Patterns of Single Gene Inheritance

Question 1

What is the difference between a sex linked and an autosomally inherited DNA mutation?

Answer 1

Sex linked genes are encoded on the X (or the Y) chromosome and are thus conferred together with gender.

Autosomal genes are encoded on one of the numeric chromosomes (1-22)

Question 2

Describe the symbols for the following individuals on a pedigree

Normal Male, Affected Male

Normal Female, Affected Female

Answer 2

Normal male: white square

Affected male: filled in square

Normal female: white circle

Affected female: filled in square

Question 3

What is the difference between an allele and a locus?

Answer 3

Alleles are alternate versions of a gene or DNA sequence at a given locus.

The locus is the position occupied by a gene on a chromosome.

Multiple alleles can exist within the same locus.

Question 4

What does hemizygous mean?

Answer 4

A genotype with a single allele for a given chromosome segment instead of the normal two alleles for a given chromosome segment

Question 5

What is a compound heterozygote?

Answer 5

A genotype with 2 different mutant alleles at one locus

Question 6

What is a polymorphism?

Answer 6

Alternate genotypes present in a population at >1%

Question 7

What is a haploinsufficiency?

Answer 7

When one normal allele is insufficient to compensate for the loss of function of the other

Example: osteogenesis imperfecta

Question 8

What are the pedigree clues that a mutation inheritance pattern is autosomal recessive?

Answer 8

Appears in more than one sibling of the proband, but not parents, offspring or other relatives

Males and females equally affected

Parents are asymptomatic carriers

Parents may be consanguineous

Firsk to each sibling of the proband is 25%

Question 9

What mating pattern leads to a higher than normal prevalence of autosomal recessive disorders?

Answer 9

Consanguinity

When related individuals produce offspring, the risk of their children having autosomal recessive disorders is greatly increased

Question 10

How is the degree of relationship (n) calculated from a pedigree?

Answer 10

The number of uninterrupted line segments connecting two blood relatives in a pedigree chart

Question 11

What is the coefficient of relationship and how is it calculated?

Answer 11

The coefficient of relationship is the proportion of genes two related individuals have in common

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

Question 12

What is the coefficient of inbreeding (F) and how is it calculated?

Answer 12

The proportion of loci at which a person is homozygous by descent

=1/2 x coefficient of relationship = (1/2)⁽ⁿ⁺¹⁾

Question 13

What is the coefficient of relationship for siblings, first cousins, and second cousins?

Answer 13

Siblings: 1/2

First cousins: 1/8

Second cousins: 1/32

Question 14

For a given coefficient of inbreeding, F, of the parents, how can the odds of inheriting a given diseased allele from both parents be calculated?

Answer 14

Risk of both parents passing on diseased gene with inbreeding coefficient F:

= 1/4 x F

Question 15

What is the difference between incomplete dominance and codominance?

Answer 15

In incomplete dominance, the heterozygotes will have a unique phenotype in between the phenotypes of the homozygotes (example: pink rose)

In codominance, contributions from both alleles are visible in the phenotype (as opposed to a half-way point between the two phenotypes)

Question 16

In osteogenesis imperfecta, describe the phenotypic differences between a point mutation in the Pro-alpha1 gene and a haploinsufficiency of the same gene.

Answer 16

A haploinsufficiency will result in a much milder result. Lower than normal amounts of collagen are produced, but the collagen that is produced is fully functional.

If a point mutation in this gene occurs, then the alpha1 chain will be misfolded leading to a severe phenotype with misfolded collagen throughout the body (3/4 chance of mutant collagen formation)

Question 17

How can mosaicism give rise to a dominant disorder in children born from two unaffected parents?

Answer 17

During gametogenesis, a mutation can occur that leads to some cells containing mutant alleles and other alleles containing healthy alleles.

This mutation can be present in the germ line cells of a father, who would be phenotypically normal despite the presence of a dominant disorder in some of his cells.

The father would pass this mutation on to his children, who will all be affected

Example: osteogenesis imperfecta

Question 18

True or false: Penetrance can be expressed as any number between 0 and 1 (or 0-100%)

Answer 18

False

Penetrance is considered an all or none phenomenon

An individual with reduced penetrance will not display the phenotype even though they have the mutant genotype

Question 19

What are some clues from a pedigree that the mode of inheritance of a disease is X-linked recessive?

Answer 19

Affected fathers transmit the disease to their grandsons through their daughters, but not through their sons

All daughters of affected fathers are carriers and have a 50% chance of transmitting the gene to their children

Affected females=carriers; affected males=express disease

Question 20

What are some clues from a pedigree that thet mode of inheritance of a disorder is X-linked dominant?

Answer 20

Affected fathers always transmit the disease on to their daughters, but never their sons

Affected mothers have a 50% chance of transmitting the disease to all their children

Question 21

What are complications to basic pedigree patterns that can impact diagnoses and/or genetic counseling?

Answer 21

New Mutations

Genomic imprinting

Reduced penetrance

Variable expressivity

Phenotypic variability

Delayed onset

Small family size

Question 22

What mode of inheritance causes a parent of origin effect?

Answer 22

Genetic imprinting

Male and female carriers will pass on the disorder differently. If imprinted inactive in males, then offspring of the male will be unaffected (50% chance to be carriers), and offspring of the female will have a 50% chance of being affected

Question 23

Describe the factors that define the inheritance of mitochrondrial DNA.

Answer 23

1) Mitochondrial DNA can be heteroplasmic: more than one type of mitochondrial DNA may be present in cells from a single individual
2) Mitochondrial DNA is inherited maternally. A small and 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