Q2 BioChem Exam 1

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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)


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