Genetics

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balanced chromosome abnormalities

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inversions, reciprocal, robertsonian translocation

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unbalanced chromosome abnormalaties

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deletions, insertions, ischromosomes, ring chromosomes

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aneuploidy

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most common cause of non-disjunction during meiosis (sister chromotids dont separate

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Mosaicism

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depends on when somatic non disjunction occured - the later the less # of affected cells, specifically trisomy mosaic

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turner

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monosomy, 45,X, not fatal because of x-inactivation since not all genes have been inactivated, broadchest, lymphoedema, obese, short

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lethal trisomy

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patau- 13 and edwards -18

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non lethal trisomy

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klinefelter - xxy and downs 21, xyy

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patau

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13, fatal at birth, cleft palate, heart defect, severe head defect

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edwards

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18, die in utero, rockerbottom feet, defect in most organs

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klinefelters

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47, xxy, tall female like males, breast development, mild IQ, osteoporosis, extra x is inactivated, no dosage increase.

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xyy syndrome

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super males, non lethal, very tall, high testosterone

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downs

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21, MR, hypotonia, brachycephaly, upslanting palpebral fissure. Caused by nondisjunction or robertsonian translocation or aneuploidy , translocation at chrom 21 and 14

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age related breakdown

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chromatid cohesion, meotic recombo, spindle fiber checkpoint control will increase non disjunction frequency

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euploidy

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gain or loss of whole set of chromosomes, pregnancy terminates in 1st trimester, accidental does not increase risk for net child

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two types of triploidy

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Digynic - 2 set maternal due to diploid ovum or asymetric uteres growth restriction, Diandric - 2 set paternal due to diploid spirm

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Philadelphia chromosome

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chronic myeloid leukemia, two genes sliced together alter function, ABL (proto) and BCR fusion due to translocation btwn chr 9 &22

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Burkitt's Lymphoma

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translocation btwn c-myc (proto) and IGH, rapid tumor of abdomen

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unbalanced examples

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cru di chat and wolf hirshorn

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polygenic trait

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no discrete phenotype, non mendelian, due to more than one gene affecting trait, additive or non additive

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liability threshold model

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describes a population's genetic and environmental susceptibility of getting disease

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genetic liability in multifactorial trait

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complex inheritance, produces discontinuous phenotype in context of continuous variation, if u have good genes but a really bad environment u will be okay. if you have bad genes then even a little bad environment will tip u over threshold. Environment, familial aggregation, if more relatives have it, not simple mendelian.

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familial relative risk

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parents siblings children = 1/2
uncle aunts, nephew, grandkids and half siblings = 1/4
cousins = 1/8

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risk of recurrance for 1st degree relative

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is sq root of pop incidence ex: 1/1000 for pop than 1/32 for sibling of affected, this is true for all polygenic traits

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heritability (h2)

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(genetic variance/ total variance) or ( [variance in DZ- variance in MZ] / variance in DZ). total variance = genetic variance + environmental. genetic component not the same as familial aggregation. h=1 then genetics, h= 0 then due to environment.

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population migration

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indicative of environmental factors

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high concordance rates

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nontramatic epilepsy, psorisis, schizo, type 1 diabetes

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association studies

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aim to find genes in polygenic disorders. test co-occurance of specific allele and trait in population by comparing frequency of allele in patient and control

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odds ratio

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risk of getting disease with allele/ risk of getting disease without allele - a/c / b/d

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relative risk

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ratio of event occurring probability in exposure group vs control group a(c+d) / c( a+b). usually a percent

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disorders with multifactorial inheritance

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congenital - cleft lip, neural tube defect.
acquired - asthma, diabetes, autism

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autosomal recessive in obesity

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leptin, leptin receptor, prohormone convertase 1 (converts proinsulin to insulin)

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autosomal dominant in obesity

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melanochortin receptor (MC4R)

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yellow agouti

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interferes with alpha MSH binding to MC4R

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obese (OB)

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defect in leptin protein

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diabetes (DB)

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defect in leptin protein receptor

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types of mutations

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silence, neutral, missense, nonsense, indels

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Missense

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change in nucleotide causing change in protein can be Loss of Function or Gain of function

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haploinsufficiency

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loss of function, hypomorph, famlilal hypercholestermia, partial dominance of protein

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dominant negative

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osteogenesis imperfecta,1, loss of function, mutation interferes with normal protein

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huntington's

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gain of function, increase protein aggregation in cns

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nonsense protein

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stop codon made, cystic fibrosis, dmd, b-thalssemia, hereditary poly colon

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hereditary non-poly colon cancer

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nonsense mutation, mutation in arginine, msh2 gene which is a dna repair gene, mutational hotspot

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tay sachs

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frameshift indel, hex A gene, dmd is also a frameshift indel

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in frame indel

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cystic fibrosis, beckers,

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thalassemia

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splice site mutation, promoter mutation, nonsense mutation

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cystic fibrosis

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nonense, inframe mutation

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alzeihmer

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promoter mutation

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xenobiotics

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can oxidize, reduce, methylate, acetylate glutathionylate, glucoronidate

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drug metabolism sites

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intake, absorption, distribution, drug cell interaction, breakdown, excretion

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screen cyt p450 for

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warfarin therapy to prevent bleeding problems

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screen factor 5 leidin mutation for

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oral contraceptive to reduce thrombosis

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screen for HER2 receptor for

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breast cancer

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colon rectal cancer

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more susceptible if they carry cyp1a1 ill to val

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gall bladder cancer

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polymorphism at cyp1a1, gstm1, p53

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phase 1 metabolism

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cyt p450, cyp 2c8, cyp 2c9, cyp c18, cyp c19

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hexobarbitone drug

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effects sleep time

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3-methylcholonthrene

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carcinogenic polycyclic aromatic hydrocarbon, causes cancers, polymorphism in ach receptor induced by cyp1a1 and gst1a differences

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Alzheimer's

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Most common dementia, aggregation of B-amyloid, neurofibrillary tangles form by hyperphosphorylation of Tau. Two types: Familial and Sporatic. promoter mutation

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Familial form of Alzheimer's

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<10 % Chrom 1 = 7-TD on presenilin-2. Chrom 14 = 7TD on presenilin-1. Chrom 21 = Amyloid precursor gene

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Sporatic form of Alzheimer's

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genetic link with APOE 4 gene on Chrom 19

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Types of Polymorphism

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RFLP, VNTR, SNP. Mutation is too frequent it becomes an allelic variation

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Detect RFLP

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by enzyme digestion, southern blotting, PCR

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SNP

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most common polymorphism, mainly in non-coding region, some cause silence, neutral, missense mutation

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SNP - Haplotype

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closely linked genetic markers on one chromosome, inherited together

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SNP - Hapmap

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track SNP to find common patterns of human genetic variation

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dna damage - short term consequence

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slow down proliferation to try and correct, alter transcription of protein, apoptosis

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spontaneous mutation --> errors of replication

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Tautomerism (chemistry of NA) and frameshift mutation ( slippage of dna polymerase)

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Xeroderma Pigmentosum

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AR, mutation in 9 NER gene, locus heterogenity, dna damage is irreversible

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Short Term --> Alter transcription -->

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Ways to deal with high frequency of mutations using Damage sensors, Transducers, Effectors

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Spontaneous lesion

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in a resting cell. Depurination, Deamination, Oxidative damage

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Damage sensor

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ATM/ATR

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Transducers

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MAPK

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Effectors

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p53

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Ataxia Telengiectasia

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AR, defect in ATM, serine threonine kinase, ocular and cerebellum problems

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Indirect Repair

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Base excision, nucleotide excision, mismatch repair (proofreading, remove small repeats)

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Strand discrimination

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humans - replication machinery and methylation

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double stranded breaks

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difficult mutation to repair, lose genetic material. two ways to repair: recombination repair, non-homologous end joining

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Bloom Syndrome

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BLM gene defect in RecQL3 DNA helicase need in recombination and replication repair. Person has a small red face from rash, diabetes, lung and immune deficiencies, narrow chin, chromosome instability ( chromosome breaks and sister chromotid exchange)

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Hereditary Non poly colon cancer

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microsatellite instability seen in tumors, simple repetative dna show size variation, mutation in MMR - MSH2. Nonsense mutation, Mutation in arginine, msh2 gene which is a dna repair gene, mutational hotspot!

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Breast Cancer

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BRAC1 &2 part of DNA repair or apoptosis, allelic heterogenity, damaged sensor causing 100s of gene mutations to grow. tumor suppressor gene. BRCA1 is expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired.

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Short term dna damage fixes

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Slow down proliferation to try and correct, alter transcription of protein, apoptosis

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Depurination

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most common, breaks glycosidic bond and lose a purine

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Deamination

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lose amine group, easy to fix, commonly cytosine becomes uracil or cytosine to thymidine and repair to be TA or CG

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oxidative damage

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leads to super oxidases and damage cells or transversion, guanosine results in mispairing of A base

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ras gene

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Ras subfamily is a protein subfamily of small GTPases that are involved in cellular signal transduction, and is also used to designate gene subfamily of the genes encoding those proteins. Activation of Ras signalling causes cell growth, differentiation and survival. Ras is the prototypical member of the Ras superfamily of proteins which are all related in structure and regulate diverse cell behaviours. Since Ras communicates signals from outside the cell to the nucleus, mutations in ras genes can permanently activate it and cause inappropriate transmission inside the cell, even in the absence of extracellular signals. Because these signals result in cell growth and division, dysregulated Ras signaling can ultimately lead to oncogenesis and cancer.

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multiplex pcr

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Multiplex polymerase chain reaction (Multiplex PCR) is a modification of polymerase chain reaction in order to rapidly detect deletions or duplications in a large gene. This process amplifies genomic DNA samples using multiple primers and a temperature-mediated DNA polymerase in a thermal cycler. for dmd

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Transition Mutation

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Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid, base mis-pairing, or mutagenic base analogs such as 5-bromo-2-deoxyuridine (BrdU).

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Transversion Mutation

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Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is adenine (A) being converted into a cytosine (C).

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Treatment 4 options

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Gene Therapy, Drugs/Diet, Stem cell therapy, Protein/Enyme replacement

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Protein Enzyme -direct

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Gaucher's, Imiglucerase drug from ovary eggs

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Protein Enzyme -indirect

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Cystic fibrosis, treat enzymes for pancreas

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Diet

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PKU, PAH, low phenylalanine. Urea Disorder give sodium phenyl butarate drug and low protein diet

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Protein enzyme therapy

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Good for single gene disorders, cross BBB, improve protein stability, pegylation of PAH prevent it from degrading

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Protein enzyme therapy production

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isolate human gene, change arginine to histidine to help mannose be added, mostly recombo proteins from culture

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Protein enzyme Pros

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Lots of volume, process post transitionally, wont transfer virus, enhance during cloning

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Protein enzyme Cons

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only a treatment not a cure, proteins are unstable, people could develop antibodies against new protein

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stem cell cons

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hard to grow a lot of them, tumor causing, unethical, low immune response

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gene therapy cons

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immune response against it, tumor formation, loss of gene overtime, not good for multifactorial disease

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stem cells good for

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heart and chronic liver disease, alzheimers, parkinson, huntingtons, ms, SPINAL CORD injury

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gene therapy

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good for genetic diseases, add gene anywhere on genome, good delivery system will target right cells and get gene into nucleus. Two delivery systems: retroviruses, adenoviruses

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genetic screening

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target screening and population screening

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target screening

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linkage analysis good for autosomal dominant, sometimes marker mixes with gene or locus heterogenty makes this hard. Good for late onset disease or reduce penetrance

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population screening

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general population, prenatal screening, neonatal screening

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prenatal screening

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detect subtle karyotype alterations like in ultrasound, chronic villus sample, amiosentesis, maternal serum\

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neonatal screening

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pku, cystic fibrosis, sickle cell

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AD

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For autosomal dominant diseases q is ½ the incidence (q = ½ I)

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Hemoglobin structure

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genetic control - chrom 16 and 11, functional a-like, functional b-like and pseudogenes. Hence, various hb species formed during development.

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embryonic

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hbE Gower 1 and gamma chain

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fetal hb

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higher 02 capacity at low 02 conc, switch gamma to beta at birth

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sickle cell

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single point mutation, change to valine at locus 6, plietropic effects, anemia, spleen megaly, worse in strep infection

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sicke cell treatment

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5- azacytidine, butarate, hydroxyurea, these drugs alter epigenetic regulatory mechanisms, change acetylation

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thalasemmia

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allelic heterogentiy, due to gene deletion, point mutation, splicing, loss of regulation. Loss of 4 genes - hydrops fetalis dead fetus

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b thalasemmia

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AR, B+ is reduced gene exression while B0 is complete supression, unpaired alpha globin, hemolytic anemia, bone deformity and fractures

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b thalasemmia

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selective pressure increases mutation in malaria pop, screen in med pop

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b thalasemmia mutation

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low b globin causes low hbA levels and increase alpha globulin unpaired causes ROS, Anemia. Point CORFU deletion removes CIS regulation or SPLICE mutation glu to lysine

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hemophilia A

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classic, factor 8, long chromosome arm xq28, large inversion of factor 8 gene, long deletion or insertion or point mutation. Partial inversion, extensive allelic heterogenity, new mutations arise