What are the characteristics of mitochondrial diseases?
- Mutations of oxidation/phosphorylation
- Most serious in CNS and muscle
- Commonly include: neuropathies, encephalopathies, myopathies
- Full mitochondrial function is linked to nuclear genes
- Progressive w/ late onset
- Defects of mitochondrial function may show autosomal, X-linked, OR matrilineal pattern of inheritance
What is matrilineal inheritance?
The sperm head generally only has room for the haploid nucleus, while the egg is much larger and contributes both cytoplasm and nucleus to the zygote. Mitochondria are usually found only in the egg, so they are transmitted from the mother to her children: matrilineally.
All children of a mother affected with a mitochondrial disorder will most likely also be affected with that disorder. No children of affected males are expected to be affected with that disorder.
What is homoplasmy?
Homozygosity for one or more cytoplasmic genes;
usually refers to a population of mitochondria that all have the same genetic composition.
All children of a homoplasmic mother should inherit the same mitochondria, so any variation between the children or between the children and their mother would arise by new mutation.
What is heteroplasmy?
Two or more different populations of mitochondria are present in a cell. Analogous to heterozygosity in the nucleus.
- A heteroplasmic mother may be unaffected and yet have affected children if the mother has a low frequency of mutant cells but passes higher frequencies on to her children.
- If the mother is heteroplasmic and affected, she may pass a low frequency of mutant mitochondria to her children, who would be unaffected.
- Thus, within families, there may be a difference in the expression of the same disease. In general, the more mutant mitochondria that are present, the more severe the disease.
What is replicative segregation?
As cells divide, the relative proportions of mutant mitochondria may change over time. The frequency of mutation within a clone can increase or decrease. If an individual had a low, non-pathogenic frequency initially, it is possible that as s/he gets older, the disease may manifest due to the growing population of “defective” mitochondria that did not previously exist.
Because there is a high mutation rate in mitochondrial DNA, it is possible for an acquired mutation to proliferate in the population, again generating a subpopulation of mutant mitochondria. Because these mutations occur in the somatic cells, they would not be transmitted to progeny.
These mechanisms also predict that, under certain conditions, mutations may be lost from the cell population.
What are some applications of DNA technologies used in forensic DNA analysis?
DNA fingerprinting (nuclear DNA): look for sequence w/ high degree of polymorphism, usu. minisatellite regions; differentiate btwn identical and fraternal twins
Mitochondrial DNA analysis: siblings and maternal relatives carry the same mitochondrial DNA (family identity, not individual identity)
Paternity testing: include or exclude a putative father (familial allele freq. differs from population freq.), minimum of 2 probes
Criminal justice: exclusion/inclusion of suspects, can link multiple events, possible post-conviction relief
What is the evidence for personalized medicine?
- Drug therapy
- Idiopathic disease
- Cancer diagnosis, prognosis, treatment
- Prenatal testing and newborn screening
What are pharmacogenetics and pharmacogenomics?
Pharmacogenetics is the study of genes and their alleles in relationship to drug response in a given patient. Relates heritable variation to inter-individual variation in drug response.
Pharmacogenomics is the study of genes related to drug metabolism, and the use of this knowledge to develop new, targeted drugs.
Genetic variability can influence how quickly a drug is metabolized, how well a drug works, or even the likelihood of side effects.
How does the number of functional CYP2D6 alleles affect an individual's ability to metabolize certain drugs?
0 copies of functional allele → poor metabolizer: lacks ability to perform appropriate conversions → accum. of chemicals in the body → toxicity
1 copy of functional allele → intermediate metabolizer: heterozygotes will convert drugs slowly → either insufficient drug for desired activity, OR toxic accum. of precursor compounds
2 copies of functional allele → extensive metabolizer: normal
2+ copies of functional allele → ultra metabolizer: either degrades drug so rapidly that it is eliminated before therapeutic levels can be reached, or rapid conversion of inactive form → drug overdose
What are some examples of assisted reproductive technologies (ARTs)?
In vitro fertilization (IVF): eggs retrieved from female → mixed in vitro w/ partner’s sperm → fertilization → embryos tested → appropriate ones implanted back into woman’s uterus
Intracytoplasmic sperm insertion (ICSI): single sperm injected into an egg, embryos implanted into the female. Helpful for males with a low sperm count
Zygote intrafallopian transfer (ZIFT): in vitro fertilized eggs transferred back to the fallopian tubes
Donor egg (e.g., for individuals w/ Turner syndrome, mitochondrial mutations)
Polar body analysis: allows for embryo selection when one or both partners carry a gene mutation → IVF
Preimplantation genetic diagnosis (PGD): screening technique for embryos at 8-cell stage (difficult ethics considerations)
What are the 3 types of population screening?
What are the principles of newborn screening?
Disease: clearly defined and treatable, reasonably high population incidence
Test: large-scale, rapid, inexpensive, low false positives, no false negatives
Follow-up: definitive diagnosis, prompt treatment, genetic counseling
What are the principles of carrier screening?
- Mutation must be in a reasonably high frequency in population
- Test must be suitable for mass screening
- Genetic counseling available to explain the results to the families
- Prenatal testing available so that when carrier couples are identified it is possible to determine when a pregnancy will result in an affected child
What are some of the most common, ethnic group-related diseases tested for in carrier screening?
Ashkenazi Jewish: Tay Sachs disease, cystic fibrosis, Gauchers disease, Canavan disease, Niemann-Pick disease
African-American: sickle cell anemia
What is the Genetic Information Nondiscrimination Act (GINA)?
A federal law that prohibits discrimination in health coverage and employment based on genetic information. Provides a baseline level of protection for all Americans.
If more protective state laws are in place, they will supersede this federal law.
- Prohibit insurers or health plan administrators from using genetic information in decisions about coverage or rates
- Prohibit employers from using genetic information for hiring, firing or promotion decisions
GINA does not:
- Cover life, disability, or long-term care insurance
- Does not apply to businesses with fewer than 15 employees
- Does not prohibit a health insurer from determining eligibility or premium rates based on the presence of a disease