Mutation and Polymorphism Flashcards
DNA is what percent identical b/w individuals
99.9% identical
only a small fraction that is different is responsible for human genetic variability
some differences= little/no effect
some differences- disease or death
B/w the extremes- narmal variation b/w people
Categories of mutation
What is a mutation
Genome mutations create?
Chromosome mutations do what?
Gene mutations do?
Mutation is any change in nucleotide sequence or DNA arrangement
Genome Mutation- create aneuploidy
Chromosome Mutations-alter structure of individual chromosomes
Gene muation- alter genes
Range from single nucleotide ot millions of bps
Germ Line Mutation
VS
Somatic Mutation
Occurs during gamete formation- perpetuated to offspring
Creates somatic mosaicism- not tx to offspring
Origin of Mutations
Genome Mutations?
Chromosome mutations?
Gene Mutations?
2 mechanisms?
Genome mutaions - mis segregation causing monosomy or trisomy
Chromo- rarely perpetuated, as normally incompatible with survival
bp subs, insertions or deletions
DNA replication error or problem during DNA repair
Origin of mutations
DNA Replication errors
Majority rapidly repaired by repair enzymes
recognize incorrect strand and replace nucleotide
w.o proofreading level of mutation would be intolerable
Origin of mutation
Repair of DNA damage
10k-100k nucleotides damaged per day
some bu not all damage is repaired
repair machinery may misread comp strand and create mutations
Nucleotide Substitutions
Missense
Missense mutations- point mutations alters triplet, replaces one aa with another
alters sense of coding strand
ex hemoglobinopathies
can cause dz when outside coding region
Nucleotide Substitutions
Chain Termination Mutations
cause normal codon to become termination codon
translation ceases- partially translated polypeptides
Creates unstable mRNA, and unstable trunctated proteins
also can destory termination codons
Deletions and Insertions
Small number of nucleotides to large segments
small detected by nucleotide sequencing
large detected by southern pr PCR
rare deletions large enough to be seen on karyotype
Small deletions and insetions
not a multiple of 3?
Multiple of 3?
frameshift mutation
add or delete aa
Deletions and Insertions
LARGE DELETION AND INSERTIONS
generally uncommon
DMD, alpha thalassemia
Insertion much rarer than deletion
Deletion and Insertion
Effects of Recombo
Deletion or duplication by recomb
normally d/t unequal crossing over
deletion of alpha globin gene in some alpha thalasemmias
DYNAMIC MUTATIONS
involve what
Amplification of trinucleotide repeat sequence
Huntingtons, fragile x
repreat can be coding or in transcribed by untranslated region
repeat may expand during gametogenesis = fynamic mutation
Estimates of germ line mutation rates
number of new mutation per locus per generation
measure indcidence of new, sporadic causes of autosomal dom or x linked disease
Sex differences in mutation rates d/t?
d/t differences in rate and timing of sperm vs oocyte formation
RFs differ b/w sexes
females: non disjunct with age
Males: rep erors with age
Human genetic diversity
many mutation not deleterious BUT?
Beneficial or neutral
Steady influx of new variation gives high degree of genetic diversity and individuality
Coding regions very similar b/w individuals
Human Genetic Diversity
Genetic Polymorphism
Rare variants
variant found >!% of pop
Found in <1% of pop
many types of polymorphism
Single nucleotide polymorphisms
SNPs - usually take 2 alleles - 2 bases in a particular location
occurs 1/1000 bps -3,000,000 differ b/w 2 people
t10 mil total variant positions
neutral or subtle effect?
Insertion - deletion polymorphims
Microsats
Minisats
1/2 are mulrialleic - variable numbers of a segment of DNA that is repeated in tandem
MICROSATELLITES
stretches of DNA with units of 2-4 nucleotides repeated many times
different allels=differing numbers of repreated units w/in microsatellite-STRPs
MINISATELLITES
Tandem insertion of varying number of copies of 10-100 bp sequences
Many allels- VNTRs
SOme VNTRS implicated in dz
Insertion deletion polymorphisms
Copy Number Polymorphisms
CNPs
Variation in number of copies of larger genome segment
recently discovered sig for human health unknownm
ABO System
4 blood types based on
4 blood types based on antigens– innate antibodies
determined by locus on CHROMOSOME 9
A & B d/t action of allele on H antigen on RBC surface
O DOES NOT ALTER H
Rh System
Rh+
vs
Rh-
Roles in hemolytic disease of newborn and transfusion incompat
People are Rh+ or Rh-
Rh+ = polypeptide encoded by RHD gene on chromo 1
frequency of Rh + varies dramatically b/w ethnic groups
Rh- persons develop antiRh when exposed to Rh+ blood
Rh- mother with Rh+ fetus + trouble
Prevent hemolytic dz with RhoGam
MHC
Location on chromo #?
Large gene cluster on short arm of chromosome 6
3 classes of genes
Class I & II correspond to HLA genes
Many hundreds of allels of HLA class ! & II are known
MHC Class I Genes
MHC Class II Genes
Class I Genes: HLA-A, HLA-B, HLA-C.
code for integral proteins of plasma membrane - present to CD8+ T cells
Class II Genes: HLA-DP, HLA-DQ, HLA-DR
Code for inegral proteins that present exogenous antigens to CD4+cells
HLA + Disease
Most are what type?
Ankylosing Spondylitis
Hemochromatosis
Autoimmune
Variation in immune response d/t polymorphism in immune reponse genes
95% B27 Positive (Variation of B allele)
80% homozygous for common mutation in HFE and have HLA-A*0301
HLA and Tissue Transplant
HLA loci primary determinants of transplant tolerance and graft rejection
Only absolutely perfect match for all HLA and blood group alleles will allow lack of immunosupressive therapy
Greatest challange for HLA /Tissue transplant
BONE MARROW
graft can reject host-GVHD
Occurs when immunocompetent lymphocytes react to new host
the better class I match the lower the incidence of GVHD
