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14.2: Non-Mendelian inheritance

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    The majority of genetic disorders are not inherited in a Mendelian fashion. Even in cases where Mendelian genetics can predict genotype, the disease phenotype may not be displayed or may be variable due to external influences. This section describes some additional factors that influence presentation and inheritance patterns.

    Penetrance refers to the display of any signs or symptoms if you have the genetic abnormality; this does not describe the variety of phenotype. As illustrated in figure 14.3, this refers to the number of "affected (purple)" versus "unaffected (white)" cells in an individual. Individuals with a greater number of purple cells may have a more pronounced phenotype than individuals with greater numbers of white cells.

    Phenotypic expression (each oval represents an individual). Variable penetrance: 4 purple, 2 white. Variable expressivity: 3 purple, 1 pink, 2 Grey. Variable expressivity and penetrance: 1 purple, 2 white, 2 pink, 1 Grey.

    Figure 14.3: Graphic representation of penetrance and expressivity.

    Variable phenotypes can present due to changes in expressivity or pleiotropy. These terms refer to the variety of presentations from a single genetic disorder (variable expression). As illustrated in figure 14.3, expressivity can be a range of "purplish" colors, which may give rise to a variable phenotype. In other more complicated genetic cases, both penetrance and expressivity must be considered when making a diagnosis. Pleiotropy of a disorder is best described as a single gene disorder having implications on several different organ systems.

    Extranuclear inheritance

    Mitochondria are unique in that they have multiple copies of a circular chromosome. This DNA is independent of nuclear DNA and inherited from the mother.

    Therefore in this inheritance modality, the females can transmit the trait to all offspring (figure 14.4), however, only female offspring will continue to transmit the disorder. Disease phenotype in mitochondrial disease is extremely variable due to mitochondrial heteroplasmy.

    Unaffected father and affected mother have 4 affected children. Affected father and unaffected mother have 4 unaffected children.
    Figure 14.4: Mitochondrial inheritance pattern.

    Heteroplasmy is a term referring to the diversity of the mitochondrial genome within each cell. During cell division, mitochondria are divided randomly between the two daughter cells, and therefore the percentage of affected mitochondrial DNA (mtDNA) will also be variable within the offspring. The mitochondria generate energy for the rest of the cell, therefore disease transmitted through mitochondrial inheritance affects high-energy organs (this is a good example of pleiotropy).

    Genomic imprinting

    Genetic information is not just stored in the actual code (e.g., ATCG), but also for many genes hereditary information is transmitted with a parental-specific imprint based on whether the gene was transmitted from the father or from the mother. This imprint can be thought of as the font of the genome (e.g., ATCG vs. ATCG vs. ATCG). For these imprinted genes, even though the nucleotide sequence in the maternal and paternal copies is identical, the expression differs depending on the parental imprint. Genomic imprinting is the most well-characterized epigenetic transmission of gene regulation. Often in cases, the imprinting of one allele is essential for a normal phenotype, and loss of imprinting or uniparental disomy (inheritance of both loci from a single parental source) can cause inappropriate expression patterns.

    Differential methylation of genomic DNA is a central mechanism in the regulation of the expression of genes. Of special importance is the methylation of cytosine in CpG (cytosine-phosphorus-guanine) dinucleotides. Many genes have numerous “CpG islands” with a large number of CpG dinucleotides located upstream of the transcriptional start. Hypermethylation in this region results in transcriptional silencing, meaning the gene can no longer be read. The methylation pattern of DNA and, consequently, the activity pattern of the genes are generally transmitted as a stable trait in mitosis; however, for imprinted or epigenetically sensitive genes, this “trait” is reset in meiosis.

    Trinucleotide repeat disorders

    Disorders in this category are caused by expansion of tandem trinucleotide repeats (figure 14.5). These repetitive regions can be within upstream regulatory elements or within the coding region themselves; typically these repeated regions are of low copy number. In each generation there is the potential for these repetitive sequences to expand, and the expansion will change gene expression.

    Protein with the healthy gene (10-26 repeats) of CAG. Protein with Huntington’s disease gene (37-80 repeats) of CAG.

    Figure 14.5: Trinucleotide repeat expansion characteristic of Huntington’s disease.

    Triplicate repeat disorders are also characteristic of anticipation where the affected phenotype of individuals becomes progressively worse with each generation. Classic repeat disorders include Fragile X and Huntingtonʼs disease. In the case of Fragile X, the repeated region becomes hypermethylated and the methylation pattern expands into the promoter region for the gene. This will lead to silencing of the transcript. The gene itself, FMR1, is involved in mRNA splicing, and the loss of this gene product has a pleiotropic effect.

    References and resources

    Text

    Clark, M. A. Biology, 2nd ed. Houston, TX: OpenStax College, Rice University, 2018, Chapter 10: Cell Reproduction, Chapter 12: Mendel's Experiments and Heridity, Chapter 13: Modern Understandings of Inheritance.

    Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 55–59.

    Nussbaum, R. L., R. R. McInnes, H. F. Willard, A. Hamosh, and M. W. Thompson. Thompson & Thompson Genetics  in Medicine, 8th ed. Philadelphia: Saunders/Elsevier, 2016, Chapter 7: Patterns of Single Gene Inheritance, Chapter 9: Genetic Variations in Populations, Chapter 10: Identifying the Genetic Basis for Human Disease.

    Figures

    Grey, Kindred, Figure 14.3 Graphic representation of penetrance and expressivity. 2021. CC BY4.0. Adapted from Introduction to Genetic Analysis 7th Ed. Figure 4.33 The effects of penetrance and expressivity through a hypothetical character “pigment intensity. From NCBI.

    Grey, Kindred, Figure 14.4 Mitochondrial inheritance pattern. 2021. https://archive.org/details/14.4_20210926. CC BY-SA 4.0. Added Mitochondrial inheritance by Domaina, Angelito7 and SUM1. CC BY-SA 4.0. From Wikimedia Commons.

    Grey, Kindred, Figure 14.5: Trinucleotide repeat expansion characteristic of Huntington’s disease. 2021.

    Additional resources

    This page titled 14.2: Non-Mendelian inheritance is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Renee J. LeClair (Virginia Tech Libraries' Open Education Initiative) .

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