Year 3 (Bioscience) Flashcards
How do we tell if a familial disease is due to genetic?
- For Mendelian pattern
a) Large Mendelian pedigree - For non Mendelian pattern:
a) Familial clustering
b) Twin studies
c) Adoption studies
What is familial clustering?
- Shows that a disease runs in the family
- Aims to show that the closer the genetic relationship, the higher the risk of disease
* it should be kept in mind that families also share their environment as well as genes
How much DNA do you share with your cousins and siblings?
- Siblings: 50%
2. Cousins: 25%
How are twin studies beneficial in identifying genetic condition?
- Based on deferences in the disease incidence between monozygotic and dizygotic twins
- MZ twins share 100% of their genes and DZ 50%
- Genetically determined diseases show a higher concordance in MZ twins than DZ
What are the two designs for adoption studies?
- Identify individual with a disease > ascertain whether the disease runs in the biological or adopted family
- Identify disease in individuals whose children have been adopted > ascertain whether adoption saves children from being affected
What is genetic disease?
Any disease which results in change of genetic material
How can genetic material be affected?
- Single gene: single gene disease
- Multiple genes: polygenic disease
- Chromosome: chromosomal disease
- Multiple genes and environment: multifactorial disease
What are the two types of cell affected in genetic disease?
- Germline cells: sperm and ova (inherited conditions)
2. Somatic cells: non germ cells (non inherited conditions)
What is an example of a single gene genetic disease?
Phenyketonuria
- Autosomal recessive
- Incidence 1:10 000
- Lack of phenylalanine hydroxylase (enzyme which converts phenylalanine to L tyrosine)
- When there is access phenylalanine, your body uses alternative pathway to get rid of them which produces phenyl ketones
- These products then gets deposited in the brain which causes mental retardation
- Among the other effects are:
a) Microcephaly
b) Growth failure
What are features of a single gene condition?
- Pathological mutation: people who have this variant has a high risk of getting this disease
- The disease is only present in people who have this variant (affected carriers)
- Significantly alter the gene and protein
- Eg: Huntington’s disease
What are features of a complex disease?
- Normal variants
- Present in everyone: although we have this disease or not we have this variant
- Subtly alters gene and proteins (the occurrence of disease depend on the environment)
What are common features of Mendelian genes and chromosome?
- Come in pairs
2. One of each pair is picked at random and is passed on to each child
What occurs during the first meiotic division?
Independent segregation of the paternal and maternal homologous chromosome
What occurs during the second meiotic division?
Separation of sister chromatids
What are the two types of chromosomal abnormalities?
- Numerical abnormality
2. Structural abnormality
Describe the normal chromosomal constitution
- Normal germ cell: haploid chromosomal constitution (23 or often referred to as N)
- Normal somatic cell: diploid chromosomal constitution (2N)
Describe abnormal chromosomal constitution
- Polyploidy: cells have chromosome in multiples of N greater than 2N
a) Triploidy
b) Tetraploidy - Aneuploidy: there is variation in number of chromosomes that is not in multiple of N
What are features of triploidy?
- Commonest form of polyploidy
- Usually results in miscarriage of foetus
- Arises by:
a) Fertilisation of egg by two spermatozoa (dispermy)
b) Fertilisation of diploid gamete (due to failure of maturation of egg or sperm)
What are features of tetraploidy?
- Arises from failure of completion of the first zygotic mitotic division
- Incompatible with life
What is monosomy of a chromosome and what are its effects?
- Monosomy: loss of copy of a chromosome
- All complete monosomy of autosomal chromosomes are lethal
- However partial monosomies may be observed in unbalanced translocation
- The only complete monosomy that is not lethal is monosomy of X chromosome (Turner’s syndrome)
What is trisomy 18 known as?
Edwards Syndrome
What are the two causes of aneuploidy?
- Non disjunction: failure of chromosomes or sister chromatids to separate at anaphase in cell cycle
- Anaphase lag: delayed movement of chromosomes after separation at anaphase
What is Klinefleter’s syndrome?
47XXY
What is the way to obtain a XYY make up?
Non disjunction in meiosis 2 of spermatogenesis
How does mosaic Down syndrome occur?
When there is mitotic non disjunction occurs shortly after conception whereby some cells are normal but some cells are trisomic
How does structural abnormality of chromosome occur?
- As a result of chromosome breakage and usually involves one or two chromosome
- Can be spontaneous
- Rate is increased by exposure to mutagenic agents such as ionising radiation and certain chemicals
- Rate is also increased in certain inherited conditions with defects of DNA replication and repair (Eg: Blooms syndrome)
What are types of single chromosomal abnormality?
- Deletion: loss of part of chromosome
- Inversion: inversion of segment of chromosome
a) Pericentric; involves centromere
b) Paracentric; does not involve centromere - Duplication: duplication of chromosomal segment in tandem or in inverse configuration with original sequence
- Isochrome: duplication of one arm of the chromosome coupled with loss of other arm (chromosome consists of two identical arm)
What are types of chromosomal abnormality involving two chromosomes?
- Insertion: breakage of material from one chromosome and insertion into another chromosome
- Translocation: exchange of materiel between two chromosomes
a) Reciprocal translocation: reciprocal exchange of material between two chromosomes
b) Robertsonian translocation: only involves acrocentric chromosomes
What are acrocentric chromosomes?
Chromosomes with very short arms (13, 14, 15, 21 and 22)
What are the outcomes in reciprocal translocation?
- Normal
- Carrier of balanced translocation
- Partial trisomy of one of the involved chromosomes accompanied by partial monosomy of the other chromosome and vice versa
What are outcomes in Robertsonian translocation?
- Normal
- Carrier of balanced translocation
- Complete trisomy of one of the involved chromosome
- Complete monosomy of one of the involved chromosome
What is the phenotypic consequence of chromosomal abnormality?
Depends on whether it involves:
- Single gene
a) If translocation to a region of active chromatin domain causes inappropriate expression (myc in Burkitt’s lymphoma)
b) Creates chimaeric gene that expressed altered protein (ABL in chronic myeloid leukaemia) - Small group of genes
a) Resulting phenotype of attributed to a lack of product of several genes
b) Known as contiguous gene syndrome - Large region of chromosomes with many genes or whole chromosomes
a) Results in severe birth defects including mental/ growth retardation and specific abnormalities
b) Largely due to dosage imbalance of only a few genes on those chromosomes
c) For most genes, having an extra copy/lack of one copy results in 50% increase/decrease in its product which is unlikely to be significant
How do we tell if a disease is genetically inherited?
Congenital (conditions present at birth)
1. Can be genetic or environmental
2. Some genetic conditions may not necessarily be present at birth
3. Genetic conditions affecting somatic cells arise later on in life
Familial
1. There are inherited (genetic) disease that may not appear to be familial (recessive conditions)
2. Can be genetic or environmental (same family subjected to the same environment)
3. Genetic conditions affecting somatic cells are not familial
Why do blastomeres become small at each cell division?
They are inside the zone pellucida which is a thick layer that cannot expand thus inhibits their growth. Every new cell is only half as large as the cell it derives from
What are features of blastomeres?
- Totipotent
- The embryo has no polarity at this stage
- The blastomeres (which were initially loose) now maximises their contact and cells are held together by tight junction
- Cells on the inside communicate using gap junction and segregate form the cell on the outside
- Arises through cleavage of zygote
When is a morula formed?
96 hours after fertilisation
What are features of a morula?
- A collection of about 30 blastomeres
- Cells on the outside become the outer cell mass (placenta) and cells on the inside the inner cell mass (embryo)
- The point at which the first differentiation occurs
What causes differentiation of cells in an embryo?
- All cells of the embryo contains the same DNA
2. Cells become different because they use different portion of this DNA and express different genes
When does the first molecular difference established and how?
- They are first established after compaction when outer cell mass and inner cell mass are exposed to different environments
- Outer cells
a) Express Cdx2
b) Cdx2 converts cells to trophoectoderm - Inner cells
a) Express Oct4
b) Mains cell pluripotent
How is a blastocyst formed?
- Through compaction of cells and accumulation of intercellular fluid leading to the formation of blastocyst cavity
- Consists of:
a) Embryoblast: 12 ES cells
b) Trophoblast: single cellular layer of 100 cells
When does hatching and implantation occur?
Occurs on the 5th day when blastocyts emerges from the pellucid zone
What occurs during implantation and why is it important?
- Blastocyst adheres on the endometrium
2. It is essential to establish feto-maternal blood circulation
How is the endoderm created?
Though the action of cells that have invaginated the epiblast and displaced the hypoblast
What is the difference between epithelial cell and mesenchymal cells?
Epithelial cells 1. Closely connected to each other by tight junction, gap junctions and adherents junction 2. Have an apico-basal polarity Mesenchymal cells 1. Lack polarisation 2. Have loose contact
What occurs to epiblast cells during epithelio-mesenchymal transition
- Epiblast cells which are closely bound together loose their contact and become motile
- Key change in EMY is that epithelial cells stop expressing high levels of E caderin (forms tight junction)
When is epithelio-mesenchymal transition necessary?
- Essential for embryonic development
a) Gastrulation
b) Formation of neural crest
c) Formation of palate - It also occurs in cancer
When does formation of the face occur?
4th week of gestation
When does face formation almost completed?
7th week of gestation
What occurs to facial development from 8th week of gestation to birth?
Final development of the face occurs slowly due to changes in proportions of the facial components
What does the ectoderm form?
- Skin
- Oral epithelium
- Tooth enamel
- Cranial nerves
What does the mesoderm form?
- Muscle
2. Part of skeleton
Who does the endoderm form?
Endocrine glands
What does the cranial neural crest form?
- Craniofacial skeleton (bones and cartilage)
- Tendons
- Connective tissue of tooth
- Sympathetic ganglia
- Glial cells
- Melanocytes
Where are cranial neural cells derived from?
Midbrain and hindbrain
What is the derivative of the first branchial arch?
- Mandible
- Maxilla
- Meckel’s cartilage
a) Incus and malleus of inner ear
b) Sphenomandibular ligament
c) Sphenomalleolar ligament
What is the derivative of the second branchial arch?
- Reichert’s cartilage
a) Styloid process
b) Stylohyoid ligament
c) Lesser horns of hyoid bone
d) Upper part of body of hyoid
What is the derivative of the third branchial arch?
- Lower parts of body of hyoid
2. Greater horns of the hyoid bone
What is the derivative of the fourth branchial arch?
Cartilages of the larynx
What are the products of the remodelling of the pharyngeal arch arteries?
- Carotid artery
- Arch of aorta
- Ductus arteriosus
Which cranial nerves innervate muscles from the 1st, 2nd and 3rd pharyngeal arches?
- 5th cranial nerve (trigeminal)
- 7th cranial nerve (facial)
- 9th cranial nerve (glossopharyngeal)
List the 5 facial prominences
- Frontonasal process x1
- Maxillary process x2
- Mandibular process x2
Describe the process of facial development
- Localised thickenings (olfactory placode) develop within the ectoderm of the frontal prominence
- Rapid plofireatiom of mesenchyme around the placode produces a horseshoe shaped ridge which forms the nasal pit
- Lateral arm of the ridge is known as lateral nasal process and the medial arm the medial nasal process
- The maxillary process grows medially but remains separated from
a) Medial nasal process: bucconasal groove
b) Lateral nasal process: nasolacrimal groove - The region of the frontal process where the nose will develop is known as the frontonasal region
- The medial nasal process continues to grow > gets displaced mesially > fuses with anatomic counterpart > forms
a) Philtrum
b) Bridge of nose
c) Part of maxilla carrying incisor teeth and primary palate - Maxilla also grows mesially and fuses with the medial nasal process with forms the upper lip
- The lower lip is formed when two streams of ectomesenchyme from the mandibular process fuse together
- Fusion between the maxillary process and lateral nasal processes occur after the nasolacrimal groove separates to form the nasolacrimal duct
What are the requirements of successful facial development?
- The facial processes need to fuse to generate intact face
- Facial progression need to reach the right size (influenced by generation, migration and proliferation of NCC)
- The epithelial between the processes must disappear
a) Epithelial cell death
b) Epithelio-mesenchymal transition
What does a palate do to the primary stomodeal?
Divides the stomodeal into oral and nasal cavity
When does the secondary plate formation commence and end?
- Commence: 7-8 weeks of gestation
2. Ends: 3rd month of gestation
Describes the process in secondary palate formation?
- The nasal septum grows downwards from frontonasal region
- Two palatine shelves (one from each side) extend from maxillary process towards the midline
- The shelves are initially directed downwards towards each side of the tongue
- After 7 weeks, the tongue is withdrawn form the shelves thus the shelves elevate and fuse with each other above the tongue
- In the process they also fuse with the primary palate
- The septum and the two shelves converge and fuse along the midline thus separating the primitive oral cavity into nasal and oral cavities
What is necessary for the fusion of palatine shelves to occur?
Disintegration of epithelial cells covering the shelves must occur (via epithelio-mesenchymal transition)
What is the cause of cleft palate?
- Delayed elevation of palatial shelves
2. Defective shelf fusion
What are the two types of bone in the head?
- Endochondral bone (formed via cartilage)
2. Intramembranous bone (formed via direct ossification)
What is the origin of head skeleton?
- Mostly by neural crest cells (forms all facial skeleton)
2. Also paraxial mesoderm
What are two parts of the skull?
- Neurocranium: calvaria and cranial base
2. Viscerocranium: facial skeleton
What are the two forms genes can be recognised as?
- DNA sequence for a protein product (deduced from the product they produce)
- Mendelian characteristics (where their existence is deduced solely from pattern of inheritance)
What causes Mendelian characteristics?
Segregation of a single pair of alleles located on an autosome or the X chromosome which governs a dominant, co dominant or recessive phenotype
Define an allele
Alternative forms of a gene or marker which segregates at meiosis
Define locus
The location/site of a gene or marker on a chromosome
Distinguish genotype and phenotype
- Genotype: the genetic consitution
2. Phenotype: the observable character
Distinguish homozygous, heterozygous and hemizygous
- Homozygous: both alleles are the same (recessive characters are expressed in homozygotes)
- Heterozygous: the alleles are different (dominant characters are expressed in heterozygotes)
- Hemizygous: when there is only one allele (Eg: males are hemizygous for loci on the X chromosome)
Describe features of autosomal dominant inheritance
- Most makings are between heterozygote affected individual with a homozygote unaffected individual
- Most clinically significant dominant traits are characterised by low frequencies
- For AD inheritance to be demonstrated, several requirements must be met:
a) Every affected individual must have at least one affected parent
b) Both males and females should be affected and equally capable of transmitting the trait (provided it doesn’t cause sterility)
c) There is no skipping of generation
d) Father to son and mother to daughter transmission should be as common as father to daughter and mother to son
e) An affected person should transmit the trait to half their offspring if the mating is Aa x aa (recurrence risk is 50%)
What are problems of pedigree interpretation?
- Penetrance: genotypically affected but phenotypically unaffected
- Delayed onset: may present later on in life phenotypically
- New mutation: not present in genotype or phenotype but is passed on to future generation
- Variable expression: two siblings inherit the same condition but express it at different severity
- Non paternity
What are features of autosomal recessive inheritance?
- Only homozygotes are affected but heterozygotes may be detected biochemically
- The type of pedigree pattern seen is dependant on the population frequency of the gene and ability of affected individuals to reproduce
- Most affected individuals are a product of mating between heterozygote carriers
- A typical pedigree consist of single sibship (group of offspring having the same parent) containing affected person
- Most cases appear sporadic with no previous family history makes pedigree interpretation difficult
- For very rare traits, consanguinity may be increased
What are features of x linked disease?
- May be recessive (common) or dominant (rare)
- Male to male transmission CANNOT occur
a) Affected male transmits the mutant gene to ALL daughters but NONE of the sons
b) The daughter will be affected if trait is dominant
c) The daughter will be carrier if trait is recessive - Manifesting heterozygote do occur
- Unaffected males NEVER transmit the gene
- If the carrier is females
a) Risk to her son is 50% (affected)
b) Risk to her daughter is 50% affected (if dominant) or carriers (if recessive) - Affected homozygous females are very rare
What are clinical and molecular genetics of Treacher Collins syndrome?
- Autosomal dominant inheritance
- Affects 1/50000 live births
- High rate of new mutation
- Results from mutation of TCOF1 which encodes for nuclear protein, Treacle
- Clinical features include:
a) Down slanting eyes
b) Unusual external ears
c) Flattening of zygomatic region
d) Posterior rotated ears
When does fusion of the primary palate occur?
5th week of gestation
What structures are formed from the fusion of the primary palate?
Upper lip and hard palate that is as far back as the incisive foramen
What causes the tongue to grow forward thus enabling the palatial shelves to elevate?
Lifting of the upper facial process from thorax
What are features of submucous cleft palate?
- Bifid uvula
- No palatine raphe
- Notch in posterior hard palate
List the prevalence of cleft lip and palate in boys and girls
Cleft lip and palate is more common in boys
Cleft palate is more common in girls