THe Human Genome Flashcards
How is mitochondrial DNA inherited?
Maternally
Describe the nuclear genome
Linear DNA organized in chromosomes 2 copies per cell 3.1 *10^9 by per haploid genome 23 pairs ( 22 autosomal and 1 sex) ~23000 genes
What pair of sex chromosomes makes a male/female?
Females: XX
Male: XY
Describe the mitochondrial genome
Circular DNA Many copies per mitochondria ~16.5k by per genome 37 genes No histones Inherited Maternally *
What genes are expressed in all cells?
Housekeeping genes
What controls cell differentiation?
Genes
How are pedigrees labeled?
Generations re indicated with Roman numerals
Individuals are identified within each generation numbered left to right
What is the proband?(propósitus or index case)
The first person identified to have a genetic disorder in a family
What is a consultant?
An unaffected individual seeking counseling
Are multiple probands possible?
Yes, if the disease was ascertained by more than one source
What is the degree of relationship in a first degree relation ship? Name some examples
50% of genes
I.e. Parent, sib, child
(One step away from person of interest)
What is the degree of relationship in 2nd degree relationships? Name some examples
25% genes in common
I.e. Aunt, uncle, niece, grand-parents, half-sib
(Two steps away from person of interest)
What is the degree of relationship in a 3rd degree relationship? Name some examples
12.5% of genes in common
I.e. First cousins ( 3 steps away from person of interest)
With every increase of the degree of relationship the % of genome in common how much?
50%
I.e 1st : 50%, 2nd: 25%, 3rd: 12.5%, 4th: 6.25%
What are choreiform movements?
Involuntary, jerky movements, facial grimacing
What are the signs of huntingtons?
Forgetful, depressed, restless and choreiform movements
What is the inheritance of Huntington disease?
Autosomal Dominant
What brain tissue shrinks in Huntington disease?
Caudate nucleus
What are the characteristics of Autosomal Dominance (AD) inheritance?
Affected parent has 50% chance of passing to offspring
Successive generations are affected (vertical transmission)
M/F equally affected
M/F transmit disease equally
M to M transmission occurs
For AD diseases where does the spontaneous mutation occur?
In meiosis of one of the parents. Usually siblings re very unlikely to be affected
Name some AD diseases
Huntington Disease Marcan Syndrome Achondroplasia Osteogenesis Imperfecta Neurofibromatosis Polycystic Kidney Disease (ADPKD)
What is penetrance?
The probiotic that individuals with a specific genotype will manifest the corresponding phenotype
All or none
What is incomplete penetrance?
Occurs when some individuals with a genotype do not manifest the corresponding phenotype
I.e generation skipping or BRCA1 for breast cancer
What is variable expressivity?
Variation in phenotype of same gene
Observed as variation in: which symptoms present and severity
What is cystic fibrosis confirmed by?
The sweat test
Na+ in sweat > 60 mM (upper limit of normal range)
What are the clinical features of Cystic fibrosis?
Lung disease Lung infections Malabsorption Salty sweat Male infertility Meconium ileus (obstruction of si due to thickening of meconium)
What are the characteristics of AR inheritance?
W/ both parents being carriers: 25% of offspring affected
Horizontal pattern on pedigree ( one generation)
M/F are affected equally
M/F transmits disease equally
M2M transmission
Name some examples of AR diseases.
Many metabolic disorders -E.g. Alkaptonuri, Phenylketonuria (PKU), Oculocutaneous Albanism, Lysosomal Storage disease Cystic fibrosis Thalassemia Sickle Cell Disease
What was found in case 3 when Nazarene failed her 8 month hearing after normal milestones were previously met.
Profound hearing loss
-her case was an AR negative
What is consanguinity?
Mating between individuals who are 5th degree or closer relatives
-e.g great great grandparents and closer
What does consanguinity cause?
An increase in genetic disease probability for offspring.
-the closer the relationship, the more likely AR phenotype will be expressed
What are the abnormalities in incestuous matings?
Intellectual -25% severe, 35% mild Autosomal recessive disorder -10-15% Congenital malformation 10%
What is a pseudominance?
A recessive trait mimics a dominant pattern
-i.e. O type blood, blue eyes, sickle cell in parts of Africa, cystic fibrosis in parts of Quebec
When can pseudodominance occur?
When a recessive gene is very common and a homozygous might mate with a heterozygous resulting in vertical transmission
What is complementation?
Mating between individuals with the same phenotype results in offspring without the phenotype due to mutations in different genes
I.e. The offspring are heterozygous in both genes
What is an example of complementation?
The gene for Congenital hearing loss
What is the 2/3 rule?
For traits inherited in an autosomal recessive manner, an unaffected sibling of an affected individual has a 2/3 risk of being a carrier
When can the 2/3 rule be applied?
In an autosomal recessive pedigree
- can be ruled out that the sibling in affected
- neither parent is affected
What are some of the sign/symptoms of Duchene Muscular Dystrophy?
- delayed motor milestones
- Use gower’s maneuver
- clumsy, first steps at 20month (late)
- muscle s no dystrophin
What are the characteristics of XR inheritance?
Males are faceted in multiple generations
- NO male to male transmission
- Generation skipping (through females)
How often are the offsprings of XR patients affected?
Fathers: 0% of sons, 100% female carriers
Mothers:50% of sons defected, 50% of females are carriers
What are obligate carriers?
Individuals who must be carriers based on logical analysis of a pedigree
-indicated by a dot on pedigree
For XR, isolated cases may be due to what?
Spontaneous mutation
What are some examples of XR diseases?
- Duchenne muscular dystrophy
- Hemophilia
- Red-Green color blindness
- Androgen insensitivity syndrome
- Hunter syndrome
- X-linked severe combined immunodeficiency
- Menke’s disease
What are the characteristics of XD inheritance?
- No male to male transmission
- 2x F > M
When XD reproduce, what offspring will be affected?
- Affected mother will have 50% affected son and 50% affected daughters
- Affected fathers will have no affected sons and ALL affected daughters
What are some examples of XD diseases?
- Rett syndrome
- Fragile X syndrome (semi dominant)
- Vitamin D-resistant rickets
- Incontinentia pigmenti type 2
What are son symptoms of Leber Hereditry optic neuropathy (LHON)?
- blurred vision, loss of color distinction
- retinal changes (optic disk swelling, tortuosity of retinal vessels)
- progressive worsening of central vision
- Maternal lineage has affected inidividuals
What are the characteristics of mitochondrial pedigree?
Maternal inheritance
- children of affected males are never affected
- children of affected females are always affected (w/ reduced penetrance)
What are some examples of Mitochondrial Diseases?
- Leber hereditary optic neuropathy (LOHN)
- Leigh syndrome (LS)
- Mitochondril encephalomyopathy wth lactic acidosis and stroke-like episodes (MELAS)
- Kearns-Sayre syndrome (KSS)
What is mosaicism?
An individual who’s body contains two or more genetically distinct cell lines
How does mosaicism occur?
Mutations that occur post-fertilization
When is Mosaicism clinically important?
- Mutant cells have an increased growth tendency
- Mutation occurred early in embryogenesis and the mutant cell line make up a significant proportion of the body
- Mutation occurs in the Germline
What is germline mosaicism?
- mutation exists in the germline
- may include other tissues
- can be passed to offspring
What is somatic mosaicism?
- mutations that does not occur in the germline but can affect other tissues
- can’t be passed down to offspring
What are some implications of germline mosaicism?
My result in multiple affected children even when genetic testing of parent is Negative
What are the implications of somatic mosaicism?
May result in disease is large enough proportion of cells are affected
-requires genetic testing if multiple tissues samples
How can germline mosaicism cause confusion in pedigree?
In an asymptomatic couple w/ a child with a dominant disorder, all subsequent children will have increased risk of being affected by same disorder even if the parents are negative for mutation
What questions should you ask yourself when you interpret a pedigree?
- Are there affecteds in multiple generations? (No = autosomal recessive)
If yes, 2. M/F equally affected?
If yes, 3. M to M transmission? (Yes= Autosomal dominant)
If no, 3a. F>M? =XD
If no, 3b. M>F? = XR
