Genetically Inherited Human Disorders
March 26, 2001
Readings: Web notes only! Visit some of the links if you are interested, but you do not need to do so.
So far, we have talked about recessively inherited conditions (#1 below), where the affected child receices two recessive alleles. However, there are other types of genetic disorders:
I. Autosomal recessive disorders: Show up only in the homozygous recessive person (aa) who inherits a recessive allele from both parents, who were carriers (Aa xAa). (25% chance of this happening)
1. Cystic fibrosis: Homozygous recessives (cc) have cystic fibrosis - body cannot make needed chloride channel, high concentrations of extracellular chloride causes mucous to build up, infections, pneumonia. Diet, antibiotics and treatment can extend life to 25 years or more.
2. Tay-Sachs: Enzyme that breaks down brain lipids is non-functional in homozygous recessives (tt). Buildup of lipids causes death by age 2-3.
3. Sickle-cell disease: The most common inherited disease of African-Americans (1:400 affected). Homozygous recessives (ss) make abnormal form of hemoglobin that deforms red blood cells and causes a cascade of symptoms (clogging of blood vessels, organ damage, kidney failure).
Heterozygote advantage: For some disease alleles, being a heterozygote is thought to offer protection against another disease, and there has a selective benefit. Examples:
- Sickle Cell Disease: Ss carriers are resistant to malaria (note: 1:10, or 10% African-Americans are carriers Ss)
- Cystic fibrosis: Cc carriers are resistant to cholera (note: 1:25, or 4% of caucasians is a carrier Aa).
- Tay-Sachs?: Tt carriers are thought to be more resistant to tuberculosis, although there is not a lot of evidence in support of this hypothesis
II. Autosomal dominant disorders: child will show the phenotype if he / she receives just 1 allele from either parent. With just 1 parent affected, 50% chance of offspring being affected.
1. Achondroplasia (dwarfism): AA = Homozygous dominant is lethal - fatal (spontaneous abortion of fetus). Aa = dwarfism. aa = no dwarfism. 99.96% of all people in the world are homozygous recessive (aa)..
2. Polydactyly (extra fingers or toes): PP or Pp = extra digits, aa = 5 digits. 98% of all people in the world are homozygous recessive (pp).
3. Progeria (very premature aging): Spontaneous mutation of one gene creates a dominant mutation that rapidly accelerates aging.
4. Huntington's chorea is also a lethal dominant condition (HH = fatal) but homozygous dominant (Hh) people live to be ~40 or so, then their nervous system starts to degenerate. Woody Guthrie died of Huntington's.
The genetic locus for Huntington's has been pinpointed to the tip of chromosome 4 - there is now a test for Huntington's - if you were from a Huntington's family, would you want to know?
Genetics problems (worksheet)
III. Sex-linked disorders in humans: Sex chromosomes not only determine sex, they also have genes for many functions.
1. Color blindness
- XA = normal vision
- Xa = color blind
The possible genotypes and phenotypes of males and females are:
- XA Y = a male with normal vision
- Xa Y = a male with color blindness (red in figure, color blind)
- XA XA = female with normal vision
- XA Xa = a carrier female with normal color vision (red in figure)
- Xa Xa = a female who is color blind (only if mom is carrier and dad is color blind)
Because daughters have two X chromosomes, they are almost always unaffected (heterozygotes). The normal allele "masks" the mutated allele. Color blind females are rare because they must inherit two recessive alleles for color blindness.
Males show the trait much more often than females do because they only inherit one allele - from their mother - if that one is mutated, they will be color blind.
2. Duchenne muscular dystrophy: affects 1:3500 males in the US. Progressive weakening of the muscles and loss of coordination leads to death in early adulthood. Children with muscular dystrophy lack a key muscle protein named dystrophin; the gene for the dystrophin protein is on the X chromosome. Thus, any mother who is a carrier for muscular dystrophy will have a 50:50 chance giving birth to a son with muscular dystrophy and a 50:50 chance of giving birth to a daughter who is a carrier.
3. Hemophilia: sex-linked recessive trait. Affected children lack the blood clotting factor VIII. Even a minor cut or scratch can cause a person with hemophilia to bleed to death. Queen Victoria was a carrier; thus her sons had a 50% chance of being affected and her daughters had a 50% chance of being carriers (Pedigree of the Royal Family).
Genetics problems (worksheet)
VII. Testing for Genetic Disorders: What is genetic testing? Analysis of genes or gene products (enzymes and proteins) to determine whether a person has a particular genetic condition.
Currently available DNA-based gene tests
How can prospective parents determine whether their child will be affected and how best to optimize outcome?
1. Carrier Screening: Tests the prospective parents with a family history of a genetic disease to determine whether they are carriers (heterozygotes), and possibly to whether their offspring have recessive mutations (examples: CF, Tay-Sachs, MCAD) .
2. Prenatal testing: Tests the fetus - Genetic disorders can be determined before birth, giving the parents time to adjust to their child's condition and make informed decisions.
- Amniocentesis: cells in amniotic fluid are cultured for 2 weeks and DNA karyotyped. Can clearly detect various chromosomal abnormalities (Trisomy 21, trisomy 18).
- FISH: Specific fluorescent DNA "probes" can directly identify genetic disorders, results within 24 hours.
- Chemicals present in amniotic fluid are diagnostic of Tay-Sachs, anencephaly, spina bifida.
- CVS: chorionic villi sampling - small amount of placental tissue removed - results are available within a few days
- Pre-implantation screening: One cell can be removed from an IVF blastocyst at the 8-cell stage or beyond to test for genetic disorders. A decision can then be made about implantation of particular eggs.
3. Newborn Screening:: Tests the newborn for genetic disorders .
- Example PKU (phenylketonuria) recessively inhertied 1:10,000 births. Children can't break down Phe, converted to toxic by-product that causes retardation.
- If PKU test (done in hospital) detects deficiency, a low-Phe diet must be maintained for life. (See warning on Nutrasweet-containing products).
- Thus, PKU is a treatable disorder if caught early enough. All newborns in the US are screened for PKU.
Newborn Screening in Indiana
Expanded Newborn Screening
4. Pre-symptomatic testing: for risk of late-onset disorders like Huntingtons, cancer, and Alzheimer's
IV. Human Genetic Analysis: Pedigree analysis:
Peas: good for genetic research. Humans: not..! Very difficult to do "controlled matings"!
Human geneticists must analyze the results of matings that have already occurred. The family's medical history can be traced by pedigree analysis.
Helps to understand the past and predict the future. (Worksheet on pedigree analysis)
1. Describe and diagram the inheritance of an autosomal