Genetics Flashcards
Define Genetics
Genetics is the study of heredity and the variations in inherited characteristics and dis- eases.
Define Epigenetics
epigenetics refers to the study of heritable processes that alter gene expression without changing the DNA sequence.
Define Alternate Splicing
Allows different isoforms of a particular protein to be expressed. Vascular endothelial growth factor and its receptors have various isoforms due to this mechanism.
What are the 4 distinct cell cycle phases
- G1 (growth, preparation for DNA synthesis) * S (DNA synthesis/chromosome replication) * G2 (growth, preparation for mitosis)
- M (mitosis and cytokinesis)
What are the phases of mitosis
- 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)
Meiosis vs Mitosis
outcome of meiosis is 4 genetically unique haploid cells, whereas the outcome of mitosis is 2 genetically identical diploid cells.
Cell cycle checkpoints
- 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.
Checkpoint regulation
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”).
Non coding DNA
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.
Transcription factors
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.
Conditions associated with Transcription factor mutations
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.
Where does splicing of introns occur
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).
X- inactivation
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.
Imprinting
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.
Prader-Willi mutation
deletion of the paternally derived 15q11–q13, resulting in the loss of this region’s normal contribution from the paternal line.
Angelman Syndrome
have a deletion of 15q11–q13, but from the maternally derived chromosome, resulting in loss of the maternal contribution.
DNA Repair
Damaged DNA sites are repaired chiefly by 2 mechanisms: excision repair and mismatch repair.
Guardian of the genome
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.
Ataxia telangiectasia
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.
Xeroderma pigmentosum
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.
Apoptosis
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.
Mutations vs Polymorphisms
Mutations are changes in DNA that can lead to disease, whereas polymorphisms are variations in DNA that were previously thought to rarely cause disease.
Mutations
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.
Deletion/Insertion mutation of DNA
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.
Gain of function Mutation
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.
Gene in AMD
CFH
Gene in Pseudoexfoliation syndrome
LOXL1
Oncogenes
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.
Examples of tumour suppressor genes
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,
Tumour suppressor genes
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.
Mitochondrial disease
Mitochondrial diseases should be considered whenever the inheritance pattern of a trait suggests maternal transmission.
Mitochondrial disease with large rearrangements of mtDNA (deletions or insertions)
chronic pro- gressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome, and Pearson marrow-pancreas syndrome
Mitochondrial disease with mutations of mtDNA-encoded ribosomal RNA (rRNA)
maternally inherited sensorineural deafness and aminoglycoside-induced deafness
Mitochondrial disease with mutations of mtDNA-encoded tRNA
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
Mitochondrial disease with missense and nonsense mutations
Leber hereditary optic
neuropathy; and neuropathy, ataxia, and RP
CPEO
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.
CPEO-plus syndromes
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.
LHON
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
Gene associated with LHON
ND-4 (50%)
ND1 and ND6
Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP)
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.
Limits of curative genetic therapies
the main long-term gene therapy vehicle—viruses—is currently limited by the size of the gene, inflammatory effects, and the risk of oncogenesis
Vectors for gene therapy
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.
