The genetic basis of complex inheritance Flashcards
Give some examples of non-mendelian inheritance
o Gene conversion o Intermediate phenotypes o Extranucleur inheritance o Genomic imprinting o Mosaicism
Define non-mendelian inheritance?
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
What are the three laws of mendelian inheritance?
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
What is the first law of mendelian inheritance?
The Law of Segregation – states that allele pairs separate during gamete formation, and randomly unite during fertilisation
What is the second law of mendelian inheritance?
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.
What is the third law of mendelian inheritance?
The Law of Dominance – 3rd law, states that one factor of pair of inherited traits will be dominant and the other recessive
Define penetrance
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.
What is incomplete penetrance?
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%
Describe cystic fibrosis
• 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.
Describe the prevalence of CF in different ethnic populations
o European Caucasians: 1 in 2,500 (4% carrier)
o Africans: 1 in 13,000
o Asians: rare
What are genetic modifiers?
Genetic modifiers: genes that have small quantitative effects on the level of expression of another gene. May involve polymorphism.
What is the CF phenotype dependent on?
Severity of mutation
Affected organs
Genetic modifiers
Environmental factors
What is genomic imprinting?
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
What causes genomic imprinting?
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.
Are the results of genomic imprinting passed on to future generations?
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
What are epigenetic modifications?
Heritable changes in gene function that cannot be explained by changes in DNA sequences
How can DNA be epigenetically modified?
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)
Define genetic deletions
Deletions - a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is lost during DNA replication.
Define point mutations
Point mutations - a mutation affecting only one or very few nucleotides in a gene sequence.
What are imprinting errors?
Imprinting errors – e.g. one of the parental genes isn’t silenced, leading to both being inherited and expressed
What is uniparental disomy?
Uniparental disomy - inheritance of a chromosome pair from one parental origin
What can cause uniparentat disomy?
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).
What is the result of gyogenic inheritance?
2 maternal genomes
• Mass of embryo
• Ovarian teratoma
What is the result of androgenic inheritance?
2 paternal genomes
• Mass of placenta
• Hydatidiform mole
Give some examples of human disorders caused by imprinting errors?
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
Describe Angelman syndrome
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
Describe Prader Willi syndrome
• Prader-Willi syndrome (PWS) – paternal chr15 deleted o Hypotonia o Mental retardation (mild-moderate) o Short stature o Marked obesity
Define extranuclear inheritance
Mitochondrial inheritance - mtDNA inherited solely from the mother
What are mutation hotspots and why do they occur?
- 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
What is heteroplasmy?
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
What is homoplasmy?
Homoplasmy refers to a cell that has a uniform collection of mtDNA: either completely normal mtDNA or completely mutant mtDNA.
How many copies of mtDNA do dividing cells inherit?
- 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.
What is mitochondrial disease?
Mitochondrial disease is a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell.
What causes mitochondrial disease?
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.
What is anticipation?
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.
Which diseases often show anticipation?
Anticipation is common in trinucleotide repeat disorders, such as:
o Huntington’s disease
o Myotonic dystrophy
o Fragile X syndrome
What is the Hardy Weinberg principle?
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.
What conditions does the Hardy-Weinberg principle rely on?
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
