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75 Cards in this Set
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Lecture 3: Genetic Markers, Linkage, DNA Structure, Mutations |
Objectives:
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What are genetic markers? |
Any characteristic located at the same position on a pair of homologous chromosomes that allow us to distinguish between the maternal chromosome and the paternal chromosome. |
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What needs to be present in order to have a genetic marker? |
Differences in the DNA sequence at a particular locus i.e. DNA polymorphism |
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True or False - Genetic polymorphisms are all deleterious? |
False - Not all changes to DNA sequence are deleterious. Some may contribute to genetic diversity and have other functions such as in gene regulation and expression. |
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What is a polymorphism? |
Variant DNA sequence found in > 1% of chromosomes in the population. Usually benign = no effect in phenotype. |
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What are the two main categories of genetic markers? |
SNP markers and Microsatellite markers. |
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What is a SNP marker? |
Single nucleotide polymorphism. A single nucleotide difference. 4 possible alleles (because 4 possible bases). Alleles are same size. |
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What is a Microsatellite marker? |
Di-, tri-, tetranucleotide repeats. Many different allelic combinations. Different sizes of alleles. |
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How can you distinguish between a SNP and a Microsatellite marker? |
SNP is only one nucleotide difference and the alleles are the same size. Microsatellite markers have repeating segments and different sizes of alleles. |
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What is a genotype? |
Alleles at one particular marker. |
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What is a haplotype? |
Alleles at all markers inherited paternally vs. maternally. |
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What is Mendel's Law of Independent Assortment (2nd Law)? |
When two or more characteristics are inherited, individual hereditary factors (genes) assort independently during gamete production, giving different traits an equal opportunity of occurring together. |
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What are linked genes? |
-Loci close together -Departure from independent assortment -Recombination occurs less. |
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What are unlinked genes? |
-Loci are far apart -Loci assort independently -Recombination occurs. |
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What is recombination? |
Process by which two DNA molecules exchange genetic information, resulting in the production of a new combination of alleles. During meiosis, exchange of material between the maternal and paternal non-sister chromatids occurs during pachytene. |
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Why is recombination important? |
-Genetic diversity -Identify maternal and paternal chromosomes/regions -Track diseases -Risk prediction when causative gene is unknown or testing is not available. |
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Which bases are the purines? Pyrimidines? |
"Pure AG". CT. |
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What is genomic DNA? |
All the 3 million + base pairs in a human genome. |
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What is coding DNA? |
Sequence of DNA that codes for genes. Transcribed into RNA and translated into proteins. (Not referring to template or coding strand, referring to double stranded segment of DNA) |
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What is non coding DNA? |
The remainder of the DNA. Likely has a role in variation, genome maintenance and gene regulation. |
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Genes are made up of what components? |
Introns, Exons, Promoters, etc. |
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What are the two main classes of mutations? |
Gene and chromosomal mutations. |
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How do gene mutations occur? |
DNA damage or improper replication (Ex. mutation in DNA repair or cell cycle checkpoint gene) |
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Point mutation |
A single nucleotide base pair change in DNA. |
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Missense mutation |
A single base pair change in DNA sequence that results in a change in the codon and resulting amino acid. |
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Nonsense mutation |
A single base pair change in DNA sequence that results in the production of a premature stop codon.
Ex. Duchenne's Muscular Dystrophy |
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Silent mutation |
A single base pair change in DNA sequence that does not change the amino acid. |
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Broad category: Loss of function mutation |
A mutation that results in the reduction or complete loss of the normal function of the protein. |
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Broad category: Gain of function mutation |
A mutation that results in an increase in the normal function of the protein. |
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Frameshift mutation |
A loss or gain of DNA sequence that is not an exact multiple of 3 bases that alters the downstream reading frame of the gene.
Ex. Tay Sachs, cystic fibrosis |
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Dominant negative mutation |
A mutation of one allele that also disrupts the function of the wildtype allele in the same cell i.e. makes the wildtype behave in a manner that it's not supposed to.
Ex. GTPase RAS |
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Splice site mutation |
A mutation that interferes with normal RNA splicing. |
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Deletion |
The loss of DNA sequence. Single base pair to parts of chromosome. |
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Insertion/duplication |
The gain of DNA sequence. It can be as small as single base pair to part of or an entire chromosome. |
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Novel Property Mutation |
A mutation that results in a protein with a new function. |
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New gene fusions |
Bring two genes together and fuse. |
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Which type of mutation produces the severest phenotype? |
I don't know. |
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What are examples of clinical gene mutation testing? |
Single gene mutation testing, Confirmation of diagnosis, Assessment of carrier status, Prenatal testing, Presymptomatic testing |
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Lecture 4: Chromosomes |
Objectives: |
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What is cytogenetics? Clinical cytogenetics? |
Cytogenetics = The study of chromosomes - structure and number.
Clinical cytogenetics = study of chromosomal abnormalities in a medical context. |
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What are balanced chromosomal rearrangements? What are unbalanced chromosomal rearrangements? |
Balanced = entire genome is represented but may be in different order.
Unbalanced = parts of genome is missing or duplicated |
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What is a karyotype? |
The characterization of the chromosomal complement of a cell, including number, size and shape of the chromosomes by band-by-band analysis - whole genome analysis. |
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What is a karyogram? |
Display of the chromosomes as a systematized arrangement of chromosome pairs in descending order of size. |
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What are the 3 major types of cytogenetic analyses? |
-Fluorescence In Situ Hybridization (FISH) -Spectral Karyotyping -Chromosomal Microarray |
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Describe FISH. |
Basically asking: Is this gene that we're looking for present or absent? Use fluorescent probe to tag specific genes or loci.
NOT a whole genome assay.
Look for specific rearrangements/translocations, or the presence or absence of a particular gene/region (deletion or duplication). |
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Describe Spectral Karyotyping. |
Advanced FISH technique where probe labeled with same color spanning whole chromosome. Color mismatching shows make up of chromosome (useful to study chromosome activity in cancer cells). |
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Describe Chromosomal Microarray. |
Allows for high resolution, whole genome analysis. Detects small and large copy number gains/losses that are NOT visible under the microscope. Indirect method that is not as visual as the other two.
Balanced abnormalities will look normal. |
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List 3 areas cytogenetic testing is ordered clinically. |
-Prenatal Diagnosis -Constitutional Studies -Cancer Studies |
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Why is cytogenetic testing required in prenatal diagnosis? |
If the mother is old (>40y), if the mother tests positive for something, if there is a family history of chromosome abnormality, or if there is an abnormal ultrasound. |
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Why is cytogenetic testing required in constitutional studies? |
Constitutional cytogenetics refers to the study of the molecular aspects of heredity, chromosome structure, and the identification of genetic aberrations and variants linked to disease.
If there is a developmental delay (mental retardation), congenital abnormalities, reproductive medicine (reproductive loss, azoospermia, premature ovarian failure, stillborn, infertility), or if there is family history (useful for assessing risk). |
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Why is cytogenetic testing used in cancer studies? |
For the diagnosis of specific cancers, prognostication, treatment decisions, disease monitoring (residual disease, post-transplant). |
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List the specimen types that cytogenetic testing can be performed on? |
-peripheral blood (constitutional) -amniotic (prenatal) -chorionic villi sample (prenatal) -bone marrow -tissues: product of conception, tumors, paraffin embedded tissue -cord blood -fetal blood (heart) -buccal -fibroblast |
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Why do we culture cells and capture them in metaphase during mitosis? |
Most condensed state of chromosomes, nuclear membrane is dissolved, line up along metaphase plate (easy to see under microscope)/ |
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Do specimens have to be fresh? |
Yes in most cases, with the exception of paraffin embedded tissue for which only the FISH studies are possible. |
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How can you identify a centromere on a karyogram? |
Indicated by constriction/pinching. |
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What is a satellite? |
Very large arrays of tandemly repeating, non-coding DNA. Satellite DNA is the main component of functional centromeres, and form the main structural constituent of heterochromatin. Satellites do not have same sequence as regular telomeres. |
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Where can you find satellite stalks? |
p arm of acrocentric chromosomes. |
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What are metacentric chromosomes? |
Centromere in middle, p and q are equal length.
Ex. Chromosome 1 and 3. |
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What are submetacentric chromosomes? |
Unequal arm length. Ex. Chromosome 4 |
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What are acrocentric chromosomes? |
Very short p arm which contains satellite stalks and satellites. |
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Why are chromosome bands significant? |
-Help us identify chromosomes -Help us identify chromosome region where a structural abnormality takes place -Provide clues on DNA composition (i.e. gene rich and gene poor areas) |
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What is band resolution? |
How well you can distinguish the individual bands. |
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Lecture 7: Population Genetics |
Objectives |
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What is population genetics? |
Quantitative study of genetic variation in populations.
How these genes are passed around, what phenotypes results, and factors influencing distribution of alleles in population. |
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State the Hardy Weinberg principle. |
p^2 + 2pq + q^2 = 1 |
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What are the assumptions for the Hardy Weinberg Principle to hold true (i.e. in order for the population to be at equilibrium)? |
-population is large and mating occurs at random -no appreciable rate of mutaton -no selection against any particular genotype -no significant immigration of individuals from a population with allele frequencies very different from the endogenous population |
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In what types of disease can the Hardy Weinberg Principle be applied? |
Auto and sex-linked recessive. |
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List the Factors Disturbing the Hardy Weinberg Equilibrium. |
-Assortative Mating -Genetic Drift -Gene Flow |
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What is assortive mating? |
Choice of mate because mate possesses certain trait. Can be positive or negative. Ex. people with similar body size mate with each other. |
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What is genetic drift? |
Chance events have much larger impact on allele frequencies of small populations than large ones. Results in decrease of gene pool. |
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What is the founder/bottleneck effect? |
Small population breaks off from the larger one, the gene frequencies in the small population may be different that in the larger population. Far greater frequency of founder alleles in newly formed population. This is a form of genetic drift. |
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What is gene flow? |
Slow diffusion of genes across a barrier (one population to another). Usually involves large population and a gradual change in gene frequency. The barrier can be geographic, racial, ethnic, cultural. |
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What is Selection (reproductive fitness)? |
Selection = the operation of forces that determines the relative fitness of a genotype in a population, thus affecting the frequency of the gene concerned. |
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What is consanguinity & inbreeding? |
Consanguinity = relationship by descent from a common ancestor i.e. KINSHIP
Inbreeding = mating of closely related individuals --> leads to increase in number of individuals who are homozygous for an allele therefore increasing the appearance of recessive traits.
A consequence of the founder/bottleneck effect. |
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What is stratification? |
Population contains a number of subgroups whose members have not freely and randomly mated with the members of other subgroups. Ex. caste system in India. |
