HUMAN GENETICS

for 1st YEAR STUDENTS

he study of inherited Mendelian traits in humans must rely on observations made while working with individual families. Classical cross fertilization breeding experiments as performed by Mendel are not allowed in humans! Human geneticists are not allowed to selectively breed for the traits they wish to study! One of most powerful tools in human genetic studies is pedigree analysis. When human geneticists first began to publish family studies, they used a variety of symbols and conventions. Now there are agreed upon standards for the construction of pedigrees.

Males are always represented by square symbols, females with circular symbols. A line drawn between a square and a circle represents a mating of that male and female. Two lines drawn between a square and a circle indicate a consanguineous mating, the two individuals are related, usually second cousins or closer relatives. When possible, the square should be placed on the left and the circle on the right of the mating line. Generations are connected by a vertical line extending down from the mating line to the next generation. Children of a mating are connected to a horizontal line, called the sibship line, by short vertical lines. The children of a sibship are always listed in order of birth, the oldest being on the left. Sometimes to simplify a pedigree only one parent is shown, the other is omitted. This neither signifies parthenogenic development nor does it signify divinely inspired conception, it merely means the parent left out is not from the family being studied and is genotypically homozygous normal for the trait being studied. Normal individuals are represented by an open square or circle, depending upon the gender, and affected individuals by a solid square or circle. Each generation is numbered to the left of the sibship line with Roman Numerals. Individuals in each generation are numbered sequentially, beginning on the left, with Arabic Numerals. For example the third individual in the second generation would be identified as individual II-3.

For more information on the construction and interpretation of pedigrees consult Gelehrter, Collins, and Ginsburg, 2nd edition, Chapter 3.

The pattern of autosomal dominant inheritance is perhaps the easiest type of Mendelian inheritance to recognize in a pedigree. One dose of the mutant gene, one mutant allele, is all that is required for the expression of the phenotype. There are three reasons why an individual with an autosomal dominant disease should always be considered as being a heterozygote until proven otherwise:

1. The disease is usually rare, with only about 1/10,000 individuals affected as an order of magnitude. To produce a homozygote, two affected heterozygotes would have to mate. This probability is 1/1,000,000 and then they would have only a 1/4 chance of having a homozygous affected offspring. Affected individuals are most likely to come from affected by normal matings. The normal parent is homozygous recessive, thus assuring that each product of the mating has at least one normal gene.
   
   
2. In the extremely rare instances where two affected individuals have mated, the homozygous affected individuals usually are so severely affected they are not compatible with life. The exceptions are the autosomal dominant diseases caused by the somatic expansion of trinucleotide repeat sequences (e.g., Huntington's disease) that we will study later.
   
   
3. The mating of very closely related individuals, the most likely way for two affected individuals to know each other, is forbidden in our society.
   
   

With the understanding that almost all affected individuals are heterozygotes, and that in most matings involving a person with an autosomal dominant trait the other partner will be homozygous normal, there are four hallmarks of autosomal dominant inheritance.

1. Except for new mutations, which are rare in nature and extremely rare on examination pedigrees, and the complexities of incomplete penetrance to be discussed later, every affected individual has an affected biological parent. There is no skipping of generations.
   
   
2. Males and females have an equally likely chance of inheriting the mutant allele and being affected. The recurrence risk of each child of an affected parent is 1/2.
   
   
3. Normal siblings of affected individuals do not transmit the trait to their offspring.
   
   
4. The defective product of the gene is usually a structural protein, not an enzyme. Structural proteins are usually defective when one of the allelic products is nonfunctional; enzymes usually require both allelic products to be nonfunctional to produce a mutant phenotype.
   
   

In 1910, Punnett developed a simple method of depicting the possible genotypes one could get from various matings. We call it the Punnett Square. Its use in predicting the genotypic ratios in the offspring is illustrated below:

Suppose a father is heterozygous for an autosomal dominant gene, with allele D, the mutant dominant allele, and allele d, the recessive normal allele. He can produce two types of gametes, D and d. Suppose also his wife is homozygous normal, having both d alleles. The Punnett Square is constructed as follows:

One gamete comes from each parent to produce the genotype of the offspring. Two out of the four possible combinations are affected; two out of four are normal.

The family represented by Pedigree 1 is a good example of how autosomal dominant diseases appear in a pedigree. Each of the four hallmarks of autosomal dominant inheritance are fulfilled. Each affected individual has an affected parent; there is no skipping of generations. Males and females are equally likely to be affected. About 1/2 of the offspring of an affected individual are affected (the recurrence risk is 1/2). Normal siblings (II-3) of affected individuals have all normal offspring. Low density lipoprotein receptors are structural proteins or polypeptides, not enzymes. If III-1, an affected female, were to produce a child that child would have a 1/2 chance of being normal and a 1/2 chance of being affected. If her normal brother, III-2, were to produce a child that child would have a nearly 0 chance of being affected.

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