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Flashcards in Midterm Deck (59)
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1
Q

What was the “one gene hypothesis” and did it turn out to be correct?

A
  • one gene makes one protein
  • Thought - Human Genome Project will provide the blueprint for everything

• No. Not correct - 300,000 + proteins (not that many genes)

2
Q

SNPs and other mutations, were thought to be the sole cause of human variation, was this assumption correct?

A

Negative. (gen. occur in non-coding region)
• Of all mammalian species, humans have the least genetic variation from one another

• Our phenotypic expression. however seems to be greater than in any other mammalian species
Phenotypic expression must largely be a result of both gene regulation, and the epigenome

3
Q

How much of the Human Genome is protein coding? How much is RVS?

A
  • 4% of the Genome is protein coding
  • most of the rest regulates that 4%.
  • 1.5-5% of the DNA is HIGHLY conserved, being found unchanged even in the simplest organism
  • 10% of the code is made of VIRAL start sequences ie endogenous RETROVIRUS SEQUENCES (RVS)
4
Q

In what people and country does most of the variability in the human genome still reside?

A

San Bushmen of Africa: 90% of all diversity

5
Q

How are mitochondrial DNA and Y chromosome DNA different, and how are they used in migration studies?

A
  • mtDNA changes at a fairly constant rate over time - estimates AGE of a species
  • Y chromosome SNP’s occur in a sequential manner throughout generations. Allows for tracing human MIGRATION patterns over the last 50,000 years

• Comparing the mtDNA “age” with the number of mutations on the Y chromosome, the timeframe and direction of migration was determined

6
Q

What were the three main problems with trying to determine the cause vs. correlation in genetic disease with genetic studies like the Genome Wide Association Study (GWAS)

A

Correlation does not = causation

The variant may be important in disease causation
Or:
1) CHANCE - association found by random chance
2) LINKAGE - association is a result of bias in the study (linkage disequilibrium - where the variant is situated close to the disease causing segment, but does nothing in and of itself)
3) STRATIFICATION - Population stratification (an ethnic group has a concentration of the variant, and the disease, though the two aren’t linked)

7
Q

Know the 5 points of control and how they work

A
  1. Chromatin Stage: DNA tightly wound up. A+T pair C+G pair
    Regulation:
    • Methylation of Cytidine in CpG islands - down regulates transcription
    • Histone modification: addition of acetyl group prevents condensation and promotes transcription. Methylation also stimulates transcription by making accessible.
    • Exon shuffling: different parts that get kept
  2. Transcriptional Stage: Transcription is the first step of gene expression, in which a particular segment of DNA is copied into RNA by the enzyme RNA polymerase.
    Regulation:
    • Promoters and enhancers upstream, includes TATA and CCAAT boxes.
    • DNA bends over to connect regions.
    • Transcription factors bind and transcription of DNA to RNA starts
  3. Translational Stage: Translation is the process through which cellular ribosomes manufacture proteins, in which messenger RNA (mRNA) is sequentially decoded by transfer RNA (tRNA).
    Regulation:
    • 5’ cap and the 3’ poly(A) tail added to mRNA
    • Introns removed, exons spliced
    • 5’ cap and the 3’ poly(A) tail of mRNA come together and enhancement translation
  4. Post translational control into cytoplasm
    Some RNAs and proteins go out through nuclear pores complexes (importins and exportins) into cytoplasm
  5. Post translational modification: the protein is modified, by folding, cutting or other processes like adding functional groups, phosphorylation.
    Regulation steps most important! What causes things to be coded.
8
Q

TATA and CCAAT boxes are examples of what

A

Promoters

9
Q

What is exon shuffling, and which part exon or intron remains as a section of the mRNA?

A

Exon shuffling is a molecular mechanism for the formation of new genes. (2+ exons from different or same genes brought together to create new exon-intron structure)
Exon sequences appear in MATURE transcripts

EXONS remain as a section of mRNA

10
Q

What is the role of enhancers found in regulation of transcription?

A

Enhancer sequences are regulatory DNA sequences that, when bound by specific proteins called transcription factors, enhance the transcription of an associated gene.

MC form of gene control
the activity of transcription factors allows genes to be specifically regulated during development and in different types of cells.

11
Q

What are the 3 major types of molecular groups that modify histones and cause epigenetic effects?

A

Methyl
Acetyl
Phosphate

12
Q

Which epigenetic marker can attach to DNA directly?

A

Methyl

13
Q

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?)

A

Gene - sequences that code for proteins (in classical medical genetics) - named as acronyms of discoverers ie EPO

Locus - The exact physical location of a gene on a chromosome. Same for all people.
marked by “p” or “q” followed by a number.

EPO is a gene with a loci of q21.13, for example

14
Q

What are DNA Marker Alleles? Are they necessarily involved in transcription or biologically active?

A

DNA Marker Alleles don’t necessarily have any function at all

they can be detected in the lab by southern blotting or PCR

15
Q

What is the difference between the Genotype and the Phenotype?

A

Phenotype: what is trait or protein is coded, observable trait - our phenotypic expression seems to be greater than in any other mammal = most variation of REGULATION!

Genotype: base pair sequence
Humans have the least genetic variation from one another.

16
Q

What are the 5 basic modes of inheritance for single-gene disease?

A
  • autosomal dominant
  • autosomal recessive
  • X- linked dominant
  • X-linked recessive
  • mitochondrial
17
Q

What is mitochondrial inheritance?

A

The locus is on the mitochondrial “chromosome”

18
Q

What is autosomal recessive inheritance?

A

The locus is on an autosomal chromosome and BOTH alleles must be mutant alleles to express the phenotype

19
Q

What are autosomal recessive pedigree characteristics?

A
  • clinically expressed only in the homozygous state, the offspring must inherit one copy of the disease causing allele from each parent
  • In contrast to autosomal dominant disease, autosomal recessive disease are typically seen in only one generation of a pedigree
  • Because these genes are located on autosomes, males and females are affect in roughly equal frequencies
20
Q

X-linked dominant inheritance

A

The locus is on the X chromosome

only one mutant allele is required for expression of the phenotype in females

21
Q

Autosomal dominant inheritance

A

Autosomal dominant inheritance - The locus is on an autosomal chromosome (1-22)
only one mutant allele is required for expression of the phenotype

22
Q

X-linked recessive inheritance

A

The locus is on the X chromosome and both alleles must be mutant alleles to express the phenotype in females

23
Q

These are pedigree characteristics of what?

• affected individuals receive a disease causing gene from ONE affected parent
- the disease is typically observed in sequential generations (Skipped generations are not typically seen because two unaffected parents cannot transmit a disease causing allele to their offspring (an exception occurs when there is reduced penetrance))
• Because these genes are located on autosomes, males and females are affected in roughly equal frequencies
The recurrence risk is thus 50%, so half the children will be affected - however if both parents are heterozygous, the recurrence risk is 75%, this is rare, and often more severe

A

Autosomal dominant pedigree characteristics

24
Q

These are pedigree characteristics of what?
• Both males and females are affected
• All offspring of an affected female are affected
• None of the offspring of an affected male is affected

A

mitochondrial inheritance pedigree characteristics

25
Q

These are pedigree characteristics of what?

• Males are affected, females are carriers of the disease

A

X-linked recessive inheritance pedigree characteristics

  • males inherit the mutant X from mother without a father’s X to cover over the diseased gene
  • It is possible for a female to get the disease, but she would have to inherit two mutant X chromosomes - and this is extremely rare
26
Q

These are pedigree characteristics of what?
• Heterozygous females are affected
• seen about twice as often in females as in males
• the disease phenotype is seen in multiple generations of a pedigree; skipped generations are relatively unusual

A

X-linked dominant inheritance pedigree characteristics

• females have two X chromosomes and thus two chances to inherit an X-Linked disease causing mutation and males have only one

27
Q

What are the characteristics of X-linked Dominant diseases?
Can they be transmitted from father to son?
Can they be transmitted from father to daughter?

A
  • Heterozygous females are affected
  • Cannot be transmitted from father to son (son will get X from his mother), obviously can be transmitted from father to daughter.
  • 2x more common in females compared to males
28
Q

Why can males get X-linked recessive diseases with just one mutated allele? (Normally two disease alleles are needed to manifest a recessive disease)

A
  • male inherits mutant X from his mother without a fathers X to counter the diseased gene
  • It is possible for a female to get the disease, but she would have to inherit two mutant X chromosomes - extremely rare

• Males are affected; females are carriers

29
Q

What is the difference between a missense mutation and a nonsense mutation?

A

Missense mutation - a single base change in the gene leading to a SNP. (Effect depends on substitution)

Nonsense - Creates a “stop” codon, releases partially complete protein –> result is a completely inactive protein or enzyme. Likely leads to severe disease (Israeli microcephaly)

30
Q

What is the difference between a gain-of-function and a loss-of-function mutation, and is one necessarily less troublesome than the other? (Think tumor suppressors vs. proto-oncogenes)

A
  • “loss-of- function” mutation causing a vital or protective protein to become non-functional in the cell (loss of Tumor Suppressors is one of the most famous examples)
  • “Gain-of-function” MC - the enzyme is over produced (Proto-oncogenes become Oncogenes) or a completely new enzyme is produced in the cell
31
Q

Why is consanguinity important in clinical medicine, even though it is rare amongst Americans?

A

• consanguinity (blood relation marriage - very common because of 1st cousins)

  • almost always results in autosomal recessive disease
  • higher likelihood of disease inheritance
  • 50% of all marriages in the world are this.
32
Q

What is Fragile X syndrome, why is it called that, and what determines its severity?

A

Fragile X Syndrome
MC inherited form of mental retardation (1/1000 males)

  • called this because it’s due to unstable repeats of CGCG at Xq27 - making it fragile (physically dangles by a thread on chromosome)
  • Severity correlates with number of CGG repeats
33
Q

What is the epigenetic significance of X Chromosome Inactivation, and what is a barr body?
Do barr bodies form when autosomal chromosomes are imprinted (as in for instance, Angelman Syndrome (AS) and Prader-Willi Syndrome (PWS)?)

A

• Female - only one X chromosome is active (Other inactivates early in fetal development - called a BARR body)
- happens in each cell, creating two different cell types - some mother X, some father X

• It occurs during gametogenesis via methylation to inactivate the decided X - maintained in all somatic cells of the offspring

  • environmental information can be imprinted during gamete formation
  • Imprinting refers to the fact that a small number of genes are transcriptionally active only when transmitted by one of the two sexes

Imprinting: one of chromosomes is shut down (like in AS and PWS)

34
Q

What is the general clinical characteristic of inherited mitochondrial disease?

A

Only passed on by females!
ALL OFFSPRING of an affected female are AFFECTED

No offspring of an affected male are affected.

Diseases: neuropathies and myopathies.
Affect small motor muscles first!

35
Q

What is the difference between penetrance, incomplete penetrance and variability?

A

Penetrance - proportion of individuals carrying a particular variant of a gene (allele or genotype) that also express an associated trait (phenotype).

Incomplete penetrance: some individuals who have the disease genotype do not display the disease phenotype

Variability - how “bad” the disease is when expressed

36
Q

What is recurrence risk (RR) and how is it calculated

A
  • 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
  • multiply the penetrance by either 25% (recessive) or 50% (dominant)
37
Q

What is pleiotropy? Is Marfan syndrome an example?

A

Pleiotropy - when a single disease causing mutation affects multiple organ systems.
Common amongst genetic diseases.

Marfans is an example with a bad fibrillin protein.

38
Q

What is anticipation? What does it imply will occur in each subsequent generation of a family carrying a mutation causing a disease characterized by anticipation?

A

Anticipation: Pattern of inheritance where severity and age of onset become more severe and occur earlier in each subsequent generation
(due to gradual expansion of trinucleotide repeat polymorphisms within or near a coding gene)

Ex: Huntington Dz

39
Q

How are the bands of a chromosome stained for a karyotype? What are the 3 types of bands that appear after staining?

A

Five different fluorescent probes are used that hybridize differentially to different sets of chromosomes
In combination with special cameras and image processing software, this technique produces a karyotype in which every chromosome is “painted” a different color
• ‘G’ bands are positive, negative or variable.

40
Q

How many BPs have to be involved in a deletion or duplication to be grossly detectable on a karyotype without using special immunofluorescent stains?
If the deletion is smaller than this number, can a FISH study be used to detect it?

A

Differences >4 Mb can be seen.

< 4Mb requires detection by FISH

41
Q

What is the main cause of NUMERICAL chromosome abnormalities?

A

meiotic non-disjunction (spindles behaving badly)

42
Q

Know the proper names (i.e. Alzheimer’s, Wilsons, etc.) and basic characteristics for trisomy 21, 18, and 13

A

-Trisomy 21: Down’s syndrome. MC autosomal trisomy, increased risk with older moms. Assoc. problems: risk of AVSD (40%), risk of ALL, decreased fertility, mental retardation, protruding large wrinkled tongue, flat nose and face, eye changes, short fifth finger, gap between 1st and 2nd toes, GI defects.
Risk: 1/1000 if younger than 30, 1/400 at age 35; 1/100 at age 40

-Trisomy 18: Edward’s syndrome - Very poor prognosis most don’t live past birth, cardiac abn: AVSD, PDA, Hand and foot malformations, Low set ears and micrognathia (undersized chin)

-Trisomy 13: Patau syndrome
- Polydactyly, Cleft lip, palate, Microphthalmia (small eyes), Microcephaly, Cardiac and renal defects
Very POOR prognosis

43
Q

Why aren’t there any autosomal Monosomies listed in the slides?

A

Autosomal monosomies are NOT compatible with life!

44
Q

Know the characteristics and Karyotype numbers for Turners syndrome, Klinefelter’s syndrome, and XYY

A

-Turner’s syndrome: ONLY monosomy consistent with life (because not autosomal, X-chromosome)
• 50% are 45,X.
- The rest are mosaics with 46,XX and 47,XXX occurring in different cells
- marked short stature (increased ht in pts tx’d with growth hormone injections), ovarian dysgenesis, and neurocognitive problems

-Klinefelter’s syndrome: 47,XXY
Predominantly male phenotype affect. Presence of both sex organs - RARE.
Hypogonadism usually manifests as low testosterone / high FSH and LH rather than testicular atrophy.
Males tend to be weaker and grow taller than average–may also have weak bones, wide hips and larger breasts which are most noticeable during puberty. Males often look normal as adults and often INFERTILE.

-XYY: Some medical geneticists question whether the term “syndrome” is appropriate for this condition because its clinical phenotype is normal (other than TALL STATURE).
• 47,XYY occurs in 1 in 1000 male births
as a result of error in chromosome separation during anaphase II of meiosis II (nondisjunction) creating sperm cells with an extra copy of the Y-chromosome.

45
Q

Through which mechanism is the Philadelphia chromosome formed?
What disease is it most often associated with?
Know how it will read on a karyotype { i.e. something like t(8;25) }?

A

Philadelphia chromosome results from reciprocal translocation of the long arms of chromosomes 9 and 22.

Results in Chronic Myelogenous Leukemia (CML)
-t(9,22) chronic myelogenous leukemia

others:

  • t(15;17) acute myelogenous leukemia (AML)
  • t(8;14) Burkitt’s lymphoma
46
Q

Can partial Monosomies occur? What would the karyotype of Down syndrome caused by a partial monosomy read?

A

Yes

Down Syndrome (trisomy 21)
45, XX or 45, XY
47
Q

Cri-du-chat results from what abnormality? Does the patient’s voice improve as they age?

A

Results from a piece of chromosome 5 missing

Cri-du-chat (cry of the cat) 46,XX or 46,XY, del(5p)

  • cry caused by abnormal larynx development
  • becomes less noticeable as the baby gets older, making it difficult to dx after 2
48
Q

For Angelman Syndrome (AS) and Prader-Willi Syndrome (PWS) - which chromosome (maternal or paternal) carries the microdeletion and what is the significance of both in the development of the field of epigenetics.

A

Angelman syndrome: Microdeletion on MATERNAL chromosome 15 (15q11-q13).
Laugh a lot, seizures, poor balance.

Prader-Willi: Microdeletion on paternal chromosome 15. Eat a lot, mental retardation, small, floppy newborns

49
Q

What is a ring chromosome, and what is its significance? How will it read on a karyotype?

A

Ring chromosome - can form when a deletion occurs on both tips of a chromosome and the remaining chromosome ends fuse together

Ring chromosomes are often lost, resulting in a monosomy ring

Karyotype: 46,X,r(X)

50
Q

In which disease is the translocation 46,XX or 46,XY, del(5p) - most often associated with?

A

Cri-du-chat

51
Q

What are isochromosomes, and are they seen in the autosomes in live patients?

A

When a chromosome divides along the axis perpendicular to its normal axis of division an isochromosome is created

This results in two copies of one, but no copy of the other

Because of the lethality of autosomal isochromosomes, most isochromosomes that have been observed in live births involving the X chromosome

52
Q

Who was George Price and what was his contribution to genetics?

A

Population geneticist

  • wrote equation that described evolution and natural selection and game theory equations.
  • Equation stated kindness was not by choice. Tried being more kind and later ended up killing himself.
53
Q

In the Overkalix studies, it was found that nutritional influences and their subsequent epigenetic markers could be transmitted to future generations.
1) When is it thought that these epigenetic effects are imprinted onto the fetus’s of women?
2) When can the influence be acquired for transmission by the males?
Also, are these the only times epigenetic effects can potentially be acquired by a person, and subsequently transmitted to future generations?

A

Females in utero, males in late childhood
imprinted during gamete formation

Not the only epigenetic effects acquired and transferred to future generations

54
Q

Did studies performed in mice at the world renowned - and prestigious - Washington State University in Pullman, demonstrate the cancer causing heritable changes in mice were not a result from a sequence change in the DNA itself?

A

Epigenetic changes can modify the activation of certain genes, but not the sequence of DNA

55
Q

Were the mice of the WSU study pregnant or pregnant and in the 3rd trimester when sprayed with pesticides? This suggests what about when epigenetic changes can take place?

A

(ans: NOOOO!)
Epigenetic changes are preserved when cells divide
Most epigenetic changes only occur within the course of one individual organism’s lifetime, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic changes are inherited from one generation to the next

56
Q

Know the major reasons gene therapy did not work out well.

A
  • Short-lived nature of gene therapy (therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable, hasn’t happened yet)
  • Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long- term benefits
  • Patients will have to undergo multiple rounds
  • Immune response - a foreign object introduced into human tissues, the immune system is designed to attack the invader
  • The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a potential risk
  • Furthermore, the immune system’s enhanced response to invaders it has seen before makes it difficult for gene therapy to be repeated in patients
  • Problems with viral vectors - Viruses, while the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient –toxicity, immune and inflammatory responses, and gene control and targeting issues
  • In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease
  • Multigene disorders - Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy.
  • Unfortunately, some the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer’s disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes (common diseases)
  • Multi-gene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy
57
Q

What is iRNA?

A

interference RNA
biological process in which RNA molecules inhibit gene expression, typically by causing the destruction of specific mRNA molecules.

58
Q

Can iRNA be passed to subsequent generations?

A

Yes

59
Q

What are knock-down studies? How do they work? What do they tell you about a gene? What is the most effective modality for performing knock-down studies?

A
  • iRNA is used to 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 (knock down studies)
  • In genetics this can be used to test the effect of mutated genes