FUN Quiz 3 Flashcards
What are the 3 Large scale types of genetic variation with a brief description of each.
Aneuploidy: One or more individual chromosomes in extra copy, or missing
Translocations/Inversions/ring chromosomes: Mixed Chromosomes
CNVs Copy Number Variants: Relatively large sections of DNA duplicated or deleted
How are ring chromosomes formed?
2 ends of the same chromosome fuse together
Distinguish briefly between heterochromatin and euchromatin. Also explain how it is shown in a karyoptype
Heterochromatin represent the dark band in karyotypes. They are AT rich yet gene poor
Euchromatin represent the light bands, are GC rich, and hence gene rich.
What are the Classifications of chromosomes based on centromereposition
Metacentric: Centromere in the middle
Submetacentric: Not in the middle nor at the terminal with one arm significantly longer than the other
Acrocentric: Centromere at terminus. Leftover DNA contains no genetic content.
What are the two arms of a chromosome and what differentiates them
Short arm is the P arm and long arm is the q arm
With the banding nomenclature of 1p13.3, where is the approximate location of the gene in question?
1: Chromosome number
p: Short arm of the chromosome
1: Region
3: Band
.3: Sub-band
Define Aneuploid
There is an abnormal chromosome number
What are the two types of chromosome abnormalities?
Numerical aberrations: incorrect number of chromosomes
Structural aberrations:
Involving 1 chromosome: Duplication, deletion, inversion, ring chromosome
Involving 2 chromosomes: Translocations;
Reciprocal translocations
Robertsonian translocations
Define Euploid
Correct number of chromosomes
Distinguish between Reciprocal translocations and Robertsonian translocations
Reciprocal translocations is the change of DNA between two non-homologous chromosomes. (Not normal cross-over)
Robertsonian Translocations: This occurs when two Acrocentric chromosomes fuse together to form one hybrid chromosome
How does Aneuploidy occur?
Chromosomal disjunction
What is Chromosomal disjunction?
It is the failure of chromosomes to separate and segregate normally either in mitosis or meiosis
Compare chromosomal disjunction in mitosis and meiosis.
When chromosomal disjunction occurs in meiosis, non-disjunction results in imbalanced gametes. If any of these gametes fertilise, all cells derived from the resulting embryo will have a chromosome imbalance.
When it occurs in mitosis, non-disjunction produces two cell-lineages derived from a single zygote causing Mosaicism
Individuals who are mosaic for a particular chromosomal aberration usually have less severe symptoms => Mitosis disjunction is less severe than meiosis disjunction. The earlier the disjunction happens during development, the more severe the outcome.
Distinguish between disjunction occurring in the first meiotic division and the second
If disjunction happens in the first division, gametes contain either both parental chromosomes or neither. If it happens in the second division, then gametes will contain two identical copies of the same chromosome.
Give three clinical signs of Down Syndrome
Developmental delay Variable intellectual disability Characteristic facial features Congenital heart defects Premature aging Risk of leukemia
What are the two ways Down syndrome can occur and which is predominant?
Trisomy (predominant), and Robertsonian translocation
What factor affects risk of trisomy 21?
Maternal age, risk increases with age
Give 3 Human Aneuploid Syndromes
Down Syndrome: Trisomy 21
Turner Syndrome: Monosomy X
Kleinefelter syndrome: XXY
Triple X Syndrome: idk
IF you included Edwards syndrome or Patau syndrome then good for you
What are the gametes produced in the following case as well as their viability when paired with a normal gamete:
Chromosome 14 and 21 fuse together by Robertsonian translocation.
Answer should only reflect chromosomes 14 and 21 in terms of gametes.
Full answer in PowerPoint
Trisomy 14 Dead Monosomy 14 Dead Trisomy 21: Down syndrome Monosomy 21: Dead T(14;21): carrier Normal
What are the two different types of structural chromosomal abnormalities and give one difference
Unbalanced abnormalities involves the loss or gain of genetic material. They often have developmental delays
Balanced abnormalities do not involve the gain or loss of genetic material. Heterozygous individuals can be at risk of passing on the abnormality to offspring.
What are the indications for prenatal cytogenetics?
- Abnormal ultrasound
- Advanced maternal age/biochemical test
- Previous birth of child with trisomy
- Infertility, recurrent spontaneous abortion
- Carrier of heritable chromosome abnormality
What are the clinical indications for post-natal Cytogenetics
Dysmorphic features
Developmental delay
Clinical features of chromosomal syndrome
What is a micro deletion syndrome
Syndrome that involves deletions that are often to small to detect by G banding
What are the viable methods for diagnosis?
Molecular cytogenetic methods including Array CHG and FISH
Why would scientists use Array CGH over FISH
Array CGH is a genome-wide detection method whereas FISH is only for a specific region or gene
Autosomal Dominant inherited disease is mostly ____ but can be seen in _________. Patients often die before _______ in heterozygotes and before ______ in homozygotes
Heterozygous
Homozygotes
Maturity
Reproductive maturity
Explain the Inheritance pattern of Autosomal dominant traits
- Pattern is vertical
- Box sexes have an equal chance of being affected
- Both sexes will transmit the mutation
- Approx 50% of the offspring of an affected parent will be affected
What is a vertical inheritance pattern
A disease that is passed from one generation to the next and each affected person has an affected parent
What is penetrance?
It refers to the proportion of individuals with a given genotype who show the associated phenotype.
Give an example of an autosomal dominant disease. Describe the disease and emphasize the the difference in severity between it’s homozygous and heterozygous state.
Familial Hypercholesterolemia is an autosomal dominant disease characterized by its mutation in the LDL receptor. This leads to an increase in levels of plasma LDL which hence increases LDL cholesterol. Individuals with this disease suffer extreme developments of plaques causing cardiovascular diseases such as myocardial infarction
Heterozygotes with this disease are more common yet have less severe levels of plasma LDL than homozygous (2x compared to 10x). Individuals with this disease in the heterozygous form tend to experience life-threatening CVDs later in life (30-40) when compared to it’s homozygous form (childhood/adolescence)
What is the most common autosomal dominant mating type? What is the expected offspring distribution
Heterozygote with dominant mates with normal homozygote. 50% of offspring will have the trait
What are some exceptions to the autosomal dominant inheritance pattern? Give examples or explain briefly
- Mutation: An individual that has no previous family history with the disease can develop a mutation with disease phenotype.
- Variable Expressivity: Some people with the same genotype might have different expressivity such as Polycystic Kidney Disease which has only 50% of patients develop the cysts in their kidney
- Reduced Penetrance: Some people with the genotype do not show any symptoms and still have offspring with that disease shown. This can be due to another gene that suppresses the disease or any other factor.
What is genetic Penetrance?
Penetrance refers to the proportion of individuals with a given genotype who show the associated phenotype.
How does a mutation at a single gene cause a disease phenotype?
- Haploinsufficiency: When a gene is transcribed onto an mRNA, a mutation can prevent the protein from being made or forcing its degredation. When heterozygote, this prevents the gene on one of the two chromosomes from producing a protein and hence there is a loss of 50% of normal activity => disease
- Dominant Negative Effect: Abnormal protein produced similar to above but in this case, the protein is not being degraded but does not function or does not function properly causing disease
- Gain of Function: Function of a mutant protein is enhanced and hence a once regulatory gene becomes permanently switched on. An example is Huntington Disease where a triple repeat makes the protein toxic to nerve cells
- Loss of Heterozygosity: Also known as dominantly inherited cancers, individuals will have an inherited copy of a mutant gene and a random loss of the normal allele. If it even occurs in a few cells, it will cause cancer.
Why are autosomal recessive diseases more common?
Carriers are not at a selective disadvantage. Even if affected individuals do not breed, the mutation can still become widespread as most are carriers.
Can autosomal recessive traits and autosomal dominant traits skip generations?
Recessive can, dominants cannot
What is the most common autosomal recessive mating type? What are the expected offspring
2 carriers mating. 25% fo offspring will have disease where it can only be shown if both gametes with the disease are passed on. There is a 1/2 chance for carriers
What is Consanguinity?
When 2 individuals that are related mate
How does Consanguinity affect recessive inheritance
Increases chances of disease to be present in offspring due to shared ancestral DNA
How are AR diseases identified?
Give 3
- Newborn Screening
- Multiple siblings affected
- Parental Consanguinity: Preferential mating behavior increases incidence of disease.
- Demonstration of a partial defect in obligate heterozygotes where there are some deficiencies present in parents. Ex. 50% enzyme activity. Or sickle cell anemia in parents.
Define Genetic Heterogeneity and define the two types.
Genetic Heterogeneity is where the same clinically diagnosed disease is caused by different DNA sequence defects, producing identical or similar clinical phenotypes.
Allelic Heterogeneity is where different DNA sequences/mutations are on the same gene
Locus Heterogeneity is where different DNA sequences are found on different genes
Explain the nomenclature of a mutation in phenylalanine hydroxylase R408W
R is Argentine => R
408 is the codon number
In this mutation R becomes W (Tryptophan) => W
Hence R408W
Explain the nomenclature of a mutation in the Cystic Fibrosis gene: F508del
Phenylalanine F
Codon 508
This codon is deleted and hence del.
Give an Example of Allelic Heterogeneity. Explain briefly.
Allelic Heterogeneity is defined as different mutations on the same gene. An example is Phenylketonuria (PKU).
PKU is autosomal recessive and occurs due to a mutation of the Phenylalanine Hydroxylase (PAH) gene located on chromosome 12.
PAH converts Phenylalanine (Phe) into Tyrosine (Tyr).
There are hundreds on mutations on the PAH gene that each give different phenotypes (since Phe is changed into multiple different kinds of molecules) but have the same diagnosis of PKU.
This range of enzyme activity can be treated in different ways based on the specific mutation.
Majority are E390G
Give an example of Locus Heterogeneity. Explain Briefly
It is the same clinical disease caused by mutations in different genes. They are often complex pathways or complex structure.
A disease example is Retinitis Pigmentosa which is associated with over 50 genes. It involves several genes that carry instructions for proteins within photoreceptors.
Symptoms of this include Night blindness, Tunnel vision, and blindness
Locus Heterogeneity often has its effects in two different ways. What are they?
Complex pathways or complex structure
The X found in G542X signifies…
Change of Guanine into a stop codon
True or false: Males are Hemizygous for the X chromosome
True
Why do males and Females produce equal amounts of proteins encoded by genes on the X chromosomes? Explain
Females have dosage compensation where quantity of protein product formed is equivalent.
This is called X-chromosome inactivation or Lyonization.
This inactivation occurs in embryonic life and is random between paternal and maternal X. This occurs in every cell (similar to mosaic). This is permanent and all daughter cells from that cell are identical.
The inactive X appears as a dark-staining mass known as a Barr-Body
Are all X-linked mutant genes fully expressed in males?
Yes since they have 1 X chromosome
Learning Outcome: Explain the effects of X inactivation that occurs in females as well as the characterization of XLR vs XLD
X linked traits are variably expressed in females. They may have:
An intermediate effect where they are clinically unaffected but Biochemically abnormal
Skewed X inactivation: Normal phenotype where more than random X chromosomes containing the mutant gene are inactivated
Manifesting Heterozygote: Clinically affected where more than random X chromosomes containing the normal gene inactivated
This means that an X-linked disease may or may not be expressed clinically in a heterozygous female.
Diseases are characterized as XLR and XLD depending on the relative proportions of females who are affected.
Diseases which are rarely expressed clinically in females are said to be X-linked recessive (most) and diseases which are expressed clinically in many females are said to be X-linked dominant (very few)
Briefly describe X-linked recessive inheritance including an example.
X-linked recessive transmission occurs in the complete absence of male-male transmission.
Males are mainly affected in the pedigree and can be born to unaffected parents.
An example of this is Hemophilia A where there is a deficiency in Factor VIII which is an essential clotting factor.
Vertical Transmission
Briefly explain XLD inheritance giving an example.
There is complete absence of male-male transmission since males only give the Y chromosome from the father.
An affected male will have no affected male offspring but all females affected. An affected female has a 50% chance to pass it on to both male and female offspring
Vertical Transmission
An example is Hypophosphatemia (Vitamin D resistant) RICKETS. It involves the inability of kidneys to retain phosphate causing low blood and high urinary phosphate levels. This causes short stature and bony deformities.
Explain Extra-nuclear inheritance giving an example
This involves the transmission of mitochondrial DNA or mtDNA. It is maternally transmitted via the ovum (since the ovum has the cell contents)
An example of this disease is Leber’s Hereditary Optic Atrophy. This involves the loss of central vision in the late 20s.
Transmission affects both sexes. Males will not transmit to offspring and females will transmit to all offspring.
Vertical Transmission
Differentiate between homoplasmy and heteroplasmy
Homoplasmy is where every mt genome contains mutation
Heteroplasmy is where there is a mixed population of normal and mutant mt genome
The greater the proportion of mt genome, the more severe the disease
What type of genetic heterogeneity are Triplet Repeat Disorders characterized as?
Give an example
Allelic Heterogeneity: Same clinically diagnosed disease caused by different DNA sequence defects producing identical or similar clinical phenotypes
PKU
Learning Outcome: Discuss triplet repeat disorders, parent of origin effects and anticipation with examples of Huntington’s disease and Fragile X syndrome
These mutations are unstable or dynamic where they can change as it passes down through a pedigree.
Normally there are a low number of repeats. Some individuals are at the upper limits of normal and are capable of expanding into a disease (permutation stage). A mutation occurs when the repeat number exceeds the limit causing disease
Triple repeat disorders may be classified as dominant, recessive, or X-linked
These disorders May be subtle (subtle disease) or explosive (Fragile X syndrome) at an individual disease.
Parent of Origin Effect: Premutation where expansion occurs. Also known as the origin of where it expands. Male germline through spermatogenesis and female Germaine through oogenesis. For Huntington’s disease, if the gene has been cast from a father to the next generation, it is likely to expand into a disorder but if it is from the mother then it is not likely. For Fragile X syndrome, it is the opposite
When the repeat expands down a pedigree, its associated with more severe and earlier onset also known as ANTICIPATION.
Fragile X syndrome: X-linked disorder and is the most common form of inherited mental disability in males with a characteristic facial appearance. Can also occur in females. The molecular defect is in the FMR1 gene which has a CGG triplet repeat in its 5’ UTR. During meiosis in female oogenesis, the repeat is unstable and can increased in length. This is an example of a modified X-linked inheritance where it expands throughout a pedigree. It is explosive.
Huntington’s disease is an autosomal dominant disorder. It is an example of a paternal parent of origin effect and anticipation where the increase in repeats occurs during meiosis in spermatogenesis. There is an earlier age of onset associated with larger repeat number. One mutated copy can cause the disease (since dominant).
What are drugs?
Substances that have beneficial biological activities
Are Vitamins and other dietary factors considered a drug?
No, unless taken in excess of normal dietary intake
LEARNING OUTCOME: Outline the limitations of using plant extracts as drugs. How are plant-based drugs made now.
Plant extracts contain many substances which increase the likelihood of toxicity
Rather than use plant extracts, we now purify active ingredients. One approach is to take a known herbal remedy and extract the active ingredient. Another approach is to screen plant extracts for biological activity.
Summary: Drugs are no longer derived directly from the plant.
