NON-MENDELIAN INHERITANCE: PATTERNS AND EXAMPLES - BIOLOGY - 2025

By " non-Mendelian inheritance " we mean any pattern of inheritance in which inherited characters do not segregate in accordance with Mendel's laws.

In 1865, Gregor Mendel, considered as the “father of genetics”, made a series of experimental crosses with pea plants, the results of which led him to propose some postulates (Mendel's laws) that sought to give a logical explanation to inheritance. of the characters between parents and children.

Non-Mendelian inheritance in wild and mutant mouse crosses for the white-tail-leg phenotype (Source: Reinhard Liebers, Minoo Rassoulzadegan, Frank Lyko via Wikimedia Commons)

This cunning Austrian monk carefully observed the segregation of parental genes and their appearance in the offspring as dominant and recessive characters. In addition, he determined the mathematical patterns that described inheritance from one generation to another and these findings were "ordered" in the form of 3 fundamental laws:

- The law of dominance

- The law of the segregation of characters and

- The law of independent distribution.

Mendel's successes and deductions were hidden for many years, until their rediscovery in the early 20th century.

Gregor Mendel, considered the father of Genetics. Source: By Bateson, William (Mendel's Principles of Heredity: A Defense), via Wikimedia Commons

At that time, however, the scientific community maintained a somewhat skeptical position regarding these laws, since they did not seem to explain the heritability patterns in any animal or plant species, especially in those characters determined by more than one locus.

Due to this, the first geneticists classified the hereditary patterns observed as "Mendelian" (those that could be explained through the segregation of simple, dominant or recessive alleles, belonging to the same locus) and "non-Mendelian" (those that did not could be explained so easily).

Non-Mendelian inheritance patterns

Mendelian inheritance refers to a hereditary pattern that complies with the laws of segregation and independent distribution, according to which a gene inherited from any parent secretes in gametes with an equivalent frequency or, better said, with the same probability.

The main Mendelian inheritance patterns that have been described for some diseases are: autosomal recessive, autosomal dominant and linked to the X chromosome, which are added to the dominance and recessivity patterns described by Mendel.

However, these were postulated with respect to visible traits and not genes (it should be taken into account that some alleles may encode traits that segregate as dominant, while others may encode the same traits, but these segregate as recessive genes).

From the foregoing it follows that non-Mendelian inheritance simply consists of any hereditary pattern that does not comply with the norm in which a gene inherited from any parent segregates in germline cells with the same probabilities, and these include:

- Mitochondrial inheritance

- "Imprinting"

- Uniparental disomy

- Incomplete dominance

- Codominance

- Multiple alleles

- Pleiotropy

- Lethal alleles

- Polygenic traits

- Sex-linked inheritance

The occurrence of these variations in hereditary patterns can be attributed to the various interactions that genes have with other cellular components, in addition to the fact that each one is subject to regulation and variation in any of the stages of transcription, splicing, translation, protein folding, oligomerization, translocation and compartmentalisation within the cell and for its export.

In other words, there are numerous epigenetic influences that can modify the inheritance patterns of any trait, resulting in a "deviation" from Mendel's laws.

Mitochondrial inheritance

Mitochondrial DNA also transmits information from one generation to another, just as does that contained in the nucleus of all eukaryotic cells. The genome encoded in this DNA includes the genes necessary for the synthesis of 13 polypeptides that are part of the subunits of the mitochondrial respiratory chain, essential for organisms with aerobic metabolism.

Mitochondrial inheritance patterns where either parent may be affected (Source: File: Autosomal dominant - en.svg: Domaina, Angelito7 and SUM1Derivative work: SUM1 via Wikimedia Commons)

Those traits that result from mutations in the mitochondrial genome exhibit a specific segregation pattern that has been called "mitochondrial inheritance", which usually occurs through the maternal line, since the ovum provides the total complement of mitochondrial DNA and no mitochondria are contributed by sperm.

"

Genomic imprinting consists of a series of epigenetic "marks" that characterize certain genes or complete genomic regions and that result from the genomic transit of the male or female through the process of gametogenesis.

There are gene imprinting clusters, which consist of between 3 and 12 genes distributed between 20 and 3700 kilo bases of DNA. Each cluster has a region known as the imprinting control region, which exhibits specific epigenetic modifications from each parent, including:

- DNA methylation on specific alleles in the cytokine residues of CpG pairs

- Post-translational modification of the histones related to chromatin (methylation, acetylation, phosphorylation, etc., of the amino acid tails of these proteins).

Both types of "marks" permanently modulate the expression of the genes on which they are found, modifying their transmission patterns to the next generation.

The inheritance patterns in which the expression of a disease depends on the specific alleles that are inherited from either parent is known as the parental origin effect.

Uniparental disomy

This phenomenon is an exception to Mendel's first law, which states that only one of the two alleles present in each parent is transmitted to the offspring and, according to the chromosomal laws of inheritance, only one of the parental homologous chromosomes can be transmitted. to the next generation.

This is an exception to the rule since uniparental disomy is the inheritance of both copies of a homologous chromosome from one of the parents. This type of inheritance pattern does not always show phenotypic defects, since it maintains the numerical and structural characteristics of the diploid chromosomes.

Incomplete dominance

This inheritance pattern consists, phenotypically speaking, of a mixture of the allele-encoded traits that are combined. In the cases of incomplete dominance, those individuals who are heterozygous show a mixture of the traits from the two alleles that control them, which implies that the relationship between the phenotypes is modified.

Codominance

It describes the hereditary patterns in which the two alleles that are transmitted from parents to their children are simultaneously expressed in those with heterozygous phenotypes, which is why both are considered “dominant”.

Example of codominance in the ABO system of blood groups (Source: GYassineMrabetTalk✉ This W3C-unspecified vector image was created with Inkscape. Via Wikimedia Commons)

In other words, the recessive allele is not "masked" by the expression of the dominant allele in the allelic pair, but both are expressed and a mixture of the two traits is observed in the phenotype.

Multiple alleles

Alleles of a gene (Source: Thomas Splettstoesser via Wikimedia Commons)

Perhaps one of the main weaknesses of Mendelian inheritance is represented by traits that are encoded by more than one allele, which is quite common in humans and many other living beings.

This heritable phenomenon increases the diversity of the traits that are encoded by a gene and, additionally, these genes can also experience patterns of incomplete dominance and codominance in addition to simple or complete dominance.

Pleiotropy

Another of the "stones in the shoe" or "loose legs" of Mendel's hereditary theories has to do with those genes that control the appearance of more than one visible phenotype or characteristic, as is the case of pleiotropic genes.

Lethal alleles

In his works, Mendel also did not consider the inheritance of certain alleles that can prevent the survival of the offspring when it is in the homozygous or heterozygous form; these are the lethal alleles.

Lethal alleles are usually related to mutations or defects in genes that are strictly necessary for survival, which when transmitted to the next generation (such mutations), depending on the homozygosity or heterozygosity of the individuals, are lethal.

Traits or polygenic inheritance

There are characteristics that are controlled by more than one gene (with their alleles) and that, in addition, are strongly controlled by the environment. In humans this is extremely common and is the case for traits such as height, eye, hair and skin color, as well as the risk of suffering from some diseases.

Sex-linked inheritance

In humans and many animals there are also traits that are found on one of the two sex chromosomes and that are transmitted through sexual reproduction. Many of these traits are considered "sex-linked" when they are evidenced in only one of the sexes, although both are physically capable of inheriting these traits.

Most of the sex-linked traits are associated with some recessive diseases and disorders.

Examples of non-Mendelian inheritance

There is a genetic disorder in humans known as Marfan syndrome, which is caused by a mutation in a single gene that simultaneously affects growth and development (height, vision, and heart function, among others).

This is a case considered to be an excellent example of the non-Mendelian inheritance pattern called pleiotropy, in which a single gene controls several characteristics.

Example of mitochondrial inheritance

Genetic disorders that result from mutations in mitochondrial DNA present a number of clinical phenotypic variations since what is known as heteroplasmy occurs, where different tissues have a different percentage of mutant mitochondrial genome and, therefore, present different phenotypes.

Among these disorders are the mitochondrial “depletion” syndromes, which are a group of autosomal recessive disorders characterized by a significant reduction in the content of mitochondrial DNA, which ends with deficient energy production systems in those organs and tissues most affected..

These syndromes may be due to mutations in the nuclear genome that affect the nuclear genes involved in the synthesis of mitochondrial nucleotides or in the replication of mitochondrial DNA. The effects can be evidenced as myopathies, encephalopathies, hepato-cerebral or neuro-gastrointestinal defects.

References

1. Gardner, JE, Simmons, JE, & Snustad, DP (1991). Principal of Genetic. 8 '"Edition. Jhon Wiley and Sons.
2. Griffiths, AJ, Wessler, SR, Lewontin, RC, Gelbart, WM, Suzuki, DT, & Miller, JH (2005). An introduction to genetic analysis. Macmillan.
3. Harel, T., Pehlivan, D., Caskey, CT, & Lupski, JR (2015). Mendelian, Non-Mendelian, Multigenic Inheritance, and Epigenetics. In Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (pp. 3-27). Academic Press.
4. Silver, L. (2001). Non-Mendelian Inheritance.
5. van Heyningen, V., & Yeyati, PL (2004). Mechanisms of non-Mendelian inheritance in genetic disease. Human molecular genetics, 13 (suppl_2), R225-R233.