Genetics

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Genetic mapping

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Ordering of genes on chromosome according to recombination frequency

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Physical mapping

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Determination of physical distances between genes using cytogenetic and molecular techniques

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Linked genes

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Genes that are located close enough on chromosome that their recombination frequency is less then 50%

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Haplotype

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Combination of alleles on each chromosome

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Recombination

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Occurence among offspring of new combinations of alleles resulting from crossovers that occur during parental meiosis

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Centimorgan

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Unit of measure of frequency of recombination between two loci - also known as map unit

1cM = 1% recombination frequency

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Syntenic loci

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Two loci located on the same chromosome - may or may not be linked

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Linkage phase

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chromosome on which each allele is located

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Markers

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Polymorphisms such as RFLP's VNTR's microsatellite repeats and blood groups that are linked to disease locus

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Recombination hot spot

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Region of chromosome in which recombination frequency is elevated

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Uninformative mating

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mating in which linkage phase cannot be established

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Positional cloning

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Isolation of partially overlapping DNA segments from genomic libraries in attempt to progress along chromosome toward disease gene

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Functional cloning

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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

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Contig map

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Physical map of chromosome region constructed by isolating overlapping DNA segments

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Sequence tagged sites

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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

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Expressed sequence tags

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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

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CG islands

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Unmethylated CG sequence that are found near 5" end of genes

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Exon trapping

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Method for isolating exons in fragment of genomic DNA by using an in vitro cell system to artificially splice out introns

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LOD score of _ is evidence of linkage

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3

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TO be useful in gene mapping linked markers should be _

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Codominant
Numerous
Highly polymorphic

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High degree of polymorphism increases probability that _

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Matings will be informative

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Linkage equilibrium

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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

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Linkage disequilibrium

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Nonrandom association of alleles at lnked loci - diminishes through time as result of recombination, can be used to infer order of genes on chromosomes

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Association

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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

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How do you use deletions to determine disease gene location

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THe region of overlap of all deletions defines approximate location of disease gene

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How do translocations affect gene

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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

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In situ hybridization

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Physical mapping technique in which labeled probe is hybridized to fixed metaphase chromosomes to determine chromosomal location of DNA in probe

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Somatic cell hybridization

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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)

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Radiation hybrid mating

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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

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Genomic library vs cDNA library

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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

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Adv and disadv of using round worm

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Adv - fate of every body cell is known
Disadv - alternative body plan

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Adv and disadv of using fruit fly

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Adv - short generation, easy to breed, lots of mutants
Dis - alternative body plan, must maintain live stock

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Adv and disadv of using zebrafish

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Adv - transparent embryos, easy to breed
Dis - small size of embryo

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Adv and disadv of using clawed frog

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Adv - large transparent embryo, can manipulate easily
Disadv - tetraploid, makes genetics difficult

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Adv and disadv of using mice

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Adv - easy to breed, mammal, good genetics
Dis - embryo manipulation challenging

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Adv and disadv of using baboon

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Adv - physiology similar to human, genetic linkage map complete
Disadv - very expensive to maintain, small population, long generation lines

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How do paracrine signaling molecules work

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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

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Name 4 main families of paracrine signaling molecules

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- Fibroblast growth factor
- Hedgehog family
- Wingless family
- Transforming growth factor beta family (TGF)

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Most common FGFR3 mutation

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Achondroplasia - dwarfism - short stature (short limbs), macrocephaly and moderate increase in FGFR3 inhibiting chondrocyte growth

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Milder form of FGFR3 mutation

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Hypochondroplasia - has less activatin and less abnormalities - no macrocephaly but limbs are short

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Most severe form of FGFR3 mutations

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Thanatophoric dysplasia - essentially lethal, very short limbs and highly activated receptor

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Describe DNA transcription factors mutations

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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

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Descrine SOX 9

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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)

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Mutation in Sox9 can cause

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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

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Mutation in SOX 10 causes

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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)

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Extracellular matrix proteins

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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

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Describe type I collagen

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- 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

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Name type I collagen disease

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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

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Which proteins coordinate microfibril assembly in ECM

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Fibrillin 1 and elastin

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Fibrillin 1 mutations cause

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Marfan syndrome - tall, have hypermobility joints, lens of eye displaced, large blood vessel size, abnormal heart, usually die from aortic dissection

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Laminin is important for _

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Anchoring cells to ECM

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LAMC2 mutation causes

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Junctional epidermolysis - individuals epithelia doesnt attach and large blisters form on skin

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Craniosynostosis caused by mutation of FGFR1

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Pfeiffer syndrome - broad first digits, hypertelorism

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Craniosynostosis caused by mutation of FGFR2

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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

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Craniosynostosis caused by mutations of FGFR3

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Crouzon - midface hypoplasia, ocular proptosis, acanthosis nigricans
Nonsyndromic craniosynostosis - digital defects, hearing loss

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SHH point mutation can cause

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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

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Pattern formation

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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

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What mutation produces left/right asymmetry (situs inversus)

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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)

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Holt Oram syndrome

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Mutation of TBX5 - thumb, radius defects

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Paralog

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HOX gene in same relative position - HOXA1, HOXB1, HOXC1

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Homeotic transformation

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Segment is moved and replaced by another

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Homeodomain

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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

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Temporal colinearity

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within each cluster, 3" Hox genes are expressed earlier than 5" Hox genes

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Spatial colinearity

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the 3" Hox genes are expressed anterior to 5" Hox genes

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Describe role of IPF1

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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

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Tumor suppressor genes

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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

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Oncogenes

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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

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DNA repair genes

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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

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APC - adenomatous polyposis coli gene

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-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

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p53

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- 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

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BRCA 1 and BRCA2

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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

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NF1

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- Located at chromosome 17q
- Normal gene downregulates RAS, if you have mutation - get the disease

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Main difference between inherited and sporadic retinoblastoma

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Inherited - bilateral
Sporadic - unilateral

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Knudsons two hit theory of cancer

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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

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Multi step model for colon cancer

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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

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Function of telomerase in cancer cells

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- 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

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RB1 mutation causes _

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Retinoblastoma
Osteosarcoma

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APC mutation causes_

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Familial adenomatous polyposis

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BRCA 1 and BRCA2 mutation causes

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Breast and ovarian cancer

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MLH1 and MSH2 mutations cause_

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HNPCC - hereditary nonpolyposis colon cancer

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Mutation in CDKN2A causes

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Familial melanoma

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TP53 mutation causes_

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Li-Fraumeni syndrome

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RET mutation causes

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Multiple endocrine neoplasia
Thyroid carcinoma

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Genomic instability

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- 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

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Loss of hetrozygosity in tumor DNA indicates what

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That normal tumor suppressor genes as well as polymorphic markers surrounding it have been lost leaving only abnormal copy of tumor suppressor gene