What was the “one gene hypothesis,”? Did it turn out to be correct?
- Hypothesis: one gene=one protein
- Not correct, 1 gene codes for at least 10 proteins
SNPs and other mutations were thought to be the sole cause of human variation, was this assumption correct?
No
humans have minimal gene variation compared to other mammals
How much of the Human Genome is Protein Coding? How much is RVS
- 4% Protein Coding
- 9% Retroviral
In what people and country does most of the variability in the human genome still reside
San Bushmen people of East Africa
How are mitochondrial DNA and Y chromosomes DNA different and how are they used in migration studies?
Comparing the mtDNA “age” with the number of mutations on the Y chromosome, the time frame and direction of migration can be determined
What did the story about kook and her kitty cat suggest about human behavior
LOOK UP
What are the three main problems with trying to determine the cause vs correlation in genetic disease and genetic studies like GWAS
- Association was found by CHANCE
- Association is result of biased in study (LINKAGE disequilibrium)
Know the 5 points of control and how they work!
- CHROMATIN STAGE:
- regulated by methylation of cytidine
- histone modification via acetyl group addition to promote transcription
- exon shuffling - Transcription:
- Promoters and enhancers upstream (TATA and CCAAT)
- Transcription factors - Translation:
- 5’ cap and 3’poly(A)tail added to mRNA
- Introns removed eons spliced - Post Translational control into cytoplasm:
- leave via exportins
- enter via inportins - Post translational modification:
- addition of functional groups
- phosphorylation
- most important regulation step
TATA and CCAAT are examples of what?
promoters
What is exon shuffling?
Which part exon or intron remains as a section of mRNA
- Exons
- Exon shuffling is when two or more exon from different genes can be brought together or the same exon is duplication to crease a new exon-intron structure
What is the role of enhancers?
a short region of DNA that can be bound by proteins (activators) to increase the likelihood that transcription of a particular gene occurs
3 main molecular groups that modify histone and cause epigenetic effects?
- Acetyl
- Methyl
- Phosphate
Which epigenetic marker can attach to DNA directly?
Acetyl
When looking at a cartoon or ideogram of a chromosome, how can you tell the locus from the gene? (essentially know the abbreviations for each. For instance is EPO the gene or the locus?
- Locus: begins with p/q
- Gene: named with an acronym or something not beginning with p/q
What are DNA Marker Alleles? Are they necessarily involved in transcription or biologically active?
Any gene or allele that is associated with a specific chromosome can be used to identify the chromosome or locate other genes or alleles
-They are not necessarily directly involved in transcription or biologically active
What is Geneotype?
What is Phenotype?
- Genotype: combination of alleles a person has
- Phenotype: any observable train, expressed by genotype
What is the disease characteristic and pedigree characteristic of autosomal dominant
Locus is on an autosomal chromosome and only one mutant allele is required for expression of the phenotype
Review your pedigrees
Just do it
What is the disease characteristic and pedigree characteristic of autosomal recessive
The locus is on an autosomal chromosome
-both alleles must be recessive to express the phenotype
What is the disease characteristic and pedigree characteristic of x-linked recessive
The locus is on the x chromosome
- both alleles must be a recessive allele to expresses the phenotype in females
- only one must be present in males
What is the disease characteristic and pedigree characteristic of X-linked dominant?
The locus is on the X chromosome and only one mutant allele is required for expression of the phenotype in females
What is the disease characteristic and pedigree characteristic of mitochondrial inheritance
The locus is on the mitochondrial chromosome
What are the characteristics of X-linked Dominant Diseases?
X-linked dominant diseases are twice as common in females than males
Can X-linked Dominant diseases be transmitted from father to son?
What about from father to daughter?
- A father can not transmit to his son (he donates the Y)
- Father can donate to his daughter (gives the X)
Why can males get X-linked recessive diseases with just one mutated allele?
-Males only have one X chromosome
What is the difference between a missense mutation and a nonsense mutation?
- Missense: Single base change in the gene that leads to a change in the codon that encodes for one amino acid
- Nonsense: a base change that results in a “stop” codon- a short and completely inactive protein/enzyme
What is the difference between gain-of-function and loss-of-function mutation and is one necessarily less troublesome than the other?
Loss-of-function: causes a vital or protective protein to become non-functional in the cell
Gain-of-function: occurs when either a completely new enzyme is produced in a cell, or more commonly, the enzyme is over produced
Why is consanguinity important in clinical medicine, even though it is rare among Americans
“kissing cousins” can give rise to genetic disease (recessive)
Why is it called Fragile X Syndrome, and what determines it’s severity?
Most common cause of mental retardation due to a number CGG repeats
-which determines severity
What is the epigenetic significance of X chromosome inactivation
- females only have one X chromosome active
- inactivated one is called a bar body
Do Barr bodies form when autosomal chromosomes are imprinted (AS and PWS)
Yes
Imprinting is when one of the chromosomes are shut down either from mom or dad
What is the general clinical characteristic of inherited mitochondrial disease?
- It is only passed through females
- Leads to neuropathies and myopathies
- always affects the small motor muscles first
What is the difference between the following:
- Penetrance
- Incomplete penetrance
- Variability
- Penetrance: the degree to which the phenotype is expressed
- Incomplete Penetrance: some people have the genotype but do not express the phenotype
-Variability:
how “bad” the disease is when it is expressed
What is recurrence risk (RR) and how is it calculated
- The likelihood that a trait or disorder present in one family member will occur again in other family members in the same or subsequent generations
- Calculate it by multiplying the penetrance by 25%(AR) or 50%(AD)
What is pleiotropy?
Is Marfan Syndrome an example?
- Pleiotropy: a single mutation that affects multiple organ systems
- YES it is an example of AD mutation
What is anticipation?
-What does it imply will occur in each subsequent generation of a family carrying mutation causing a disease characterized by anticipation?
- A pattern of inheritance in which individuals in the most recent generations of a pedigree develop a disease at an earlier age or with greater severity than do those in the earlier generation
- usually due to gradual expansion of trinucleotide repeat polymorphisms within or near a coding gene.
How are the bands of a chromosome stained for a karyotype?
What are the three types of bands?
- Glemsa staining
- Done via 5 fluorescent probes that hybridize differently to different sets of chromosomes
- Positive
- Negative
- Variable
How many BP’s have to be involved in a deletion or duplication to be grossly detectable on a karyotype without using special immunofluorescent stains?
- Need >4Mb to be seen
- FISH detects less than 4Mb
What is the main cause of NUMERICAL chromosome abnormalities?
Meiotic nondisjunction due to spindle fibers behaving badly
What disease is Trisomy 21
Down’s Syndrome
What disease is Trisomy 18
Edwards syndrome
- poor prognosis
- AVSD, PDA
- hand food and mouth malformations
- low set ears and microganthia
What disease is Trisomy 13
Patau Syndrome
- polydactyly
- cleft lip/palate
- microphtalmia (small eyes)
- microcephaly
- cardiac and renal defects
- poo prognosis
Why aren’t there any autosomal monosomes listed in the slides?
They are incomparable with life
What are the the characteristics and Karyotype numbers for Turners syndrome
- only monosomy consistent with life
- Karyotype 45/X, 46XX and 47XXX
- short stature
- ovarian dysgenesis -neurocognitive problems
What are the characteristics and Karyotype numbers for Klinefelter’s Syndrome
- Karyotype : 47XXXY
- Males predominantly effected
- Presence of both sex organs is rare
- Hypogonadism
- Low testosterone/high FSH and LH rather than testicular atrophy
- Males tend to be weaker and grow taller than average
- Males have larger breasts, wide hips and most noticeable during puberty, often look normal as adults
- Often infertile
What are the characteristics and Karyotype numbers for Alien 3 Syndrome?
- 47XYY
- Normal Phenotype and occurs during abnormal separation of chromosomes during anaphase II resulting from nondisjunction leaves sperm cell with extra Y
Through which mechanism is the philadelphia chromosome formed?
What disease is it associated with and what is its significance?
- Formed via Reciprocal Translocation
- chromosome 9 and 22
- If it occurs on hematopoietic cells it can result in Chronic myelogenous leukemia
What are the Philadelphia chromosome numbers?
- t(9;22)
- 5(15;17)
- (t(8;14)
Can partial monosomes occur?
Yes
What disease is this Karyotype??
-46,XX,-14,
-46,XY,-14,
Down Syndrome caused by partial monosomy read?
Cri-du chat results from what abnormality?
Does the patients voice improve as they age?
-results from deletion on short arm of chromosome 5
- abnormal larynx development “cry of cat”
- most develop normally after age 2
How did Angelman Syndrome and Prader-Willi Syndrome (PWS_ work?
What is their significance in the development of the field of epigenetic?
Angelman syndrome:
- micro deletion of maternal 15
- causing happy children who are ataxic and epileptic
Prader-Willi Syndrome:
- Microdeletion in paternal chromosome 15
- child who intensely craves food
- Floppy baby
What is a ring chromosome, and what is its significance?
- forms when a deletion occurs on both tips of a chromosome and the remaining chromosome ends fuse together
- results in monosomy
What are the three karyotypes for a ring chromosome and what do they mean?
- R-Ring Chromosome
- T-Translocation
- I-Isochromosome
A chromosome that divides along the axis perpendicular to its normal axis of division that results in two copies of the chromosome but no copy of the other is called what?
Isochromosomes
Are Isochromosomes seen in autosomes in live patients?
No
-incompatable with life, most observed in live births involving X chromosome
In the overkalix studies it was found that nutritional influences and their subsequent epigenetic markers could be transmitted to future generations:
When was it thought that these epigenetic effects are imprinted onto the fetus of women
- Females In Utero
- Males Late Childhood
Who was George Price and what was his contribution to genetics?
-Population geneticist who wrote equation that described evolution,natural selection, game theory equation
In the overkalix studies it was found that nutritional influences and their subsequent epigenetic markers could be transmitted to future generations:
When can the influences be acquired for transmission by males?
Are these the only times epigenetic effects can be acquired?
- During gamete formation
- Not the only time
What is the major reason gene therapy did not work out?
- Infecting gene via virus into humans can be challenging and potentially harmful
- Problems with integrating therapeutic DNA into the genome and then rapidly dividing nature of many cells prevent gene therapy form achieving any long-term benefits
What inhibits gene expression or translation by neutralizing targeted mRNA
iRNA
Interference RNA:
Can iRNA be passed to subsequent generations
Yes
What are Knock-down studies?
How do they work?
What do knock-down studies tell you about a gene?’’
What is the most effective modality for performing knock-down studies?
Studies that use RNA to see if it can be used for large-scale screens that systematically shut down each gene in the cell, which can help identify the components necessary for a particular cellular process or an event such as cell division
-used to test the effect of mutated genes