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85 Cards in this Set

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Genetic mapping
Ordering of genes on chromosome according to recombination frequency
Physical mapping
Determination of physical distances between genes using cytogenetic and molecular techniques
Linked genes
Genes that are located close enough on chromosome that their recombination frequency is less then 50%
Haplotype
Combination of alleles on each chromosome
Recombination
Occurence among offspring of new combinations of alleles resulting from crossovers that occur during parental meiosis
Centimorgan
Unit of measure of frequency of recombination between two loci - also known as map unit

1cM = 1% recombination frequency
Syntenic loci
Two loci located on the same chromosome - may or may not be linked
Linkage phase
chromosome on which each allele is located
Markers
Polymorphisms such as RFLP's VNTR's microsatellite repeats and blood groups that are linked to disease locus
Recombination hot spot
Region of chromosome in which recombination frequency is elevated
Uninformative mating
mating in which linkage phase cannot be established
Positional cloning
Isolation of partially overlapping DNA segments from genomic libraries in attempt to progress along chromosome toward disease gene
Functional cloning
Method of isolating genes in which a gene whose protein product's function is already known is evaluated as a candidate gene responsible for trait or disease
Contig map
Physical map of chromosome region constructed by isolating overlapping DNA segments
Sequence tagged sites
DNA sequences of several hundred bp that are flanked by PCR primers. Their chromosome location has been established making them useful as indicators of physical positions on genome
Expressed sequence tags
Several hundred bp of known cDNA sequence flanked by PCR primers - because they are derived from cDNA libraries these sequences represent portions of expressed genes
CG islands
Unmethylated CG sequence that are found near 5" end of genes
Exon trapping
Method for isolating exons in fragment of genomic DNA by using an in vitro cell system to artificially splice out introns
LOD score of _ is evidence of linkage
3
TO be useful in gene mapping linked markers should be _
Codominant
Numerous
Highly polymorphic
High degree of polymorphism increases probability that _
Matings will be informative
Linkage equilibrium
If we study a large collection of families and find there is no preferential association between disease gene and specific allele at linked marker locus - so if mutation occurs equal with marker 1 and with marker 2 - markers are in linkage equlilibrium
Linkage disequilibrium
Nonrandom association of alleles at lnked loci - diminishes through time as result of recombination, can be used to infer order of genes on chromosomes
Association
Two traits appear in general population statistically more then predicted, more often then by chance alone but do not imply linkage
DISEQUILIBRIUM is an example of association
How do you use deletions to determine disease gene location
THe region of overlap of all deletions defines approximate location of disease gene
How do translocations affect gene
Balanced chromosome translocations often have no effect on translocation carrier because individual still has complete copy of his or her genetic material - however when translocation happens to interrupt gene, it can produce genetic disease which can aid in mapping of a gene
In situ hybridization
Physical mapping technique in which labeled probe is hybridized to fixed metaphase chromosomes to determine chromosomal location of DNA in probe
Somatic cell hybridization
Physcical mapping technique in which human and rodent cells are hybridized result in cells that have reduced number of human chromosomes -panels of such cells are used to correlate presence of gene with the consistent presence of one chromosome (or when translocations are available with specific segment of chromosome)
Radiation hybrid mating
Uses cell line containing human chromosome that is irradiated to produce chromosome breaks. Those human chromosome fragments are fused with rodent chromosomes so that they survive, presence of human chromosome material in rodent cells can be detected by presence of Alu sequences - closely linked loci are frequently found on same chromosome whereas loosely linked loci are rarely found on same chromosome fragment
Genomic library vs cDNA library
Genomic library contains all of human genome - introns, exons, enhancers, promoters and vast stretches of noncoding DNA that separate genes
cDNA library - ONLY DNA corresponding to EXONS - obtained by purifying mRNA from specific tissue such as liver or skeletal muscle and then exposing it to reverse transcriptase
Adv and disadv of using round worm
Adv - fate of every body cell is known
Disadv - alternative body plan
Adv and disadv of using fruit fly
Adv - short generation, easy to breed, lots of mutants
Dis - alternative body plan, must maintain live stock
Adv and disadv of using zebrafish
Adv - transparent embryos, easy to breed
Dis - small size of embryo
Adv and disadv of using clawed frog
Adv - large transparent embryo, can manipulate easily
Disadv - tetraploid, makes genetics difficult
Adv and disadv of using mice
Adv - easy to breed, mammal, good genetics
Dis - embryo manipulation challenging
Adv and disadv of using baboon
Adv - physiology similar to human, genetic linkage map complete
Disadv - very expensive to maintain, small population, long generation lines
How do paracrine signaling molecules work
Paracrine signaling molecules are secreted, diffuse short distance and bind to receptor that effects response - these signals cause gene expression changes - phosphorylation of proteins, signal transduction cascades
Name 4 main families of paracrine signaling molecules
- Fibroblast growth factor
- Hedgehog family
- Wingless family
- Transforming growth factor beta family (TGF)
Most common FGFR3 mutation
Achondroplasia - dwarfism - short stature (short limbs), macrocephaly and moderate increase in FGFR3 inhibiting chondrocyte growth
Milder form of FGFR3 mutation
Hypochondroplasia - has less activatin and less abnormalities - no macrocephaly but limbs are short
Most severe form of FGFR3 mutations
Thanatophoric dysplasia - essentially lethal, very short limbs and highly activated receptor
Describe DNA transcription factors mutations
DNA transcription factors are those that bind to DNA and either activate or repress gene expression. Usually transcription factors effect multiple targets - can be transcription factors and can be part of cascade effect - causes pleiotropic effect
Descrine SOX 9
SOX9 encodes for mammalian testis determining factor - expressed in genital ridges of both sexes but there is an increase in males and decrease in females
Also regulates chondrogenesis and Col2A1 (collagen gene)
Mutation in Sox9 can cause
Camptomelic dysplasia - skeletal defect+ sex reversal of XY fetuses (producing a female) and short limbs - this can be fatal since effect involved multiple things - pleiotropic effect
Mutation in SOX 10 causes
Hirschsprung disease - involves neural crest - enteric neurons do not develop properly, there is colon hypomotility and severe constipation - 4 times more common in males then females (can be sporadic (multifactorial) or familial (mutation in transcription factor)
Extracellular matrix proteins
Secreted macromolecules that serve as scaffolding for tissues and organs - collagens, elastins, laminins, fibronectins, tenascins - separate cells and provide matrix for migration. Cells bind to ECM using specific proteins. Integrins link between ECM and cytoskeleton and glycosyltransferases bind glycosyl residues on ECM
Describe type I collagen
- Made up of triple helix where multiple helices from fibrils -for every third residue there is glycine in the helical region that is inside, when mutation occurs in glycine, this disrupts fibril formation and bone formation is disrupted
Name type I collagen disease
Osteogenesis imperfecta - can be mild to lethal form, basically glycine is the only amino acid that will fit inside helix to keep it stable but once mutation occurs function is disrupted - baby born with osteogenesis imperfecta can have broken bones which can even occur inside womb - in xray there are beads on bones signifying constant breaking and healing
Which proteins coordinate microfibril assembly in ECM
Fibrillin 1 and elastin
Fibrillin 1 mutations cause
Marfan syndrome - tall, have hypermobility joints, lens of eye displaced, large blood vessel size, abnormal heart, usually die from aortic dissection
Laminin is important for _
Anchoring cells to ECM
LAMC2 mutation causes
Junctional epidermolysis - individuals epithelia doesnt attach and large blisters form on skin
Craniosynostosis caused by mutation of FGFR1
Pfeiffer syndrome - broad first digits, hypertelorism
Craniosynostosis caused by mutation of FGFR2
Apert - fusion of digits, midface hypoplasia
Pfeiffer - broad first digits, hypertelorism
Crouzon - midface hypoplasia, ocular proptosis
Beare-Stevenson - midface hypoplasia, corrugated skin
Jackson Weiss - midface hypoplasia, foot anomalies
Craniosynostosis caused by mutations of FGFR3
Crouzon - midface hypoplasia, ocular proptosis, acanthosis nigricans
Nonsyndromic craniosynostosis - digital defects, hearing loss
SHH point mutation can cause
abnormal midline brain development - SHH is involved with cholesterol in membranes which is essential for proper cell patterning. If mother is given cholesterol inhibitor while pregnant - can cause defect in baby
Pattern formation
When tissue and organs are established and get general body plan in embryo - there is a systematic way where it defines cells in region, establishes signalling centers to provide positional information and differentiation of cells in response to cues
What mutation produces left/right asymmetry (situs inversus)
Mutation in Z1C3 - zinc finger protein of cerebellum, member of GLI transcription factor family on X chromosome - affected males have randomized effects, heterozygote females have L/R reversal (mirror image)
Holt Oram syndrome
Mutation of TBX5 - thumb, radius defects
Paralog
HOX gene in same relative position - HOXA1, HOXB1, HOXC1
Homeotic transformation
Segment is moved and replaced by another
Homeodomain
Patterning occurs along anterior posterior axis that is controlled by cluster of genes that encode transcription factors containing a DNA binding domain of approximately 60aa
Temporal colinearity
within each cluster, 3" Hox genes are expressed earlier than 5" Hox genes
Spatial colinearity
the 3" Hox genes are expressed anterior to 5" Hox genes
Describe role of IPF1
Pancreas beta cells require IPF1 to express insulin, it is also needed to properly develop pancreas - if there is mutation in IPF1 it will block pancreatic development. This gene doesnt only regulate insulin but pancreatic cell maturation and differentiation
Tumor suppressor genes
Tumor suppressor genes normally control cell cycle so that growth is in control and regulated. In cancer production there is a mutation in tumor gene suppressors which inhibit it from controlling cell cycle and causes proliferation of cells. Examples of this type of cancer class would be Rb1 and CDK inhibitors
CDK - cyclin dependent kinase
Oncogenes
Oncogenes originate from proto oncogenes, which are genes involved in normal cell growth. When mutation in proto-oncogene occurs, it becomes an oncogene - a gene whose constantly active product can lead to unregulated growth and cell differentiation. This class of cancers is rare in inherited cancers
DNA repair genes
There are several repair mechanisms that all humans have to correct errors that occur in the process of making DNA. These repair mechanisms help to maintain integrity of genome, however if repair mechanisms do not work you have increased mutation rate. Examples - BRCA1 and BRCA2
APC - adenomatous polyposis coli gene
-Predisposes to colon cancer
- Responsible for majority of sporadic cases of colon cancer, one of the earliest alterations leading to colon tumorogenesis
- This tumor supressor gene has been shown to function as major regulator of Wnt signal transduction pathway via interaction iwth beta-catenin
- It is also involved in cell adhesion control and in maintaining chromosome stability during mitosis
p53
- Mutations of this gene is found in more then 50% of all tumors
- This gene encodes transcription factor that induce either cell cycle arrest or apoptosis in response to damaged DNA
BRCA 1 and BRCA2
Mutations in BRCA1 and BRCA 2 are responsible for significant proportion of inherited breast cancer cases, especially those of early onset
- These mutations usually result in truncated protein product and loss of function
- Protein products of these genes play important role in DNA REPAIR
NF1
- Located at chromosome 17q
- Normal gene downregulates RAS, if you have mutation - get the disease
Main difference between inherited and sporadic retinoblastoma
Inherited - bilateral
Sporadic - unilateral
Knudsons two hit theory of cancer
Cell can initiate tumor only when it contains two damaged alleles - therefore a person who inherits one copy of mutant retinoblastoma gene must experience a second somatic mutation in one or more retinoblasts to get cancer.
Two somatic mutations can also occur in single retinoblast or nonpredisposed fetus - producing sporadic retinoblastoma
Multi step model for colon cancer
1. APC mutation
2. Gain of function mutation in KRAS gene - in 50% of APC mutations
3. Mutation in p53 gene - 50% of colon cancers
4. Tumor supressor gene SMAD4 also altered- this mutation allows cancer to become metastatic
Function of telomerase in cancer cells
- 90% of tumor cells have activated telomerase
- Allows tumor cells to continue to divide which permits accumulation of additional mutations that may further contribute to aggressiveness of tumor
RB1 mutation causes _
Retinoblastoma
Osteosarcoma
APC mutation causes_
Familial adenomatous polyposis
BRCA 1 and BRCA2 mutation causes
Breast and ovarian cancer
MLH1 and MSH2 mutations cause_
HNPCC - hereditary nonpolyposis colon cancer
Mutation in CDKN2A causes
Familial melanoma
TP53 mutation causes_
Li-Fraumeni syndrome
RET mutation causes
Multiple endocrine neoplasia
Thyroid carcinoma
Genomic instability
- Can result from defects in DNA repair, frequently observed in tumor cells and is characterized by widespread mutations, chromosome breaks and aneuploidy. These alterations can cause cancer when they affect pathways that regulate cellular proliferation
Loss of hetrozygosity in tumor DNA indicates what
That normal tumor suppressor genes as well as polymorphic markers surrounding it have been lost leaving only abnormal copy of tumor suppressor gene