Genetics

Question 1

Define Genetics

Answer 1

Genetics is the study of heredity and the variations in inherited characteristics and dis- eases.

Question 2

Define Epigenetics

Answer 2

epigenetics refers to the study of heritable processes that alter gene expression without changing the DNA sequence.

Question 3

Define Alternate Splicing

Answer 3

Allows different isoforms of a particular protein to be expressed. Vascular endothelial growth factor and its receptors have various isoforms due to this mechanism.

Question 4

What are the 4 distinct cell cycle phases

Answer 4

• G1 (growth, preparation for DNA synthesis) * S (DNA synthesis/chromosome replication) * G2 (growth, preparation for mitosis)
• M (mitosis and cytokinesis)

Question 5

What are the phases of mitosis

Answer 5

• prophase (chromatin is condensed into chromosomes)
• metaphase (chromosomes align in the middle of the cell)
• anaphase (chromosomes split and migrate to opposite poles of the cell)
• telophase (2 daughter nuclei form at the poles of the cell)

Question 6

Meiosis vs Mitosis

Answer 6

outcome of meiosis is 4 genetically unique haploid cells, whereas the outcome of mitosis is 2 genetically identical diploid cells.

Question 7

Cell cycle checkpoints

Answer 7

• G1: transition from G1 to S * G2: transition from G2 to M
  At the G1 checkpoint, cell size and the availability of nutrients and growth factors are assessed, and the cell is checked for DNA damage. After completion of this checkpoint, the cell is committed to proceeding with cell division; otherwise, it enters the quiescent G0 phase. Before the cycle progresses to the M phase, further inspection of the DNA occurs at the G2 checkpoint. If damaged DNA is detected at either checkpoint, it may be repaired, or programmed cell death (see the section Apoptosis) may be initiated.

Question 8

Checkpoint regulation

Answer 8

occurs via a family of proteins known as cyclins and cyclin- dependent kinases (CDKs).
At the G1 checkpoint, CDK phosphorylation of proteins of the retinoblastoma (Rb) family facilitates downstream transcription in preparation for S phase. Tumor suppressor genes like the Rb family often have a role in regulation of the cell cycle, dysregulation of which can lead to cancer (see the section “Tumor suppressor genes”).

Question 9

Non coding DNA

Answer 9

Noncoding DNA is composed of highly repetitive sequences, some of which include satellites, microsatellites, short interspersed elements (SINEs), and long interspersed elements (LINEs). The 300-base-pair (bp) Alu sequence, named after the re- striction enzyme used to identify it, is the repetitive DNA that appears most frequently. Noncoding DNA comprises introns, promoters, and other regions within chromosomes and mitochondria and is involved in regulating gene expression and exon splicing.

Question 10

Transcription factors

Answer 10

There are numerous families of these genes, including the homeobox and paired box genes. PAX6 acts as a master control gene for the development of the eye, an example of the key role of transcription factors in embryogenesis.

Question 11

Conditions associated with Transcription factor mutations

Answer 11

PAX2 mutations cause colobomas of the optic nerve and renal hypoplasia.
PAX3 mutations cause Waardenburg syndrome with dystopia canthorum (types WS1 and WS3).
PAX6 muta- tions are the basis of virtually all cases of aniridia, occasional cases of Peters anomaly, and several other rarer phenotypes, specifically autosomal dominant keratitis and dominant foveal hypoplasia.

Question 12

Where does splicing of introns occur

Answer 12

Splicing takes place in specialized structures called spliceosomes, which are composed of RNA and proteins. Errors of splicing can lead to genetic disease. For example, mutations in proteins that are vital in splicing can cause retinitis pigmentosa (RP).

Question 13

X- inactivation

Answer 13

The random permanent inactivation of 1 of the 2 X chromosomes in the female, result- ing in the lack of expression of the majority of genes on that chromosome, is a significant event during early development of the human embryo. The time of X-inactivation is not precisely known but is thought to vary over a period of several cell divisions during the blastocyst–gastrula transition. X-inactivation is also known as lyonization, after its dis- coverer, Mary Lyon. Lyonization affects the severity of the phenotype of several X-linked retinal conditions, such as RP and incontinentia pigmenti.

Question 14

Imprinting

Answer 14

Genomic imprinting is a heritable yet reversible process by which a gene is modified, de- pending on which parent provides it. The mechanism is unclear but appears to operate at the chromatin organization level and involves heterochromatization and methylation of CpG (cytosine-phosphate-guanine) sites.

Question 15

Prader-Willi mutation

Answer 15

deletion of the paternally derived 15q11–q13, resulting in the loss of this region’s normal contribution from the paternal line.

Question 16

Angelman Syndrome

Answer 16

have a deletion of 15q11–q13, but from the maternally derived chromosome, resulting in loss of the maternal contribution.

Question 17

DNA Repair

Answer 17

Damaged DNA sites are repaired chiefly by 2 mechanisms: excision repair and mismatch repair.

Question 18

Guardian of the genome

Answer 18

p53 revents cells from proliferating if their DNA is irreparably damaged. Levels of p53 increase after UV or ionizing radiation exposure. The p53 gene inhibits DNA replication directly and binds with 1 of the RNA polymerase transcription factors, TFIIH. If the degree of damage is slight, increased production of p53 induces reversible cell arrest until DNA repair can take place. If DNA damage is too great or irreversible, p53 production is massively increased and apoptosis occurs, probably through stimulation of the expression of the BAX gene, whose product promotes apoptosis. Loss of p53 causes cells to fail to arrest in response to DNA damage, and these cells do not enter apoptosis. Thus, mutations of p53 predispose to tumorigenesis.

Question 19

Ataxia telangiectasia

Answer 19

The gene mutated in ataxia-telangiectasia (Louis-Bar syndrome), a protein kinase called ATM, also appears to be integrally involved in DNA repair, possibly by inform- ing the cell of radiation damage. The ATM gene product associates with synaptonemal complexes, promotes chromosomal synapsis, and is required for meiosis. Individuals with ataxia-telangiectasia have a threefold greater risk of cancer.

Question 20

Xeroderma pigmentosum

Answer 20

a severe condition in which the functions of enzymes that repair UV-damaged DNA are crippled. Patients with this condition typically have diffuse pigmented anomalies on their sun-exposed skin and are at high risk for basal cell and squamous cell carcinoma, as well as melanoma. Ocular surface cancers (squamous
cell carcinoma and melanoma) can also develop in affected patients.

Question 21

Apoptosis

Answer 21

Apoptosis is the process of programmed cell death that occurs in multicellular organisms, in contrast to necrosis, a form of traumatic cell death that results from acute cellular injury.Morphological changes include cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation.

Question 22

Mutations vs Polymorphisms

Answer 22

Mutations are changes in DNA that can lead to disease, whereas polymorphisms are variations in DNA that were previously thought to rarely cause disease.

Question 23

Mutations

Answer 23

can involve a change in a single base pair; simple deletion or insertion of DNA material; or more complex rearrangements such as inversions, duplications, or translocations.

Question 24

Deletion/Insertion mutation of DNA

Answer 24

Deletion, insertion, or duplication of any number of base pairs in other than groups of 3 creates a frameshift in the entire DNA sequence downstream, resulting in the eventual formation of a stop codon and truncation of the message.

Question 25

Gain of function Mutation

Answer 25

Mutations can also lead to a gain of function that may be beneficial (leading to evolution) or detrimental (leading to disease). An example of a beneficial gain in function is the emergence, among bacteria, of antibiotic resistance. An example of a detrimental gain of function is a receptor protein that binds too tightly with its target protein, creating loss of normal physiologic function. Most autosomal dominant disorders are of this type.

Question 26

Gene in AMD

Answer 26

CFH

Question 27

Gene in Pseudoexfoliation syndrome

Answer 27

LOXL1

Question 28

Oncogenes

Answer 28

Oncogenes behave the same way that autosomal dominant traits behave, and only 1 mutant allele is needed for tumor formation, presumably by a dominant-negative effect on regulation of signal transduction.

Question 29

Examples of tumour suppressor genes

Answer 29

genes for retinoblastoma, Wilms tumor, neurofibromatosis types 1 and 2, tuberous sclerosis, ataxia-telangiectasia, and von Hippel–Lindau disease. All of these examples (except ataxia-telangiectasia) behave as autosomal dominant traits,

Question 30

Tumour suppressor genes

Answer 30

If 1 allele is already defective because of a hereditary mutation, the other allele must also be lost for tumor formation to occur (also known as the 2-hit hypothesis). This loss of the second allele is termed loss of heterozygosity, and it can occur from a second mutation, gene deletion, chromosomal loss, or mitotic recombination.

Question 31

Mitochondrial disease

Answer 31

Mitochondrial diseases should be considered whenever the inheritance pattern of a trait suggests maternal transmission.

Question 32

Mitochondrial disease with large rearrangements of mtDNA (deletions or insertions)

Answer 32

chronic pro- gressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome, and Pearson marrow-pancreas syndrome

Question 33

Mitochondrial disease with mutations of mtDNA-encoded ribosomal RNA (rRNA)

Answer 33

maternally inherited sensorineural deafness and aminoglycoside-induced deafness

Question 34

Mitochondrial disease with mutations of mtDNA-encoded tRNA

Answer 34

syndromes of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes),MERRF (myoclonic epilepsy with ragged red fibers), MIDD (maternally inherited
diabetes and deafness), and (in about 30% of cases) CPEO

Question 35

Mitochondrial disease with missense and nonsense mutations

Answer 35

Leber hereditary optic
neuropathy; and neuropathy, ataxia, and RP

Question 36

CPEO

Answer 36

CPEO is a disorder involving progressive ptosis and paralysis of eye muscles associated with a ragged red myopathy, usually as a result of deletion of a portion of the mitochondrial genome.

Question 37

CPEO-plus syndromes

Answer 37

Kearns-Sayre syNdrome, CPEO is associated with heart block and severe RP with marked visual impairment.
Pearson marrow-pancreas syndrome results from a large deletion of mtDNA and presents in younger patients with an entirely different phenotype involving sideroblastic anemia and pancreatic exocrine dysfunction.

Question 38

LHON

Answer 38

more prevalent in males than in females but does not fit a classic X-linked pattern of transmission. The trait is not transmitted to the offspring of affected males, but virtually every daughter and son of a female patient with LHON inherits the trait

Question 39

Gene associated with LHON

Answer 39

ND-4 (50%)
ND1 and ND6

Question 40

Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP)

Answer 40

associated with a single base-pair mutation at nucleotide position 8993 in the ATPase-6 gene. The NARP phenotype occurs when the percentage of mutant mtDNA is less than 80%, whereas the same mutation present at much higher proportions (greater than 95%) can cause Leigh syndrome, a severe neurodegenerative disease of infancy and early childhood. The 8993 mutation is demonstrable in fibroblasts and lymphoblasts.

Question 41

Limits of curative genetic therapies

Answer 41

the main long-term gene therapy vehicle—viruses—is currently limited by the size of the gene, inflammatory effects, and the risk of oncogenesis

Question 42

Vectors for gene therapy

Answer 42

Vectors used to carry the genetic material into the cells include adenoviruses, retroviruses (especially adeno-associated viruses [AAVs]), and plasmid–liposome complexes. AAV vector gene therapy has been successful in curing many disorders in animal models, such as the RPE65 gene mutation that causes RP in the Briard dog.