Human Monogenic Traits

1. Why can't human genetics be represented the way we set up Mendel's laws for peas?
   • We do not have populations of humans that are purebred like commercial peas.
   • A pea plant may produce hundreds of peas. Today humans usually produce two children.
   • You can mate any pea plant to any other pea plant. Humans either select their own mates or very strict cultural rules determine who marries whom.

2. How then do we represent human traits for breeding analysis?
   • We use a pedigree which we construct from a family history.
   • In a family history we ask questions about a trait that may or may not run in a family and try to include as many relatives as is feasible (usually three generations).
   • In a pedigree we use symbols to diagram the relation among the family members. These include a square for males; a circle for females; and a filled in square or circle for an affected individual (one who shows some unusual trait).

3. Do Mendel's rules apply to pedigrees?
   • Yes, and we can represent the genotypes and phenotypes the same way. The major difference is in the P1 which does not deal with the parents of purebred lines but just some particular generation of interest to us (like the parents of a child who is an albino or who is an achondroplastic dwarf).
   • A second difference is our assumptions. In a cross of peas involving yellow x green we assume the packet of seeds we use comes from a purebred strain (i.e., that it is homozygous gg for green peas or GG for yellow peas). In a human we cannot assume the homozygosity of any genotype; we have to work it out from analysis of one or more pedigrees for that trait.

4. What types of monogenic traits are in humans?
   • There are 70,000 to 100,000 genes in a human genome.
   • A human genome is the collection of all genes in all chromosomes present in an egg or sperm.
   • Of these, about 5000 have been identified and associated with clinical disorders.
   • Monogenic traits may be recessive or dominant depending on their function in the human life cycle.
   • In general recessive disorders represent a loss of a normal function.
   • In general dominant disorders represent a developmental defect in gene expression (they tend to mess up the way the embryo forms).

5. How do recessive disorders work in humans?
   • With rare exceptions, the two parents of a child with a homozygous recessive disorder are both normal in appearance. The two parents are each heterozygous. Thus the parental generation for the normal parents giving rise to a child who is an albino would be represented as:
     P1 Aa x Aa

   • Mendel's law of segregation predicts a 3 to 1 phenotypic ratio of 3 normal to one albino offspring from such a cross.
   • We can use a standard Punnett square to demonstrate this:

     		for the sperm
     		0.50 A	0.50 a
     for the eggs	0.50 A	0.25 AA	0.25 Aa
     	0.50 a	0.25 Aa	0.25 aa

   • Thus the F1 or offspring for each pregnancy will be 1 in 4 at risk of being an albino [having the aa genotype]

6. Why are two parents usually both normal for a child with a recessive trait?
   • Most of us are carriers (heterozygous) for one or more traits that are harmful but we do not know this. Whatever choice we make for a mate we rarely know that person's genotype for harmful recessive genes that we ourselves might carry.
   • In the population we live in, for every person with an expressed homozygous recessive disorder there are about 20 to 100 people who carry that gene in the heterozygous state and are unaware that they do so.
   • Many recessive disorders impair life and persons who die young or who live with chronic disabilities or health problems are unlikely to get married or have children.

7. So what are the risks when we do become parents?
   • For most of these 5000 known disorders, the risks are individually rare, about 1 in 1000 to 1 in one million of having a child with a disorder. Among those where it is higher (about 1 in 1000) are cystic fibrosis (mostly among white people), sickle cell anemia or albinism (mostly among black people), Tay Sachs syndrome or Gaucher syndrome (mostly among Ashkenazic Jewish people).
   • Many are ethnic disorders because the gene frequency is higher in those populations than in the rest of the world. It is human evolution that leads to differences in gene frequency because humans do not breed randomly.
   • Cousins who get married and have children are also at higher risk because they have a common grandparent who might have carried one of these 5000 different mutant genes and passed it on to both first cousins. The risk then shifts to 1 in 64 for the child of first cousins expressing that grandparent's heterozygous mutant gene.

8. If I have a sibling with a recessive disorder, what are my risks?
   • Since you do not have the defect expressed, you are one of the three types of normal fertilizations, two of which are heterozygous like your parents and one of which is homozygous normal. Hence your risks as a normal sibling are 2 out of 3 (67%) of being a carrier and 33% of being homozygous for the normal allele.

9. What about my chances of having a child with the disorder?
   • If only 1 in 50 people are carriers your odds would be relatively good for having normal offspring. In a genetics course you would learn to work out the odds, which are 1 in 300 of having a child with the disorder your sibling has. Most people go to a genetic counselor to do that for them (even their physicians are not good at this and they refer their clients to go to a genetic counselor who specializes in this).

10. How are dominant traits inherited?
    • For one thing, if we use Huntington disease as a typical example, they are almost always of the P1 genotypes:
      P1 Hh x hh

      where H is the allele for Huntington disease and h is the normal allele.

    • That's because it is very rare for a person with some medical disorder to marry a person with the same medical disorder. More often a person with a rare dominant disorder marries a person who does not have that disorder.
    • And that in turn is because most dominant disorders are very rare in the population (about 1 in 25,000 people).
    • If we look at the P1 cross, the heterozygous individual expresses the dominant trait. Thus this person produces two types of gametes, half with the dominant allele H and half without it and thus of h genotype in the haploid condition.
    • The other parent is homozygous normal, so all those gametes are h.
    • This gives us .50 fertilizations are Hh and .50 fertilizations are hh. We say the odds are 50% that a person with a dominant trait passes on the defect to a child.

11. You mean there aren't any homozygous dominant persons around for genetic disorders?
    • Just about. It's rare for two people with a dominant disorder to have children and it is rare for the homozygous dominant disorder to live past infancy. Most mutations are lethal (they kill mostly at the embryonic stage and abort) and we don't see homozygous recessive lethals or homozygous dominant traits that in the homozygous state act as lethals.

12. Why don't all dominant traits die out if they are so bad for the individual?
    • Most dominant disorders persist for only a few generations and do die out. They are replaced by new mutations. Most normal genes mutate with a frequency of 1 in 100,000 to 1 in a million to produce a new dominant mutation. When you have 200 million people that can lead to several hundred or a few thousand new cases per generation.

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