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MEDICAL GENETICS INTRO - Coggle Diagram
MEDICAL GENETICS INTRO
Genetic Variation
Germline mutations or somatic mutations
Mutations
DNA damage, replication, insertion, deletions
classified on genetic structure, chromosomal mutations(structure), genomic mutations (n of chro) and gene mutation (at nucleotide level)
POINT
base substitution
tranversion or transition
insertion or deletion, frameshift
alteration of reading of sequence, completely different AA
Premature stop codon is produced
if mutable of 3, the reading of frameshift is preserved
splicing mutation at splice site
they destroy acceptor and donor splice site, create a new splice site. which lead to cryptic splice site.
consequence exon skipping, if exon length is not a multiple of 3, frameshift mutation
cry-ting splice site, exons and introns, seq that resemble splice junction but inactive
reguolatory mutation, promoter or regulatory seq
mutation affect promoter like TATA, CAAT or GC box.
alter gene transcription level
missense mutation
changes in 1 AA in the protein sequence.
CADD > 20 pathogenic
AlphaMissense
nonsense mutations
premature stop codon of DNA seq
without C terminal
no translation, no protein is produced
depredated by proteasome
elongation mutation
no stop codon, continuously
polymorphism - more frequent 1% popula
not disease but pathological traits
single nucleotide is the most common genetic variation. substitution and small insertion or deletions
intergenic polymorphism, lined between genes.
functional classification of mutation based on FUNCTION, FITNESS, STRUCTURES
loss of function mutation
Onco suppressor - phenotype recessive
gain of function mutation
oncogenes - dominant phenotype
dominant negative mutation - interfere with the activity
lethal mutation - prevent survival
death
mutation evolution - not well fitness, less likely to have progeny
micro satellites - short repetitive seq CACACACACACACAACACA
forensic DNA analysis and paternity testing
gene
transcriptional unit, by RNA polymerase
regulatory regions, promoters
transcription site is at position 1, not 0
nucleotides upstream numbered with negative numbers
introns and exons
exons can contain coding or non coding regions
at pos 5' untranslatied are found upstream are transcribes but NOT translated. because UTR
coding regions start AUG. 3' UTR are at downstream of stop codon and are transcribes but NOT translated
splice site- junction between introns and exons. Donor splice (at the beginning INTRONS, GU nucleotides), acceptor (end of INTRONS, contain AG nucleotides)
PEDIGREE
relations between family members
square male, circle woman
Filled is affected individuals, and hollow is unaffected.
diamond, sex is unknown
men are on the left, woman are always right.
generations are labelled with roman numbers, individuals with arabic numbers
proband- individuals from whom the analysis begins
estimate the risk of disease for offspring
Ethnicity is important for disease spread
also family relationship or conflict
Autosomal dominant inheritance
single mutant allele, sufficient produce phenotype for disease
trait appears every generation in pedigree
affected individuals have affected parents
males and female, affected equally because it is autosomal inheritance.
age of onset- some can appear later in life
reduced penetrance: found in the genotype therefore not 100% expressed in the phenotype
INCOMPLETE PENETRANCE: probability that a genotype produces a phenotype. both dominant and recessive.
ex. MORGAN syndrome (connective tissue), Neurofibromatosis type 1, dwarfism, Hundington's disease, branchydactyly/polydactyly
Autosomal Recessive inheritance
two mutant alleles are required to appear
skips a generation
parents are usually carriers
half shaped symbols in pedigrees, not very shown in the pedigree
male and female equally because autosomal
Cystic fibrosis, sickle cell anemia, phenylketonuria (metabolic disorder)
X-linked dominant inheritance
Gene responsible for the disease in X chromosome
females have 2X therefore are affected by the father's X chromosome
in females, one X chromosome is inactive forming the Barr Body. Reduce severity, because inactivated affected chromosome
fragile X syndrome, Alport syndrome
X-Linked recessive inheritance
most individuals are male, because male have only one X chromosome
skip a generation
Hemophilia, affects blood coagulation factors, A --> factor 8, B--> factor 9. Color blindness, associated with X chromosome, Achromatopsia - absence of colour, Daltonism, common type of blindness.
Y-Linked inheritance
only by Y chromosome, only male affected, affected father to all sons
example. Hypertrichosis, Hairy ears, male infertility by deletions.
pedigree mutations
De novo mutations - probing affected, singular case.
arises during gametogenesis.
initially looks like a sporadic case
can also be for environmental factors
gremlin mosaicism
extends de novo mutation but during embryonic development, not gametogenesis
can affect somatic tissue, and precursor cell
mitochondrial inheritance
each cell contains hundreds of mitochondria, from the mother. endosymbiotic origin.
sperm mitochondria are destroyed after fertilisation
father carries a mitochondria mutation, no children carry. but if mother has affected mutation, all christen are affected.
heteroplasty, since cell contain many mitochondria they can exist in mutant or wild type molecule.
once egg is fertilised, they can receive low or high mitochondrial DNA. depending on the severity.
phenocopy the environmentally induced phenotype that resembles the phenotype produced by a genetic mutation.
may look genetic but environmental
example is deafness. can be genetic or trauma or workplace exposure.
20% Parkinson are mandelian, the rest is environmental.
like fertilisers
phocomelia, limb malformation with thalidomide.
complementation
phenomenon for which two different defective alleles complement each other in heterozygous restoring wild type.
ex.normal hearing. can appear and disappear even if the parents are affected
pedigree disorder
linkage analysis to identify the gene which perform on multiplex families and use polymorphic markers to map the disease locus.
the disease marker cause aggregate.
to be both transmitted must be close locus
a prerequisite for analysis is polymorphism, because repeated. ex. CA repeats. micro satellite length differentiated. can be used in forensic analysis.
longer alleles migrate less far in Gel Electrophoresis.
by comparing the segregation of the disease phenotype with the segregation with the known genetic markers.
if co-segregate, they must be close on the chromosome. Recombinant or non recombinant
micro satellite markers
D1S- DNA 1 is the chromosome numbers, S means sequence is single and unique, therefore the repeated locus is present only one in the genome.
after genotyping must recontrstuct haplotypes; groups of alleles along the chromosome.
requirements for linkage analysis
families in which disease segregation must be clearly followed.
genetic markers with known position
multiplex familie, multi generational families with multiple affected individuals
full penetrance
Recombination fraction (theta)
frequency of recombination between two loci.
from 0-50, if theta is > 50, the loci are independent or different chromosome. if theta is <50 loci are linked or close together.
we search for the the minimum theta value
biological loci= the smaller the distance between loci, the lower the probability that a crossing over event will occur between them.
RF= number of recombinant gametes // number of informative meiosis
informative vs non informative meiosis.
the greater the recombination fraction, the further apart the two loci are.
for the wild type, and - for the mutant disease allele
two point analysis, one disease locus is compared with one marker at a time. recombinant can be recognised only if they are double compound heterozygotic for both the polymorphism and the disease trait.
recombination cannot always be recognised unequivocally.
complication of two point analysis: reduced penetrance of error