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56 Cards in this Set
- Front
- Back
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What are the three categories of structural DNA changes
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1. chromosomal rearrangements and aneuploidies
2. large rearrangements of DNA (duplications, deletions) 3. Changes involving a few nucleotides, mostly single gene disorders |
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mutation
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change in normal base pair sequence, usually destroys protein function and causes disease
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What are the single gene (mendelian) disorders
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autosomal dominant
autosomal recesive x- linked dominant and recessive |
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Locus
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specific physical location of a gene on a chromosome.
ex: chromosome 15 (15q 21.1) |
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Alleles
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alternative forms of a gene at a given locus.
wild type and mutant |
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Dominant condition
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single mutant allele causes disease reguardless of the form of the other allele
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recessive condition
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two mutant alleles must be present for disease
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homozygous and heterozygous
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alleles are the same at a given locus (aa or AA)
alleles are different at a given locus (Aa) |
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Compound heterozygote and example
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two different abnormal alleles appear at one locus in an individual
ex: cystic fibrosus |
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genotype and phenotype
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genetic composition of a person, allels at a specific location
Phenotype = genotype + environment ex: in PKU observed clinical or physiological characteristics of an individual |
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things to ask about when taking a genetic family history
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Birth defects, stillbirths, multiple miscarriages,
MR, recognized genetic conditions Ethnic background Consanguinity Symptoms similar to proband Often have to clarify relationships (half-sibs etc.) |
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characteristics of autosomal dominant inheritance
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only one mutant allele necessary
heterozygote has 1/2 chance of passing to offspring homozygous normal (dd) not at risk |
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characteristics of autosomal dominant pedigree
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vertical transmission
number males to females infected equal - male to male transmission observed * key point - unaffected individuals have unaffected children |
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clinical characteristics of autosomal dominant disorders
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variable expression
- penetrance - pleiotropy - de novo mutation - germline mosaicism - genetic heterogeneity - anticipation |
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variable expression
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different people express same mutant allele with various degrees of severity
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treacher collins syndrome and neurofibromatosis I shows what??
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variable expression
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penetrance
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proportion of individuals who have a disease causing mutation and show clinical signs of the disease
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complete pentrance
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100% of people with mutation are clinical affected
ex: neurofibromatosis I penetrance is often age dependant |
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incomplete or reduced pentrance
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frequency of expression of phenotype is less then 100%
ex: postaxial polydactyl - only 65% of mutants actually have polydactyly non-pentrance - person with mutant allele but not with disease obligate heterozygote |
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pleiotropy
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multiple phenotypic effects in different tissues and organs are produced by a single gene mutation
Ex: Marfan syndrome - multiple systems involved, skeletal, heart, eye |
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De novo mutation
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unaffected parents have a child with a dominant disorder
ex: achondroplasia 80-90% new mutations mutation rates increase with paternal age for some autosomal dominant disorders |
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germline mosaicism
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mutation occurs in gonadal tissue of an unaffected parent of a child with an "apparently" new mutation
EX: osteogenesis imperfecta II germline mosaicism are caused by post-zygotic mutations phenotypically normal parent has increased risk of having more than one affected child, ex with guy having kids with wife and secetary |
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causes for variable expression
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enviromental factors
modifying background genes genetic heterogeneity (allelic or locus heterogeneity) |
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allelic heterogeneity
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different mutation (alleles) at same locus can result in variable expression
ex: hirschsprung disease |
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locus heterogeneity
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particular disease phenotype due to mutations at different loci
ex: tuberous sclerosis complex (TSC) can be caused by mutations at TSC1 or TSC2 |
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Anticipation
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tendency for certain diseases to show progressively earlier onset and increasing severity in successive generations
ex: myotonic dystrophy |
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myotonic dystrophy
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displays anticipation
- difficulty in relaxing muscles, expressionless face - caused by unstable trinucleotide (triplet) repeat - number of repeats determines severity of the disease and age of onset |
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Consanguinity
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relationship by descent from a common ancestor
increases risk of autosomal recessive mutations being passed -more frequently seen in individuals who have rare autosomal recessive disorders |
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clinical characteristics of autosomal recessive disorders
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cluster in ethnic groups
penetrance is usually complete, less phenotypic variability most are enzyme abnormalities |
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tay-sachs
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shows cluster in ethnic groups of ashkenazi jews
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risk determination for recessive conditions
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use carrier frequency and risk of passing on that certain allele
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mitochondrial inheritance features
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all children of affected females will be affected, equal number males to females affected, but only transmitted through mom
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homoplasy
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all mtDNA are the same
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heteroplasy
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more than one type of mtDNA within a cell
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replicative segregation
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amount of mtDNA to each cell is not always the same, random segregation of mitochondria
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somatic mosaicism
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two different cell lines in somatic cells, gene mutation or chromosamal anomaly during mitosis
1. not inherited from parent, not passed on ex: proteus syndrome, aging, neoplasm clinical clues? |
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germline mosaicism
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mutation occurs in germline cells
- can be passed to offspring - phenotypically normal parents have more than one child with a new dominant mutation |
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osteogenesis imperfecta, Type II
and Duchene muscular dystropy show what? |
germline mosaicism
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uniparental disomy
heterodisomy isodisomy trisomy rescue |
inheritance of both members of a chromosome pair from one parent
heterodisomy - both homologs from one parent (occurs because of nondisjunction, know which stage, meiosis I) isodisomy - duplication of one of parents homologs (meiosis II) trisomy rescue - nondisjunction caused disomy gametes which then become trisomy and lose one of the chromosomes to make it disomy again |
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genomic imprinting
describe pedigree for each |
some genes are expressed differently when inherited from mom or dad
an imprinted allele is not expressed. if paternal imprinting then dad won't give disease to kid, kids will only be a carrier maternal imprinting, females kids only are carriers of the dominant disease because of imprinting |
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Prader-willi syndrome
angelman syndrome |
prader willi syndrome - illustrates genomic imprinting, deletion of gene from father, lose SNRPN protein, presents by oesity, short stature cognitive impairment, almond shaped eyes, hypogonadism
angelman syndrome - inherit deletion from maternal chromosome, sever cognitive and speech impairment, gait ataxia |
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Trinucleotide repeat expansion disorders
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fragile X syndrome, myotonic dystrophy, huntington disease
CAG repeats increase in number beyond threshold it causes disease, repeats can expand in subsequent generations |
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anticipation
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wosrsening iof the disease from one generation to the next, due to trinucleotide repeats usually. gets earlier and earlier presentation
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Hemoglobin differences at birth and types
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Alpha - always present
beta - only after birth about six months gamma or fetal hemoglobin - prevelant at birth but goes down atferwards know when defects would present |
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sickle cell anemia
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Hb S, causes sickle RBC
heterozygotes have mild symptoms. homozygous individuals are in bad shape, read syllubus |
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Hemoglobins with decreased and increased oxygen affinity
know consquenses |
decreased affinity - offload more oxygen in tissues, are anemic because loweer hemoglobin level is required
higher affinity - don't unload oxygen in tissues as well, need way more hemoglobin than usual, polycythemia |
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thalassemias
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decreased globin chain production, named for chain that is reduced production
degree of mismatch of chains determines degree of disease if ratio 2:1 between alpha and beta, get mild if any symptoms, if more than 2:1, get minor or major symptoms if alpha globin production is insufficient, then beta globin tetramers are formed and don't carry oxygen well |
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alpha thalassemias
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have 4 genes for alpha chain production, number of genes affected
thalassemia minor - smaller RBC mild degree Thalassemia major - lots of homotetramers, very mismatched, not good oxygen to body, anemia, leads to iron overload |
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dosage compensation
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theroy that acitvity of x linked genes is equal in both genders, even though females have two genes of each, explained by X-inactivation
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X-inactivation
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in female somatic cells one of the X chromosomes becomes inactive
females become a moasic for the X chromosome genes ex:incontinentia pigmenti |
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skewed inactivation
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where one X is inactivated non-randomly over the other
ex is when there is a balanced reciprocal translocation, the normal X is inactivated so that the somatic genes still get expressed on the mutated X chromosome |
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pseudoautosomal region
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region of X chromosome where some genes escape inactivation. this is why 45, X and those with multiple X's abnormal
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turner syndrome
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45, X
symptoms short stature, horseshoe kidney, webbed neck, congenital heart defects, cystic hygroma which results in the webbed neck after birth, wide inter-nipple spacing |
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klinefelter syndrome
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47, XXY
bilateral gynecomastia, eunuchoid body habitus, small penis, reduced testicular volume, infertility treatment is testosterone replacement therapy |
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multiples of X and Y
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more X's the worse it gets
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sex reversal
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46,XX in aminocentesis but had a boy,
most have X;Y translocation leading to sex reversal the SRY, sex reversal on Y gene, gets put onto an X chromosome so a boy pops out with 46,XX |
