Human Genetics: Inherited Disorders
and Exceptions to Mendel's Rules
April 5, 2004
"Heredity provides for the modification of its own machinery" --James Mark Baldwin, 1896
I Review: Genetically Inherited Human Disorders:
1. 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)
A.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.
B.Tay-Sachs: Enzyme that breaks down brain lipids is non-functional in homozygous recessives (tt). Buildup of lipids causes death by age 2-3. People with Ashkenazi Jewish ancestry are often carriers fro this trait.
C. 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 offers protection against another disease. Examples:
- Sickle cell disease: Ss carriers are resistant to malaria (note: 1:10, or 10% Africans 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. Research still needs to be done on this.
- LEFT: Recessive inheritance; RIGHT: Dominant inheritance
2. 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.
A. 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)..
B. Polydactyly (extra fingers or toes): PP or Pp = extra digits, aa = 5 digits. 98% of all people in the world are homozygous recessive (pp).
C. Progeria (very premature aging): Spontaneous mutation of one gene creates a dominant mutation that rapidly accelerates aging
D. 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.
E. Marfan's syndrome - individuals have defects in skeletal system, eyes, and cardiovascular system. All these defects are due to one underlying defect - the body's ability to make connective tissue - one defect has widespread implications in the body.
These diseases are DOMINANT diseases: The person will show the disease even if they have only ONE domainant allele! In this case, if one parent has the trait, the offspring will have a 50% chance of inhetiting the trait. If BOTH parents hace the trait, there is a 75% chance that their offspring will inherit the trait. (genetics problems)
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).
- If we have time, we will do a bit of pedigree analysis in class!
Do Mendel's Laws Always Apply?
We know today that there are many exceptions to Mendel's laws (ie not every gene has alleles that are strictly dominant or recessive). Does this mean that Mendel was "wrong"? NO, it means that we know more today about disesase, genes, and heredity than we did 150 years ago! Four of the most common exceptionss (we will work problems only with Blood Types):
II. Incomplete dominance / Codominance: (example: blood type)
One example of a three-allele gene: the ABO blood types of humans: In this case BOTH the IA (A) and IB (B) gene are dominant and are expressed in the phenotype. The recessive gene i is only seen in the phenotype (Type O) if the parents are heterozygotes or are Type O themselves.
Note that the IA and IB alleles two alleles are both dominant to i - but one isn't dominant over another. This is called Incomplete Dominance or Codominance
Real life question: Kathy and Jim both have type A blood. Their daughter Julia has type O blood.
(a) What blood type alleles do both Kathy and Jim have?? ________________
(b) Their son Ian has never had his blood typed. What are the possible blood type alleles he might have? ____________________
Knowing blood types of the parents and the baby can aid in paternity suits. (Worksheet)
III. Continuous Variation: Mendel studied "either-or" traits (purple vs white), but many characters such as human height and skin color vary as a continuum in populations (bell shaped curve)
1. Modifier genes: (example: eye color) Eye color is not a simple trait controlled by different alleles of one gene. Rather, eye color in controlled by at least 3 genes: EYCL, the Green/blue eye color gene (probably located on chromosome 19); EYCL2, the central brown eye color gene (possibly located on chromosome 15), and EYCL3 , the Brown/blue eye color gene located on chromosome 15. These three genes contribute to the typical patterns of inheritance of brown, green, and blue eye colors
For EYCL3, B = brown or b = blue eyes. However, grey eye color, hazel eye color, and multiple shades of blue, brown, green, and grey come from the ccombined action of all three genes PLUS the action of modifier genes that control how much pigment is deposited in the iris of the eye.
Cool eye color website : predict your kid's eye colors! (just for fun).
More info: Eye color at birth is often blue, and later turns to a darker color. Why eye color can change after birth not known (it is most likely due to changes in gene expression, but why?!) An additional gene for green is also postulated, and there are reports of blue eyed parents producing brown eyed children, which the three known genes can't easily explain. Mutations, modifier genes that supress brown, and additional brown genes are all potential explanations....so don't get worried if your eye color doesn't seem to fit with the rest of your family!!!
2. Polygenic Inheritance: (example: human height) more than one gene controls a particular phenotype
In polygenic inheritance, more than one gene controls a particular phenotype. ie skin color is thought to be controlled by 3 alleles (A, B, C).
A person with the alleles AABBCC is very dark skinned, a person with aabbcc alleles is very light skinned, and a person with AaBbCc (or any combo) has an intermediate skin color.
Different "units" produce different shades (AAbbCc, aaBbcC, etc...)
Just added Monday, April 5: Study advances insight into autism's genetic hot spots
Many human disorders like Autism and Schizophrenia are multi-factorial - they are not 'caused' by one dominant or recessive gene, but may be the result of several inherited genetic susceptibilities PLUS environmental factors.
Example: Autism: usually shows itself in infancy or toddlerhood as a social withdrawl disorder. There are at least 4 genes linked to this neurodevelopmental condition, particularly on Chromosomes 2, 3, 7, 15, and X. Some of these genes have to do with language development, some with brain development, some with producing brain neurotranmitters. While knowledge of the genetics behind these conditions may not result in a direct treatment, finding out about the genes involved in these conditions may allow for earlier diagnosis, targeted therapies or drug development based on the knowledge of the gene's function. Read more at exploringautism.org
Example: Schizophrenia: usually shows itself in adolescence, characterized by a person's inability to determine what is real and what is not (delusions, hallucinations, etc). There are several genes linked to the development of this disorder, including Chromosome 22 plus a combination of family genetics and environmental factors. Read more at the Mayo Clinic's Schizophrenia site
March 2004: Interesting article on genetics and environment in many Personality Disorders (PDs)