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Author: Laurie Ann Demmer, M.D.
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Mendelian Genetics (Part 1)

Readings

Jorde, Carey, Bamshad & White: Medical Genetics, 3rd edition, C.V. Mosby Publishing, 2005.

  • Mitochondrial genetics, chapter 5, 101-105
  • Multifactorial inheritance, chapter 12, 248-277

Objectives

  1. Understand that mitochondrial inheritance is maternal, and understand the concept of heteroplasmy.
  2. Understand the concept of multifactor inheritance including threshold effect, liability, and recurrence risk.

Mitochondrial Inheritance

In Mendelian inheritance, abnormal phenotypes result from the transmission of mutant genes located in the nucleus of the cell. However, not all DNA coding for genes necessary for cellular function resides in the nucleus. Each cell contains hundreds of mitochondria, each of which contains multiple copies of a 16.5 Kb circular DNA molecule. The entire human mitochondrial chromosome has been cloned and sequenced. It consists of 16,569 base pairs of DNA and encodes 37 genes, of which 2 are for ribosomal RNAs, 22 transfer RNAs, and 13 for polypeptides involved in oxidative respiration. Although most proteins functioning in the mitochondria are encoded by nuclear genes, some are encoded by mitochondrial genes, and mutations can lead to energy failure.

In humans, at fertilization, the ovum contributes significantly more cytoplasm to the zygote than does the sperm. The sperm mitochondria degenerate upon penetration of the ovum. Thus, mitochondria in offspring are exclusively maternal in origin. This phenomenon results in a maternal transmission of the phenotype.

Another important concept that results from mutations in the mitochondrial genome is heteroplasmy. (Heteroplasmy: the mtDNA is a mixture of normal and mutant forms. Homoplasmy: the mtDNA is all the same type, ie. all normal or all mutant). There are hundreds of copies of mitochondrial DNA molecules in each cell, in contrast with nuclear genes where there are only two copies per cell. During cell division, each mitochondrial DNA molecule replicates, but unlike nuclear genes, the newly synthesized mitochondrial molecules segregate passively to the daughter cells. As a result, some daughter cells may have many copies of the mutant mitochondrial DNA, while other cells may have only a few (or none).

When eggs are formed in a female carrying mutant forms of mitochondria, some of her eggs may have many copies of the mutant mitochondria, while some of her eggs may carry only a few. The offspring accordingly may be severely affected by the resulting disease, or may have only mild evidence of the disease. In addition, the proportion of mutant mtDNA molecules may change over time through replicative segregation as mitochondria proliferate and cells divide. The percentage of mutant mtDNA can increase or decrease over time due to either chance variation (genetic drift) or because of a selective advantage of one mtDNA molecule over another.

Human disorders that are the result of mutations in mitochondrial DNA include: Leber's optic atrophy, Kearns-Sayre syndrome, MELAS syndrome (mitochondrial myopathy, lactic acidosis, and stroke-like episodes), MERRF syndrome (myoclonus epilepsy and ragged red fibers syndrome), Alpers progressive infantile poliodystrophy, and Leigh subacute necrotizing encephalomyelopathy. Most of these syndromes affect cell types that are especially susceptible to chronically decreased synthesis of ATP, such as skeletal, muscle, heart and brain.

For many of the above conditions, the DNA mutations are known and prenatal diagnosis is theoretically possible. However, because of the presence of heteroplasmy, and the fact that different tissues can be affected to different degrees, predicting severity of disease by prenatal diagnosis can be extremely difficult.

Multifactorial Inheritance

A multifactorial trait is a is a phenotypic characteristic that is caused by the sum of effects from many different genetic and environmental factors. Multifactorial traits can be expressed as "normal" human features, such as variable height, intelligence and skin color, or may result in abnormal disorders and malformations.

Quantitative Traits: caused by the additive effects of many genetic and environmental factors and can be measured on a numerical scale (i.e., height, weight, blood pressure). Tend to follow a normal, or ‘bell-shaped’ distribution in populations.

Threshold Traits: a trait is either present or absent (club foot, diabetes, cleft lip). Here there is thought to be a normal or bell-shaped distribution in the population with respect to liability to a trait, but only those individuals exceeding the threshold on the liability scale will actually exhibit the trait.

Because multifactorial traits are not the result of a single gene defect, they do not follow the patterns of single gene inheritance. Many common human disorders are inherited as so called "complex" traits, implying that more than one gene, and/or a combination of genetic and environmental factors are responsible for the conditions. Examples of complex traits in humans includes: hypertension, asthma, Alzheimer’s disease, autism, diabetes, multiple sclerosis, glaucoma, neural tube defects, club foot, congenital heart disease, cleft lip and/or palate, pyloric stenosis, and schizophrenia. In total frequency, multifactorial disorders are much more common than genetic disorders known to be caused by single genes.

Evidence of a Genetic Contribution to a Disorder Comes from Observations of Familial Aggregation:

  • The disease is more common in biologic relatives (who share a portion of genes) than in spouses (or other family members sharing the environment).
  • Monozygotic twins are more frequently concordant than dizygotic twins.
  • Monozygotic twins reared separately have greater concordance than expected by chance.
  • Adopted children more closely resemble biologic than adoptive parents in disease frequency.

Multifactorial Disorders are Characterized by:

  • Familial concentration without a set pattern of inheritance.
  • Absence of clear biochemical defects resulting from a single abnormal gene
  • Considerable variation in severity and expression of the phenotype.
  • Often sex differences in the frequency of occurrence.

Recurrence risks in multifactorial traits are based upon population and family studies and are called "empiric risks". Risk of occurrence and recurrence is often different for males and females. Recurrence risk is less than in single gene disorders, but is not insignificant. The actual recurrence risks vary substantially for a given disorder, but a good general number to remember is 49.

Rules of Multifactorial Inheritance:

  1. The recurrence risk is higher if more than one family member is affected.
  2. The greater the severity of disease in the proband, the higher the recurrence risk.
  3. The recurrence risk is greater if the proband is of the less commonly affected sex.
  4. The recurrence risk usually decreases rapidly in more remotely related individuals.
  5. The recurrence risk for first-degree relatives is approximately the square root of the population incidence of the trait.