and white-flowered plants, we didn’t discuss any other phenotypes associated with the two flower colors. However, Mendel noticed that the flower colors were always correlated with two other features: the color of the seed coat (covering of the seed) and the color of the axils (junctions where the leaves met the stem).
In plants with white flowers, the seed coats and axils were colorless. In plants with purple flowers, on the other hand, the seed coats were brown-gray and the axils were reddish. Thus, rather than affecting just one characteristic, the flower color gene actually affected three.
Genes like this, which control multiple, seemingly unrelated features, are said to be pleiotropic (pleio- = many, -tropic = effects). We now know that Mendel’s flower color gene specifies a protein that causes colored particles, or pigments, to be made. This protein works in several different parts of the pea plant (flowers, seed coat, and leaf axils). In this way, the seemingly unrelated phenotypes can be traced back to a defect in one gene with several jobs.
Simple schematic illustrating pleiotropy.
In pleiotropy, one gene affects multiple features (feature 1, feature 2, feature 3.
Caption: One gene affects multiple characteristics.
Importantly, alleles of pleiotropic genes are transmitted in the same way as alleles of genes that affect single traits. Although the phenotype has multiple elements, these elements are specified as a package, and the dominant and recessive versions of the package would appear in the offspring of two heterozygotes in a ratio of .
Pleiotropy in human genetic disorders
Genes affected in human genetic disorders are often pleiotropic. For example, people with a hereditary disorder called Marfan syndrome may have a set of seemingly unrelated symptoms, including the following:
- Unusually tall height
- Thin fingers and toes
- Dislocation of the lens of the eye
- Heart problems (in which the aorta, the large blood vessel carrying blood away from the heart, bulges or ruptures).
These symptoms don’t seem directly related, but as it turns out, they can all be traced back to the mutation of a single gene. This gene encodes a protein that assembles into chains, making elastic fibrils that give strength and flexibility to the body’s connective tissues. Mutations that cause Marfan syndrome reduce the amount of functional protein made by the body, resulting in fewer fibrils.
How does the identity of this gene explain the range of symptoms? Our eyes and the aortas normally contain many fibrils that help maintain structure, which is why these two organs are affected in Marfan syndrome. In addition, the fibrils serve as “storage shelves” for growth factors. When there are fewer of them in Marfan syndrome, the growth factors cannot be shelved and thus cause excess growth (leading to the characteristic tall, thin Marfan build).
For the alleles that Mendel studied, it was equally possible to get homozygous dominant, homozygous recessive, and heterozygous genotypes. That is, none of these genotypes affected the survival of the pea plants. However, this is not the case for all genes and all alleles.
Many genes in an organism’s genome are needed for survival. If an allele makes one of these genes nonfunctional, or causes it to take on an abnormal, harmful activity, it may be impossible to get a living organism with a homozygous (or, in some cases, even a heterozygous) genotype.
Example: The yellow mouse
A classic example of an allele that affects survival is the lethal yellow allele, a spontaneous mutation in mice that makes their coats yellow. This allele was discovered around the turn of the 20th century by the French geneticist Lucien Cuenót, who noticed that it was inherited in an unusual pattern.
When yellow mice were crossed with normal agouti (brown) mice, they produced half yellow and half brown offspring. This suggested that the yellow mice were heterozygous, and that the yellow allele, , was dominant to the agouti allele, . But when two yellow mice were crossed with each other, they produced yellow and brown offspring in a ratio of , and the yellow offspring did not breed true (were heterozygous). Why was this the case?
Two yellow mice ( genotype) are crossed to one another. The Punnett square for the cross is:
|(dies as embryo)||(yellow)|
There is a phenotypic ratio of 2:1 yellow:brown among the mice that survive to birth.
As it turned out, this unusual ratio reflected that some of the mouse embryos (homozygous genotype) died very early in development, long before birth. In other words, at the level of eggs, sperm, and fertilization, the color gene segregated normally, resulting in embryos with a ratio of , , and genotypes. However, the mice died as tiny embryos, leaving a genotype and phenotype ratio among the surviving mice.
Alleles like , which are lethal when they're homozygous but not when they're heterozygous, are called recessive lethal alleles.
Lethal alleles and human genetic disorders
Some alleles associated with human genetic disorders are recessive lethal. For example, this is true of the allele that causes achondroplasia, a form of dwarfism. A person heterozygous for this allele will have shortened limbs and short stature (achondroplasia), a condition that is not lethal. However, homozygosity for the same allele causes death during embryonic development or the first months of life, an example of recessive lethality.
Some human disorders are also caused by dominant lethal alleles. These are alleles that cause death when they are present in just a single copy. If an allele leads to death of heterozygotes before birth, we’ll never see that allele in the living human population (but rather, as an implantation failure or miscarriage). However, if a dominant lethal allele allows heterozygotes to survive past birth, it can be seen in the population as a genetic disorder.
In fact, if a dominant lethal allele lets a person survive to reproductive age, it may even be passed on to children. This is the case in Huntington’s disease, a fatal genetic disorder affecting the nervous system. People with a Huntington allele inevitably develop the disease, but they may not show any symptoms until age 40 and can unknowingly pass the allele on to their children.
Want to join the conversation?
- Are there also genetic disorders that are Y-linked?(9 votes)
- Yes there are genetic disorders that are Y-linked. Y-linked genetic disorder means the the disorder of gene of the Y chromosome. As males have only Y chromosomes. Genetic disorders are likely to pass from the father to son.(so all girls....you guys are safe)(21 votes)
- I am a 13-year-old with achondroplasia. Does that mean I am heterozygous for the trait, since obviously I've survived this long?(11 votes)
- Hi! If the color of the flower correlates to the seed coat and the axil color, then How do we know that gene coding for seed cover nor axil color are pleiotropic? I mean, can't one argue that the gene coding for the axil color is what affects the flower color?(7 votes)
- The control of purple color in flowers, axils, and seed covers is all from the same gene – the most noticeable phenotype is the flower color, so that is how people generally talk about the gene. However, the gene is actually what is known as a transcription factor and is needed for expression of proteins that make a purple pigment (anthocyanin).
Naming of genes is actually quite chaotic and sometimes very confusing - for example a gene that does the same thing in different organisms will often have a different name.(7 votes)
- Does it means that dominant lethal alleles are more harmful than recessive lethal alleles?(4 votes)
- Yeah, if you have recesive lethal allele, you can live a happy life as long as you are heterozygous (= you have good dominant allele) , but if you have dominant lethal allele, you will die (no matter what other alleles are). Dominant alleles are rare tho, since carriers often die before they can pass it to next generation.(7 votes)
- can the alleles that cause sickle cell be seen as lethal alleles in this case.(3 votes)
- Yes, sickle cell is when a mutation happens in red blood cells where the amino acid glutamic acid is misplaced by the amino acid valine. This prevents the hemoglobin to form correctly: form crescent instead of the normal disc-shaped. We know that shape determines function, so without having the correct shape, hemoglobin can no longer function. Homozygous recessive will be lethal. However, in some areas where malaria is common, heterozygous will benefit because it helps resist malaria.
If you want to dive deeper, use this link: https://www.sciencedirect.com/topics/medicine-and-dentistry/heterozygote-advantage(2 votes)
- Is there such a thing as codominance or incomplete dominance in lethal alleles?(3 votes)
- https://biology.stackexchange.com/q/107991/67251 These phenotypic dominance terms you learn in school - autosomal recessive/dominant, co-dominance, incomplete dominance... these are all just descriptive terms based on phenotype that become somewhat irrelevant and outdated once you have a better molecular understanding of what exactly goes on with different alleles of a gene. If none of them apply well, that's fine, because the real world doesn't follow these basic rules.(1 vote)
- what is achondroplasia?(2 votes)
- Achondroplasia is a genetic disorder with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. In those with the condition, the arms and legs are short, while the torso is typically of normal length. Those affected have an average adult height of 131 centimetres (4 ft 4 in) for males and 123 centimetres (4 ft) for females. Other features can include an enlarged head and prominent forehead. Complications can include sleep apnea or recurrent ear infections. Achondroplasia includes short-limb skeletal dysplasia with severe combined immunodeficiency.
Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that results in its protein being overactive. Achondroplasia results in impaired endochondral bone growth (bone growth within cartilage). The disorder has an autosomal dominant mode of inheritance, meaning only one mutated copy of the gene is required for the condition to occur. About 80% of cases occur in children of parents of average stature and result from a new mutation, which most commonly originates as a spontaneous change during spermatogenesis. The rest are inherited from a parent with the condition. The risk of a new mutation increases with the age of the father. In families with two affected parents, children who inherit both affected genes typically die before birth or in early infancy from breathing difficulties.The condition is generally diagnosed based on the clinical features but may be confirmed by genetic testing.
Treatments may include support groups and growth hormone therapy. Efforts to treat or prevent complications such as obesity, hydrocephalus, obstructive sleep apnea, middle ear infections or spinal stenosis may be required. Achondroplasia is the most common cause of dwarfism and affects about 1 in 27,500 people.(2 votes)
- what if the mouse caring both trait of AA will it have a birth defect?(1 vote)
- It will die as an embryo. So technically no, the mouse caring AA will not have a chance to survive to actually carry a birth defect, since, in order to have birth defects, one must be birth first, right? :D(3 votes)
- why mitochondria is maternal contributor?(1 vote)
- The current thinking seems to be that paternal mitochondria are auto-digested soon after fertilization. Here's an article from 2011 about it: http://science.sciencemag.org.ezproxy.auckland.ac.nz/content/334/6059/1141(4 votes)
- I don't understand why "achondroplasia" as described would be considered "recessive". It is expressed in the description. Furthermore, I checked the Wikipedia entry (Mar 13, 2017) and the allele is described as "genetically dominant" albeit it is described as fatal if homozygous.(1 vote)
- Achondroplasia with one copy is not lethal so it is recessive for being lethal even though the dwarfism is dominant.(3 votes)