Q2 BioChem Exam 1
What is a polygenic disease? What is multifactorial disease?
polygenic disease: combined affect of multiple genes multifactorial disease: polygenic + environmental factors
What is Hemophilia B? What type of mutation is the cause? What are the genetics? What are the symptoms?
-*X linked recessive* -*point mutation* of promoter/untranslated region -A==> G change affects binding of TF for *factor IX* -1/3 normal factor IX expression
How are mitochondrial diseases unique?
-*all mtDNA is inherited from the mother* -show *considerable variability* due to heteroplasmy -there is a *phenotypic threshold* based on how many mutated mtDNA were inherited
What is neurofibromatosis Type I (NF1)? What are the genetics? What is unique about the phenotype? What are some symptoms? What is the mechanism?
-*autosomal dominant disease* -*highly variable phenotype* -cafe-au-lait spots, neurofibromas, lisch nodules -*point mutation*==> *nonsense*==> stop codon into NF1 coding region==> unstable shortened product -50% are result of *new mutation*
What is familial hypercholesterolemia? What are the genetics? How do the genotypes differ?
-*autosomal dominant* -loss of function of *LDL receptor gene* -heterozygous: elevated LDL, increased risk of heart disease, cholesterol in tendons/skin -homozygous: same symptoms but *earlier and more severe*, death due to *MI*
What is hurler syndrome? What are the genetics? What are the symptoms?
-*autosomal recessive* -*lysosomal storage disease*, mutation of *alpha-L-iduronidase* -buildup of glycosaminoglycans==> short stature, retardation, corneal clouding,
What is Tay Sachs Disease? What are the genetics? What is the mutation? What populations? What symptoms?
-*autosomal recessive* -*point mutation* that alters proper *splicing* of hexA mRNA==> abnormal mRNA (GT==> CT mutation) -lysosomal storage disease, Ashkenazi Jews, build of GM2 ganglioside==> neuronal damage
What is hereditary hemochromatosis? What are the genetics?
-*autosomal recessive* -mutation in *HFE* gene==> 2-4x normal iron==> iron accumulates in liver, heart, pancreas, joints, endocrine, skin -adult males more likely (lack of menstration?) -treated through *bloodletting*
What are characteristics in autosomal dominant diseases?
-*both sexes* in equal proportions -affected individuals transmit to *half of offfspring* -*no skipping of generations* (vertical transmission) -*father to son*
What is Charcot-Marie-Tooth disease CMT? How common is it? What is the mechanism?
-*demyelination of peripheral nervous system*==> progressive atrophy -most common inherited neuro disorder -*duplication of 1.5 mill bp's on chromosome 17* -caused by *misalignment during recombination* -critical protein= *PMP22*
What is Pyloric Stenosis? What are the genetics? What are the symptoms?
-*hyperplasia of pylorus muscles* -*4x* more prevalent in males, clusters in families, multifactorial -females= *higher threshold of liability* -symptoms: recurrent vomiting, dehydration, electrolyte imbalance
What do autosomal dominant disease usually affect? What is one example?
-*non-enzymatic structural proteins* -ehlers danlos syndrome (stretchy face)
What are epigenetic changes?
-*not true mutations* -heritable alterations in phenotype w/out alteration in genotype -ex: *methylation of cytosine*==> methylated DNA usually silent -environmental factors
How are occurence risk and recurrence risk different? What are they with autosomal dominant diseases?
-*occurence risk*: risk of producing affected child when *no children have been produced* -*recurrence risk*: risk of producing affected child when *one or more affected children* have been produced -autosomal dominant==> both risks are 50%
What is Sickle Cell Disease? What are the genetics? What are the populations? Transversion or Transition?
-*point mutation*==> missense ==> *A for T* into beta-globulin *protein* -1/12 africans carry one allele -transversion
What causes most of inter-individual variation between people? What are the different types?
-*polymorphisms* -*SNP* single nucleotide polymorphism -*STRP* microsatellites, 2-6 bp repeats -*VNTR* minisatellites 20-70 bp repeats -*CNV* 1k-1mil bp repeats
What is mendel's second law?
-*principle of independent assortment* -genes at different loci are transmitted independently
What is mendel's first law?
-*principle of segregation* -genes are in pairs, sexual reproduction==> one of each pair to offspring -offspring==> share intact genes from parents
What is the threshold model of inheritance?
-*qualitative traits*= all or nothing -affected by disease==> must exceed *threshold of liability* -*threshold does not change for a given population* -individual liability changes based on *genetic and environmental factors*
What is the additive polygenic model of inheritance? (think of height as an example)
-*quantitative traits*= measurable traits -as number of genes affecting a trait increases==> increased phenotypes==> distribution looks like a bell curve
What are the unusual features of mtDNA?
-*replicative segregation*: relaxed control of segregation, random mtDNA daughter cell distribution -high rate of *mutations* in mtDNA -*homoplasmy*: daughter cell received all normal or all mutated mtDNA -*heteroplasmy*: daugther cell received mixed mutated/normal mtDNA
What causes the anticipation in myotonic dystrophy?
-*slippage of DNA polymerase* during DNA replication -5-50 repeats= no symptoms -50-100 repeats= mild symptoms -100-1k repeats= full myotonic dystrophy
What is germ line mosaicism? When should it be considered? (complications to inheritance patterns)
-*some* of germ line cells of parent are mutated==> some of offspring will have diseases -not enough mutations to produce phenotype in parent -*higher recurrence risk* than single germ line mutations -consider when *two or more offspring* and *no family history*
What is Huntington's Disease? What are the genetics? What are the symptoms?
-*trinucleotide repeat of HD gene*, protein function unkown -*autosomal dominant* -*dementia*, *choreic movements*, late age onset
What is Fragile-X syndrome? What are the genetics? What is the mechanism? What are the symptoms? How does it appear in females?
-*x-linked dominant* -mutated *FMR1* gene -*anticipation* occurs==> trinucleotide expansion -symptoms: mental retardation, distinctive facial appearance -females: reduced penetrance
How many generations of humans have there been? How many genetic variations are among us?
-4k generations -over 3 million variable bases
Why does having more barr bodies create a problem? What percentage of genes escape? What regions are they and what are they called?
-X inactivation is *incomplete* -15% escape inactivation -escaped regions: *XIST* and *PAR1* and *PAR2* -*pseudoautosomal regions*
What is anhidrotic ectodermal dysplasia?
-abnormal development of nails, hair, sweat glands -males= no sweat glands -females= random patterns w/out glands
Draw punnet squares for X linked: carrier female + affected male
-affected sons come from mother
What is allele frequency? What is genotype frequency?
-allele frequncy: how often a particular *gene sequence* occurs in a population -genotype frequency: how often a given genotype occurs in a population
What is alpha-thalassemia? HbH4 disease? Hydrops fetalis? What causes all of these diseases?
-alpha-thalassemia: two functional alpha-globin 1 and 2 plus one nonfunctional alpha-globin. -HbH4: only one working copy of alpha-globin protein -hydrops fetalis: homozygous for non working alpha-globin -*large gene deletions*
What is genomic imprinting? When does re-imprinting occur? (complications to inheritance patterns)
-altered expression of same gene depending on paternal/maternal origin -if other parent has deletion on same gene as spouses *imprinted* gene==> child missing working section of that gene -70 human genes are imprinted -*re-imprinting* during oogenesis
What is Beta Thalassemia? What are the genetics? What is the mechanism? What are the symptoms?
-autosomal recessive -*point mutations* affecting: transcription, splicing, coding, and stability -causing decrease of beta-globulin
What is Tay Sachs disease? What are the genetics? What is the most common mutation? What are the effects?
-autosomal recessive disease -*4 bp insertion into hexA gene* -affects down stream==> frameshift
What is Cystic Fibrosis? What are the genetics? What is the most common mutation? What are the effects?
-autosomal recessive, *small deletions* on *GFTR gene F508* -most common: *deletion of three nucleotides in coding region*==> loss of single amino acid -CFTR= Cl channel==> can't move Cl to membrane==> thick mucous
What is the difference between a mutation and a polymorphism?
-both changes in DNA, differ in *frequency* -polymorphism= commonly seen mutation >1% -polymorphisms do not affect fitness of the organism
What are "new mutations"? How is it determined? (complications to inheritance patterns)
-child shows *dominant* disease with no disease in the family==> new mutation -determination: *in depth family study* -recurrence risk: low -occurrence risk: high (for offspring)
What is complete dominance? incomplete dominance? codominance?
-complete: one allele complete masks another (huntington's) -incomplete dominance: one allele does not complete mask another==> blended (familia cholesterolemia, achondroplasia) -codominance: neither allele masks the other==> a little of each (AB blood type)
What is mtDNA considered a remnant of?
-considered a remnant of *bacterial DNA* -16.5 kb in size
What are barr bodies?
-dense chromatin in *interphase* of somatic cells, not found in males -barr bodies= one less than number of X chromosomes
What is anticipation? (complications to inheritance patterns)
-disease displays earlier age of onset with each new generation -ex: myotonic dystrophy, huntingtons, fragile-x
What is delayed age of onset? What are examples? (complications to inheritance patterns)
-disease doesn't manifest until adulthood -harder for natural selection -ex: huntington's, hemochromatosis
What is the bottleneck effect?
-disease/disaster==> drastic decrease in population -surviving individuals dictate new genetic pool -ex: atoll of Pingelap, Micronesia
What is dominant inheritance? What are the three types of dominant inheritance?
-dominant: causes recognizable phenotype in homozygous or heterozygous -three types: complete dominance, incomplete dominance, codominance
What does dystrophin do? What is a manifesting carrier?
-dystrophin: structural integrity of cell's cytoskeleton -manifesting carrier: heterozygous DMD female showing symptoms via *X-inactivation* (8-10%)
What is genetic burdern?
-each person carries five lethal recessive heterozygous genes -lethal phenotype if homozygous -don't marry your cousin
What is the founder effect?
-early founder of population is a carrier of mutation -ex: BCKD in mennonite's
What is a chromosomal disorder?
-en entire chromosome is missing, duplicated, or altered
What is gene flow?
-exchange of genes between populations -sickle cell in african americans vs africans
What is located on the Y chromosome?
-few genes -*no* vital genes -some house keeping genes have inactivation homolog on X chromosome
What is the difference between a frame shift mutation and an in-frame mutation? What does each cause?
-frameshift: insertion/deletion of *1-2 bp*==> change in the entire reading sequence -in-frame mutation: insertion deletion of *3 bp*==> does not change reading sequence
What is the Hardy Weinberg principle? What assumptions are made?
-frequency of alleles related to frequency of genotypes -random mating, large population, no mutations/migration/natural selection
What is pleiotropy? (complications to inheritance patterns)
-gene that effects *multiple* aspects of physiology/anatomy -difficult to narrow down to single problem -ex: CF, diabetes, marfan syndrome, VG disease
What is the difference between a gene, locus and allele?
-gene: DNA sequence specific to inherited trait -locus: location in a chromosome of specific gene -allele: one or more alternative forms of a gene in a population
What is the punnet square of autosomal recessive? What do autosomal recessive diseases usually code for? How does this relate to metabolism?
-genes that encode *enzymes* -most diseases of metabolism are autosmal recessive -both parents usually *carriers*
What influences phenotype? Does a change in genotype always mean a change in phenotype? Does a change in phenotype always mean a change in genotype?
-genotype and environment -changes can be multifactorial (think flamingos)
What are the two types of mutations in terms of genetics?
-germline or somatic
What are some common X linked diseases?
-hemophilia A and B -G6PD -OTC deficiency -Lesch-Nyhan syndrome -red-green color blindness= *abberrant recombination* -duchenne/becker muscular dystrophy
How related are two humans? chimpanzee? orangutan? mouse? broccoli?
-humans= 0.1% different -chimpanzee= 1% difference -orangutan= 3% difference -mouse= 66% identical -broccoli= 33% identical
What things increase recurrence risk with multifactorial diseases?
-increased *family members* affected -increased *degree of relationship* with proband -increased* severity of disease in the proband*
What is Prader-Willi Syndrome? What are the causes? What are the symptoms? What genes are involved?
-inherited long arm chromosome *deletion on paternal chromosome 15* -symptoms: short, hypotonia, obesity, small hands/feet, mild retardation -*SNRPN* protein
What is Angelman Syndrome? What genes are involved? What are the symptoms?
-inherited long arm deletion on *maternal chromosome 15* -*UBE3A* gene -symptoms: severe retardation, ataxic gait, seizures
What usually causes large deletions? How are chromosomes with only three copies created?
-large deletions usually caused by *aberrant recombination* -recombination after *misalignment*= chromosomes with 3 or 1 copies
How does male pattern baldness change in men vs women?
-men: acts as autosomal dominant -women: acts as autosomal recessive
What is Mitochondrial inheritance?
-mitochondria: contain's 37 genes in *mtDNA*, mostly encoding for oxidative phosphorylation -100's of mitochondria per cell==> multiple mtDNA per mitochondria -divided up between gametes during meiosis==> random inheritance of mtDNA
What are the patterns for X-linked recessive inheritance?
-more common in males -pattern of inheritance is like autosomes, mosaicism possible in heterozygotes -behaves like dominant gene in males
What are the pedigree characteristics of X-linked dominant inheritance?
-more frequent in females -*no father to son* -vertical transmission -affected males==> *100% transmission to daughters*
What are the mitochondrial diseases?
-mostly *muscle and CNS* diseases -CPEO -Kearns-Sayre Syndrome -Leigh Syndrome -LHON -MERRF -MELAS -Pearson Syndrome
How can you distinguish a single gene disease from a multifactorial disease?
-multifactorial==> occur in isolation -multifactorial==> occur more in one sex with no clear sex pattern -multifactorial==> more in certain ethnic group -multifactorial==> *environmental factors* change the risk of the disease
What is Duchenne Muscular Dystrophy DMD? What are the genetics? What genes are involved? What is the mechanism? What are the symptoms?
-mutated *dystrophin* gene (largest known gene 2.5 mill bp's) -*x-linked recessive* -deletions==> complete protein absence -symptoms: progressive weakness, muscle loss, high serum creatine levels -other mutations==> milder Becker MD
What is Marfan Syndrome? What are the genetics? What are the symptoms?
-mutation in *FBN1* gene -*autosomal dominant* -symptoms: disproportionately tall, skeletal abnormalities, cardiovascular problems -25% are *new mutations*
What is a heterogeneity? (complications to inheritance patterns)
-mutations at *different loci* produce same phenotype -ex: osteogenesis imperfecta= mutations in col1A1 (17) *or* col1A2 (7) -both genes needed==> type 1 collagen triple helix
What is the african prevelance of the sickle-cell mutation an example of?
-natural selection
What are the ultimate source of all new genetic material?
-new mutations
What are the causes of genetic variation?
-new mutations -founder effect -bottleneck effect -consanguinity -natural selection -genetic drift -gene flow
How do you distinguish X-linked recessive inheritance?
-no father to son transmission -can skip generations via *carrier females*
What are the characteristics of mitochondrial inheritance?
-non-mendelian inheritance -both males and females affected -*only females transmit disease to offspring* -100% offspring of affected female will present the disease
How do you calculate recurrence risk and occurence risk in multifactorial diseases?
-occurence risk not calculated in multifactorial -recurrence risk==> empirical evidence for similar population groups
Point mutations that affect phenotype are usually what type? Where do the mutations occur?
-often missense or nonsense mutaitons -not restricted to coding regions, all over
What is X-linked inactivation? What is the lyon hypothesis?
-one copy of X-linked genes are inactivated in females -lyon hypothesis: inactivation for *dosage compensation*==> early in development==> female "mosaic"
What is a multifactorial trait?
-one produced by multiple genes and environmental factors
What is reduced penetrance? (complications to inheritance patterns)
-penetrance: portion of genotype producing symptoms -RB shows 90% penetrance==> 10% of kids won't show RB -10% can *still* transmit disease to offspring
What is achondroplasia? What are the genetics? What are the symptoms?
-point mutation in *FGFR-3 gene*==> glycine to arginine, gain of function mutation, -symptoms: dwarfism -*autosomal dominant*==> 90% are results of *new* mutations -homozygotes are more sever (true for *all* aut. dom. except huntingtons)
What causes the molecular fingerprint of individuals? What is CODIS?
-polymorphism provide fingerprint -CODIS: panel of *13 VNTR's* for FBI
What is myotonic dystrophy? What causes it? What genes are involved? What is it an example of?
-progressive muscle deterioration disease -*DMPK* gene -expansion of *tri-nucleotide repeat* CTG -example of *anticipation* more "repeats" in each new generation
What is recessive inheritance?
-recognizable phenotype only in homozygous
What is variable expression? (complications to inheritance patterns)
-refers to *severity of disease*, severity of symptoms differ between those who have the phenotype -*is not penetrance* -ex: NF1= 100% penetrance with variable expressivity
What are the characteristics of autosomal recessive inheritance?
-seen in siblings but *not in earlier generations* -*males and females equal* -*1/4* offspring affected -*consanguinity* present
What is a sex limited trait?
-sex limited: autosomal trait expressed *only* in one sex -due to *anatomical* differences not genetic -ex: uterine motility, sperm defects -*can be transmitted to offspring*
What is the difference between a sex-linked trait and a sex influenced trait?
-sex linked: caused by genes in X or Y chromosome -sex influenced: autosomal trait expressed more frequently in one sex ex: male pattern baldness, gout, hemochromatosis
Who would have a higher recurrence risk, siblings of male proband for pyloric stenosis or siblings of female proband for pyloric stenosis?
-siblings of female proband -females already have higher threshold==> female proband must have a lot of genetic and environmental factors contributing to the disease
What is genetic drift?
-some individuals leave behind more descendents -random, due to chance
Where does x inactivation start? What does it contain? What helps stability of inactivation?
-starts at *XIC*, contains *XIST* -XIST==> only expressed from inactive chromosome==> XIST RNA coats inactive X chromosome -*methylation* and *histone hypoacteylation* help long term stability
What is a proband?
-the first person in a pedigree to be identified as having the disease in question
What do monogenic, unifactorial or mendelian traits have in common? What are some examples?
-they are all produced by a single gene -autosomal, sex linked, or mitochondrial
What are the two types of point mutations?
-transitions: purine for purine *or* pyrimidine for pyrimidine -transversions: purine for pyrimidine (vice versa)
