Mendelian Inheritance of Human Disease

Question 1

Define the following terms: 
Chromosome
Gene
Locus
Allele

Answer 1

• Chromosome = linear DNA molecule
• Gene = length of DNA which encodes a particular protein
• Locus = position of a gene on a chromosome
• Allele = Alternative forms of a gene

Question 2

How many alleles does a chromosome bear at a given locus ?

Answer 2

Each chromosome bears only a single allele at a given locus

Question 3

Define homozygous and heterozygous.

Answer 3

Homozygous: same allele on both maternal and paternal chromosome of homologous pair

Heterozygous: different allele on maternal and paternal chromosomes of homologous pair

Question 4

What is a genetic disease ? Give examples of genetic changes which can lead to disease.

Answer 4

One caused by a change in the genes

• Chromosome aneuploidies (extra or missing chromosome)
• More subtle chromosome abnormality:
-Extra piece of chromosome
-Missing piece of chromosome
• Change in gene sequence:
-Insertion or deletion of a few bases
-Change of a single base where it matters

Question 5

Identify different kinds of mutations in DNA sequence and state where they have an effect.

Answer 5

1) Promotor and splice site sequence changes: Stop transcription or cause abnormal splicing

2) MISSENSE- Base change causing an amino acid change: Change in protein sequence which may or may not reduce protein function
(Some missense mutations make a protein work faster)
! Not every base change causes disease

3) NON-SENSE- Base change causing a premature stop codon: Causes early cessation of translation
4) Insertion or deletion of bases: May be “in-frame” or “out of frame” (if out of frame, = frameshift mutation)
5) Trinucleotide repeat expansions: replication of a trinucleotide

Question 6

Define Mendelian and non-Mendelian Inheritance.

Answer 6

Mendelian inheritance: A change in a single gene, sufficient to cause clinical disease, is inherited in a fashion predicted by Mendel’s laws

Non-Mendelian Inheritance: Everything else including common “multifactorial” diseases.

Question 7

Identify the main different Mendelian patterns of inheritance.

Answer 7

Autosomal dominant
Autosomal recessive
X-linked
Mitochondrial

Question 8

Describe the main symbols of pedigrees.

Answer 8

Males = Squares
Females = Circles
Miscarriage = Triangle
Affected = Shape filled up 
Unaffected = Shape not filled up 
Dead = Shape striked through

Question 9

What is the percentage of genes shared between first degree relatives ? between second degree relatives ? between third degree relatives ?

Answer 9

FIRST DEGREE RELATIVES (parent, sibling, or child)

• Normal siblings: 50%
• Parents/children: 50%
• Identical twins: 100%

SECOND DEGREE RELATIVES (uncles/aunts, nephews/nieces, grandparents, grandchildren, half-siblings, and double cousins)

• Grandparent/Grandchild: 25%
• Aunt/Uncle and Niece/Nephew: 25%
• Half Siblings: 25%
• Double cousin: 25%

THIRD DEGREE RELATIVES (first-cousins, great-grandparents or great grandchildren)

• First cousins: 12.5%
• Great grandparent/Great child: 12.5%

Question 10

Define autosomal dominant disease.

Answer 10

-If you inherit the abnormal gene from only one parent, you can get the disease
-50% risk of affected child if parent is affected
-Disease severity can be variable
(individuals with a mutation may not show disease)
-Males and females equally likely to be affected

Question 11

Define allelic heterogeneity.

Answer 11

Different mutations in the same gene can cause the same disease

Question 12

Define locus heterogeneity.

Answer 12

The same disease might be caused by mutations in one of several genes

Question 13

What information must you have to do a gene test ?

Answer 13

You need to know approximately where to look

Question 14

Define autosomal recessive disease.

Answer 14

• must inherit abnormal allele from both parents to get disease
• Often only one generation affected
• 1 in 4 risk of an affected child if parents carriers
• Increased likelihood in consanguineous families

Question 15

Which type of inheritance is sickle cell ?

Answer 15

Autosomal recessive

Question 16

Define X-linked inheritance.

Describe what happens if a female carrier and an affected male have children (separately, with unaffected partners).

Answer 16

-a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males (who are necessarily hemizygous -having only one copy of a gene- for the gene mutation because they have one X and one Y chromosome) and in females who are homozygous for the gene mutation

• A female carries a mutation but will not show major features of disease
• For a female carrier:
  – Half of the male children of a carrier will be affected
  – Half of the female children will be carriers
• If an affected male has children
  – All of male children will be normal (no male to male transmission) – All of female children will be carriers

Question 17

Describe Duchenne Muscular Dystrophy.

Answer 17

•  Mild developmental delay
•  Slow to walk
•  Difficulty standing 
•  Unable to run
•  On examination:
–  Hypertrophy of calf muscles 
–  Proximal muscle weakness

• Creatine Kinase 10,000iu

Question 18

Identify some complications to basic pedigree patterns.

Answer 18

1. Nonpenetrance = failure of a genotype to manifest
2. Variable Expression= different family members may show different features of a disorder

• Both seen more often in dominant conditions
• Due to influence of other genes and environment, as well as chance

Question 19

Where, other than the nucleus of cells, is DNA kept ?

Answer 19

In mitochondria

Question 20

Describe the main features of mitochondrial DNA.

Answer 20

• Circular DNA
• 16,559 base pairs
• Many copies (because of many mitochondria) in a cell
• Contains important genes for mitochondrial metabolic pathways and ribosomal RNAs
• Inherited almost exclusively maternally
• Point mutations and deletions occur (possible to have mutations in some copies but not others)

Question 21

Describe the main features of mitochondrial genetic disorders.

Answer 21

• Mitochondrial disorders quite rare
• Maternal transmission only
• Sons and daughters equally affected
• Nerves and muscle are two of the tissues that are most affected by mitochondrial genetic disorders (because both use a lot of energy)