Patterns of Single Gene Inheritance

Question 1

Genotype

Answer 1

genetic constitution of an individual or locus

Question 2

phenotype

Answer 2

outward characteristics of an individual or gene product

Question 3

Allele

Answer 3

One of both versions of a gene or DNA sequence at a given locus

Question 4

Locus

Answer 4

Position occupied by a gene on a chromosome

Question 5

Homozygote

Answer 5

Genotype will identical alleles at a given locus

Question 6

Hemizygous

Answer 6

Genotype with a single allele for a given chromosome segment. Males are hemizygous for X.

Question 7

Heterozygote

Answer 7

Genotype with different alleles at a given locus

Question 8

Compound Heterozygote

Answer 8

genotype with 2 different mutant alleles at one locus

Question 9

Polymorphism

Answer 9

alternate genotypes present in population greater than 1%

Question 10

Penetrance

Answer 10

The proportion of mutant individuals manifesting disease. It is an All or None effect.

Question 11

Expressivity

Answer 11

The extent to which a mutation exhibits a phenotype. The extent to which the disease manifests itself.

Question 12

Carriers

Answer 12

Have a single mutant allele that is obscured by the normal copy

Question 13

Genetic Heterogeneity

Answer 13

Can result from different mutations at 1 locus (allelic), or from mutations at different loci. It is where different genes contribute to the same disease or phenotype such as height.

Question 14

Phenotypic Heterogeneity

Answer 14

Occurs when the same mutations manifests itself differently among individuals.

Question 15

Sex-Linked

Answer 15

encoded on the X-chromosome (or Y-chromosome) thus conferred together with gender.

Question 16

Autosomal

Answer 16

encoded on the autosomes or the numerical chromosomes, all chromosomes but X and Y

Question 17

Recessive

Answer 17

Both alleles must be affected for the trait to be displayed

Question 18

Dominant

Answer 18

A single mutant allele confers a phenotype

Question 19

Recessive Inheritance Patterns

Answer 19

For single gene disorders, a phenotype is considered recessive if it manifests itself in the homozygotes. Needs two copies of the recessive allele to manifest disease. Individuals carry 1-5 recessive alleles that are lethal in homozygotes. Recessive disorders often display a clustering of disease among siblings and is absent among ancestors, although consanguinity may be present. Both parents are carriers and the recurrence risk for siblings is 1 in 4. Unaffected siblings of the proband have a 2/3 chance of being a carrier. Males and females are equally affected and parents are asymptomatic carriers. These seem to come out of no where!

Question 20

Dominance Inheritance Patterns

Answer 20

A characteristic is dominant if it manifests itself in the heterozygote. If the disease is not lethal, the disease phenotype is usually seen in every generation. A child of an affected parent has a 1/2 chance of being affected. Males and females are usually equally affected.

Question 21

Codominance

Answer 21

Both alleles, the dominant and recessive allele, are expressed equally in the heterozygote. This is seen with A and B blood type to get type AB

Question 22

Incomplete Dominance

Answer 22

Get an in-between in the heterozygote. It is not red, not white, but pink. Each cell expresses half, not one or the other. The dominant allele is not quite as dominant as we think.

Question 23

Haploinsufficiency

Answer 23

The single normal copy produces an insufficient quantity of the normal gene product for the requirements of the organism. An example is Familial Hypercholesterolemia in which now only 50% of the normal LDL receptor is present and this level is not enough to maintain blood cholesterol levels in the normal range.

Question 24

4 things determine that a mutant allele is dominant

Answer 24

1) The single normal copy produces an insufficient quantity of the normal gene product for the requirements of the organism (haploinsufficiency)
2) The product of the inactive mutant gene interferes with the function of the normal gene product (dominant negative effect)
3) The product of the mutant gene acquires a new or enhanced function (simple gain of function)
4) The affected gene is a tumor suppressor resulting in predisposition to cancer that is inherited as a dominant trait because even a single cell losing the function of the other allele by mutation is enough to cause cancer.

Question 25

Identify the percent of alleles related individuals have in common or the coefficient of relationship =

Answer 25

(1/2)^n where n is the degree of relationship

Question 26

Calculate the probability of inherited disease in a child from consanguineous parents

Answer 26

When two related individuals mate, there is a probability that a child will receive both alleles for a particular gene from the same ancestor, one descending through the mother and one through the father. This probability is called the Coefficient of Inbreeding (F). It is also the proportion of loci at which a person is identical by decent.

F (coefficient of inbreeding) = 1/2 * Coefficient of relationship

Question 27

Consanguinity

Answer 27

It is the relationship that results from common ancestry. It increases the chance that both parents are carriers of the same mutant allele from a common ancestor.

Question 28

X-linked Recessive Inheritance Patterns

Answer 28

The incidence of the trait is much higher in males than females because they only have one X. Heterozygous females are usually unaffected but males do not have an extra X chromosome to compensate for the mutation. The trait is usually transmitted from an affected male to 50% of his grandsons through his daughters. Males never transmit the disease directly to their sons because they pass on a Y to their sons.

Question 29

Reduced Penetrance

Answer 29

An individual may not have the disease although they have the bad allele. When they have a kid, they can pass this gene on.

Question 30

X-linked Dominant Inheritance Patterns

Answer 30

This is very rare. Affected females have a 50% chance of passing it on to sons and daughters if they are heterozygous. It is more frequent among females. Affected fathers ALWAYS pass the trait on to their daughter but not their sons. Affected females usually have a milder phenotype because they can be heterozygous.

Question 31

Somatic Mosaicism

Answer 31

When a mutation occurs in the course of development only that part of the body derived from the mutant cell may ultimately be affected

Question 32

Germline Mosaicism

Answer 32

When a mutation affects germ cells, the parents may be negligibly affected but multiple offspring will exhibit a severe form of the disease. X-inactivation can lead to Duchenne’s Muscular Dystrophy

Question 33

Describe genomic imprinting and inheritance of Prader-Willi and Angelman Syndromes

Answer 33

Genomic imprinting is when a certain sex silences genes while another keeps it active. Thus, if the parent passes on the disease in the chromosome that is affected and not silenced, then we can get disease because there is not a second allele to make up for it. These two result from a micro-deletion in the q-arm of chromosome 15 (15q11-q13). In a pedigree for these, for a defective genes imprinted active in the female during oogenesis, affected and carrier females should always produce children in which 1/2 are affected. Males, affected and carriers, should always produce children in which 1/2 are carriers. For defective genes imprinted active in males, the opposite results would be expected.

Question 34

Understand how triplet repeat disorders, dynamic mutations and anticipation are related

Answer 34

In diseases such as huntington’s disease the parents have less repeats than the offspring will because when the DNA is replicated, the polymerase will skip and create even more repeats. Once a certain threshold of triple repeats is met, the disease will start to manifest itself. It is dynamic mutation because it is not a mutation of one gene, rather it is the changing number of triple repeats in the next generation. This thus leads to anticipation because the next generation will have even more repeats and thus more severe expression of the disease and earlier onset.

Question 35

Explain replicative segregation, heteroplasty and maternal inheritance of mitochondria

Answer 35

Cells contain about 1,000 mitochondrial DNA molecules at several copies per mitochondrion. Every mitochondrial DNA molecule contains 37 genes of which 22 are tRNA genes. Nuclear and mitochondrial DNA are NOT interchangeable; several triplets translate into different amino acids or stop codons. The mature oocyte contains 100-fold more copies of mitochondrial DNA than the sperm and thus mitochondrial DNA is maternally inherited, as are mitochondrial diseases. Replicative segregation is the distribution of the mitochondrial DNA among daughter cells. It is a random event and disease is only passed on if the proportion of diseased mitochondrial DNA reach a certain threshold. THREE factors define the inheritance of mitochondrial diseases:

1) Mitochondrial DNA can be heteroplamic meaning that more than one type of mitochondrial DNA may be present in cells from a single individual. Mom can pass on many types of DNA and it has to reach a mutant threshold to manifest disease.
2) Mitochondrial DNA is inherited maternally. A small random sample of mitochondrial DNA is selected for inclusion in the oocyte during oogenesis
3) Mitochondrial DNA undergoes random segregation through multiple rounds of mitosis during embryogenesis. The mutant DNA may or may not be present is offspring depending on how much mutant DNA the offspring received.

Different offspring may inherit a a different, random sample of mutant mitochondrial DNA from there mom and thus could manifest the disease differently. If a male is affected, the disease turns into a dead end because he does not pass it on. On the pedigree an affected female passes it on significantly to her offspring where a male doesn’t pass it on at all.

Question 36

Some Complications to pedigree patterns that may affect counseling and/or diagnosis

Answer 36

1) New mutations- especially for autosomal dominant disorders.
2) Genomic imprinting- different phenotypes depending on the parental source of the mutation
3) Reduced penetrance- not all patients with the disease genotype express symptoms
4) Variable expressivity- The severity of the disease differs in patients with the same genotype
5) Phenotypic variability- disorders that affect multiple organs can produce different symptoms in related family members (pleiotropy) due to effects of environment or other genes
6) Delayed onset- e.g. triple repeat expansion disorders such as huntingtons disease, myotonic dystrophy, etc.
7) Small family size- limited pedigree information on which to base counseling recommendations