Question

(a) In humans the mitochondrial genome encodes a low number of proteins, rRNAs, and tRNAs but imports approximately 1100 proteins encoded by the nuclear genome. Yet, with such a small proportion from the mitochondrial genome encoding proteins and RNAs, a disproportionately high number of genetic disorders due to mtDNA mutations have been identified (Bigger, B. et al. 1999 ). What inheritance pattern would you expect in a three-generation pedigree in which the grandfather expresses the initial mtDNA defect? What inheritance pattern would you expect in a three-generation pedigree in which the grandmother expresses the initial mtDNA defect? (b) Considering the description in part (a) above, how would your pedigrees change if you knew that the mutation that caused the mitochondrial defect was recessive and located in the nuclear genome, was successfully transported into mitochondria, and negated a physiologically important mitochondrial function?

Short answer

Answer: The inheritance pattern of mtDNA defects depends on the source of the defect. If the initial mtDNA defect is in the grandfather, none of the three generations will exhibit the defect because mtDNA is exclusively inherited from the mother. If the grandmother has the initial mtDNA defect, all three generations will show the defect, but it will only be passed down through the female line. However, if the mutation causing the defect is recessive and located in the nuclear genome, the pedigrees will reflect Mendelian inheritance patterns of a recessive trait, rather than the distinct maternal inheritance pattern seen in mitochondrial inheritance.

Step-by-step solution

Understand mitochondrial inheritance

Mitochondrial DNA is exclusively inherited from the mother. This means that all children (both sons and daughters) of a woman with a mutated mtDNA will inherit the mtDNA defect. However, only the daughters will pass the mutated mtDNA to their children.

Analyze the grandfather scenario

If the grandfather carries the initial mtDNA defect, he will not pass it on to any of his children (both sons and daughters), because mtDNA is only inherited from the mother. As a result, none of the three generations in the pedigree will exhibit the mtDNA defect.

Analyze the grandmother scenario

If the grandmother carries the initial mtDNA defect, she will pass it on to all of her children (sons and daughters). In the next generation, only her daughters will pass the mtDNA defect to their children. Hence, all three generations will show the mtDNA defect, but it will only be passed down through the female line. #Part B#

Understand nuclear inheritance of recessive mutations

In this case, the mutation is in the nuclear genome and recessive. Recessive inheritance means that the defect is only expressed when two copies of the recessive allele are present (homozygous recessive).

Modify the pedigrees

Since the mutation is now in the nuclear genome and recessive, we need to consider Mendelian inheritance patterns and evaluate the likelihood of inheriting the defective allele from both parents. In the grandfather scenario, his children will be carriers but will not express the defect, while the grandchildren may or may not inherit the defect, depending on the mother's genotype. In the grandmother scenario, all children will be carriers but will not express the defect, while the grandchildren may or may not inherit the defect, depending on the father's genotype. In both cases, the pedigrees will reflect the Mendelian inheritance pattern of a recessive trait, rather than the distinct maternal inheritance pattern seen in mitochondrial inheritance.

Key concepts

Mitochondrial DNA Mutations

Mitochondrial DNA (mtDNA) mutations are changes that occur in the DNA of mitochondria—the powerhouses of the cell that generate energy. Unlike nuclear DNA, which comes from both parents, mtDNA is inherited solely from the mother. This unique inheritance pattern can lead to certain diseases being passed along the maternal line.

When a woman carries a mutated mtDNA, all her children inherit the mutation because the mitochondria in the zygote are derived from the mothers' egg cells. However, only her daughters will further transmit the mutation to subsequent generations. Therefore, if a disease is caused by mtDNA mutations, it will appear in every generation along the maternal line but not on the paternal side.

Although the mitochondrial genome is small, containing 37 genes responsible for cellular respiration and energy production, mutations in these genes can have severe consequences. They can disrupt the mitochondria's ability to produce energy, leading to a variety of mitochondrial disorders, which often affect organs with high-energy demands like the brain and muscles. Given their critical role in cellular energy production, even a small number of mutated mitochondrial genes can disproportionately affect bodily function.

Mendelian Inheritance Patterns

Mendelian inheritance patterns refer to the principles of heredity first outlined by Gregor Mendel in the 19th century. These principles explain how traits are transmitted from parents to offspring through genetic alleles. There are two types of alleles for a gene: dominant and recessive. A dominant allele will express its trait even if only one copy is present (heterozygous), while a recessive allele must have two copies (homozygous) to manifest its trait.

Recessive genetic disorders, therefore, occur when an individual inherits two copies of a recessive allele, one from each parent. A person with only one recessive allele is a carrier of the trait but typically does not show symptoms of the disorder. In a pedigree, this Mendelian pattern would show the disorder manifesting only when both parents contribute a recessive allele.

Understanding these patterns is crucial for predicting the likelihood of an offspring inheriting a trait or disorder. For genetic counseling and prediction of disease inheritance, healthcare professionals utilize Mendelian genetics as a fundamental framework, though actual human inheritance can be more complex due to the involvement of multiple genes and environmental factors.

Recessive Genetic Disorders

Recessive genetic disorders occur when both copies of a gene in an individual are mutated; these mutations usually lead to the loss of normal protein function. Such disorders are often severe and can be life-limiting. They do not typically affect the person carrying only one copy of the mutated gene – the carrier. For a child to be affected by a recessive genetic disorder, both parents must be carriers of the mutated gene.

Examples of recessive disorders include cystic fibrosis, sickle cell anemia, and Tay-Sachs disease. Each parent of an affected child carries one copy of the mutated gene, but because they also have a normal copy, they do not exhibit symptoms themselves. This is where pedigrees and genetic screening become essential, as families with a history of a recessive genetic disorder can be unaware of their carrier status until they have an affected child.

For those looking to understand their risks or the risks of potential offspring, genetic counseling is often recommended. Through the identification of carriers within a family, future generations can be better informed about their likelihood of passing on or inheriting recessive genetic disorders.