The genetic basis of complex inheritance

Question 1

Give some examples of non-mendelian inheritance

Answer 1

o	Gene conversion
o	Intermediate phenotypes
o	Extranucleur inheritance
o	Genomic imprinting
o	Mosaicism

Question 2

Define non-mendelian inheritance?

Answer 2

Non-Mendelian inheritance is a general term that refers to any pattern of inheritance in which traits do not segregate in accordance with Mendel’s laws. These laws describe the inheritance of traits linked to single genes on chromosomes in the nucleus

Question 3

What are the three laws of mendelian inheritance?

Answer 3

o The Law of Segregation – states that allele pairs separate during gamete formation, and randomly unite during fertilisation
o The Law of Independent Assortment – when two or more characteristics are inherited, individual hereditary factors assort independently during gamete production, giving different traits an equal opportunity of occurring together.
o The Law of Dominance – 3rd law, states that one factor of pair of inherited traits will be dominant and the other recessive

Question 4

What is the first law of mendelian inheritance?

Answer 4

The Law of Segregation – states that allele pairs separate during gamete formation, and randomly unite during fertilisation

Question 5

What is the second law of mendelian inheritance?

Answer 5

The Law of Independent Assortment – when two or more characteristics are inherited, individual hereditary factors assort independently during gamete production, giving different traits an equal opportunity of occurring together.

Question 6

What is the third law of mendelian inheritance?

Answer 6

The Law of Dominance – 3rd law, states that one factor of pair of inherited traits will be dominant and the other recessive

Question 7

Define penetrance

Answer 7

Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (allele or genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. Penetrance can be full, partial, incomplete or low.

Question 8

What is incomplete penetrance?

Answer 8

Incomplete penetrance or reduced penetrance - Penetrance is said to be reduced or incomplete when some individuals fail to express the trait, even though they carry the allele e.g. BRCA related breast cancer, 80%

Question 9

Describe cystic fibrosis

Answer 9

• Cystic fibrosis (CF) is a genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in males, among others. Different people may have different degrees of symptoms.
o CF is inherited in an autosomal recessive manner. It is caused by the presence of mutations in both copies of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Those with a single working copy are carriers and otherwise mostly normal. CFTR is involved in production of sweat, digestive fluids, and mucus. When CFTR is not functional, secretions that are usually thin instead become thick.

Question 10

Describe the prevalence of CF in different ethnic populations

Answer 10

o European Caucasians: 1 in 2,500 (4% carrier)
o Africans: 1 in 13,000
o Asians: rare

Question 11

What are genetic modifiers?

Answer 11

Genetic modifiers: genes that have small quantitative effects on the level of expression of another gene. May involve polymorphism.

Question 12

What is the CF phenotype dependent on?

Answer 12

Severity of mutation
Affected organs
Genetic modifiers
Environmental factors

Question 13

What is genomic imprinting?

Answer 13

Genomic imprinting is the epigenetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. If the allele inherited from the father is imprinted, it is thereby silenced, and only the allele from the mother is expressed. If the allele from the mother is imprinted, then only the allele from the father is expressed

Question 14

What causes genomic imprinting?

Answer 14

Genomic imprinting is an inheritance process independent of the classical Mendelian inheritance. It is an epigenetic process that involves DNA methylation and histone methylation without altering the genetic sequence.

Question 15

Are the results of genomic imprinting passed on to future generations?

Answer 15

These epigenetic marks are established (“imprinted”) in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism

Question 16

What are epigenetic modifications?

Answer 16

Heritable changes in gene function that cannot be explained by changes in DNA sequences

Question 17

How can DNA be epigenetically modified?

Answer 17

Covalent modifications of either:

• DNA (e.g. cytosine methylation and hydroxymethylation)
• histone proteins (e.g. lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation)

Question 18

Define genetic deletions

Answer 18

Deletions - a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is lost during DNA replication.

Question 19

Define point mutations

Answer 19

Point mutations - a mutation affecting only one or very few nucleotides in a gene sequence.

Question 20

What are imprinting errors?

Answer 20

Imprinting errors – e.g. one of the parental genes isn’t silenced, leading to both being inherited and expressed

Question 21

What is uniparental disomy?

Answer 21

Uniparental disomy - inheritance of a chromosome pair from one parental origin

Question 22

What can cause uniparentat disomy?

Answer 22

UPD can be the result of:

• heterodisomy, in which a pair of non-identical chromosomes are inherited from one parent (an earlier stage meiosis I error)
• isodisomy, in which a single chromosome from one parent is duplicated (a later stage meiosis II error).

Question 23

What is the result of gyogenic inheritance?

Answer 23

2 maternal genomes
• Mass of embryo
• Ovarian teratoma

Question 24

What is the result of androgenic inheritance?

Answer 24

2 paternal genomes
• Mass of placenta
• Hydatidiform mole

Question 25

Give some examples of human disorders caused by imprinting errors?

Answer 25

Angelman syndrome - inactivation of maternal chr15 while paternal copy is imprinted and silenced

Prader Willi syndrome - paternal chr15 deleted

Both conditions occur due to mutations in the same chromosomal region: 15q11-13

Question 26

Describe Angelman syndrome

Answer 26

Angelman syndrome (AS): inactivation of maternal chr15 while paternal copy is imprinted and silenced
o Epilepsy
o Mental retardation (severe)
o Awkward gait
o Inappropriate laughter and hand flapping

Question 27

Describe Prader Willi syndrome

Answer 27

•	Prader-Willi syndrome (PWS) – paternal chr15 deleted
o	Hypotonia
o	Mental retardation (mild-moderate)
o	Short stature
o	Marked obesity

Question 28

Define extranuclear inheritance

Answer 28

Mitochondrial inheritance - mtDNA inherited solely from the mother

Question 29

What are mutation hotspots and why do they occur?

Answer 29

• High mutation rate: 100-fold higher than the nuclear genome.
• Lack of efficient DNA repair system.
• Lack of protective proteins, such as histones.
• Damaged by reactive oxygen species (ROS), such as free radicals

Question 30

What is heteroplasmy?

Answer 30

A cell can have some mitochondria that have a mutation in the mtDNA and some that do not. This is termed heteroplasmy. The proportion of mutant mtDNA molecules determines both the penetrance and severity of expression of some diseases

Question 31

What is homoplasmy?

Answer 31

Homoplasmy refers to a cell that has a uniform collection of mtDNA: either completely normal mtDNA or completely mutant mtDNA.

Question 32

How many copies of mtDNA do dividing cells inherit?

Answer 32

• A unique feature of mtDNA is that, at cell division, the mtDNA replicates and sorts randomly among mitochondria. In turn, the mitochondria sort randomly among daughter cells. Therefore, in cells where heteroplasmy is present, each daughter cell may receive different proportions of mitochondria carrying normal and mutant mtDNA.
• Polyploidy: up to thousands mitochondria per cell.
• 2 - 10 copies per mitochondrion.

Question 33

What is mitochondrial disease?

Answer 33

Mitochondrial disease is a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell.

Question 34

What causes mitochondrial disease?

Answer 34

Mitochondrial diseases are sometimes (about 15% of the time) caused by mutations in the mitochondrial DNA that affect mitochondrial function. Other causes of mitochondrial disease are mutations in genes of the nuclear DNA, whose gene products are imported into the mitochondria (mitochondrial proteins) as well as acquired mitochondrial conditions.

Question 35

What is anticipation?

Answer 35

In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase of severity of symptoms is also noted.

Question 36

Which diseases often show anticipation?

Answer 36

Anticipation is common in trinucleotide repeat disorders, such as:
o Huntington’s disease
o Myotonic dystrophy
o Fragile X syndrome

Question 37

What is the Hardy Weinberg principle?

Answer 37

The Hardy–Weinberg principle states that allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences.

Question 38

What conditions does the Hardy-Weinberg principle rely on?

Answer 38

o	Mutations can be ignored (A mutation will neither help or hinder an organism)
o	Migration is negligible
o	Population size is large
o	Mating is random
o	There is no selective pressure