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Genetics Fundamentals 1
Terms in this set (92)
Importance of Human Genetics in Medicine
causes mental retardation and developmental disabilities
40% child mortality related to genetics
in every generation
any child has a 50% chance
not sex influences
IE) Huntington's (CAG trinucleotide repeat mutation), mytonic dystrophy, Osteogenesis imperfecta
both copies of gene are dysfunctional
generally a loss of function
sex is usually not influencial
Not transmitted to son from father.
all daughters of infected father are affected.
If mother is heterozygotic: 50% of offspring will be affected
If mother is homozygotic, 100% of offspirng will be affected
Sons of heterozygotic mothers have 50% chance of being affected.
Males won't get it
%/proportion of individual who's phenotypic traits match thier genotype (A quantitative measure)
Non-penetrance is the lack of phenotypic evidence that a genotype is present
-does it show or not
IE) 2 identical twins have the gene for tongue rolling but only 1 can actually roll his/her tongue.
one genotype produces a range of phenotypes (A qualitiative measure)
-ranges from mild to severe
IE) rates have one gene for fur color but their fur colors are different shades
Mitochondrial Inheritance Features
1) Replicative Segration
-mt replication is not tightly controlled so copies made can replicate and sort randomly causing some cells to get more mutatnt than normal DNA or the other way around. The reason for the polar body to be created with no active DNA.
2)Homoplasmy: daughter cell recieves only mutant or only normal DNA
3) Heteroplasmy: daugher cell receives mixed populations of mt DNA
4) only maternally inhertied. Sperrm cells have not mito.
Complex Genetic Traits
Definition: traits that are influenced by environmental and hereditary components.
Multifactorial (Complex) Inheritance
Other names: Polygenic/ Quanitative inheritance
Definition: Inheritance of phenotypic traits that is attributable to 2 or more genes and their interaction with the environment.
Phenotype varies along a gradient depicted by a bell curve
Not like mendelian inheritance
Complex Pedigree Recognition
ie) Charcot Tooth Syndrome
not straight line connections
Definition: the extent to which genetic individual difference contribute to individual's phenotypic differences.
The higher the heritability the greater the contribution of genetic difference among people in causing variability of the trait.
Twin Studies in Complex Inheritance
-Describe Concordance rates as well
MZ Twins: arise from cleavage from a single zygote
DZ Twins: siblings in the same womb but seperate zygotes.
Concordance Rates: Presence of the same trait in both members of the twins.
CR < 100% in MZ twins means non-genetic factors play a part in the trait/disease
CR in MZ > CR in DZ proves that genetics plays a big role in the disease
Neural Tube Defects
Definition: defect in the closure in the neural tube which normally closes by 28 days. They occur due to mutlifactorial inheritance.
Open Neural Tube Defect
brain/SC exposedat birth through defect in skull or vertebrae
IE) Spina bifida, anecephaly, encepholocele, hydraencephaly
Closed Neural Tube Defect
spinal dect covered by skin
IE)) lipomyelocepholocele, lipomenigocele, tethered cord
Prevention of NTD (dosages)
Folic Acid supplementation
1 month prior to conception and 2 months post-conception
past NTD: 4-5mg/day
Cleft Lip and Cleft Palate Description
Failure of the union of the frontonasal process of the face with the lateral maxillary prominence
-suppossed to happen at 3-4 weeks after conception
Definition: study of inherited changes in phhenotype/gene expression caused by mechanisms other than changes to the underlying DNA sequence. They stay for the cell's life even through cell divisions
-nongenetic factors cause the organism to behave differently
Some gametes carry a mutation but the rest are normal.
The cause is usually a mutation that occurred in an early stem cell that gave rise to all or part of the gonadal tissue.
Random X Chromosome Inactivation
Random inactivation of one of the 2 copies of the X chromosome in a female
occur in any of the cells in the body except the germ cells and are NOT passed to the children
Trinucleotide Repeat Mutations
A repeat in the CODING REGION-> abnormal protein product
A repeat in TRANSCRIBED BUT UNTRANSLATED REGION-> interfere with transcription,mRNA processing, or translation
IE) CAG in Huntington's
RFLP Analysis: Restriction Fragment Length Polymorphism
Occurs when the length of a detected fragmnt varies btw individuals
1)DNA fragmented by restriction enzyme
2)gel electrophoresis: separate by length
3)Southern Blot: hydridization with probe that determines the length of fragments which are complementary to the probe
CGH: Comparative Genomic Hybridization
Analysis used to measure the difference between DNA samples in copy number or daosage on a particular DNA fragment.
Compares normal and abnormal cells
2)place in microchips/dishes
3)look at hybridization pattern in microarray
4)a strong color means there is a difference
Implies that different alleles in the SAME gene can cause a similar variant phenotype
Locus (Genetic or Nonallelic) Heterogeneity
Implies that mutation in different genes may explain one variant phenotype
Branch of genetics that is concerned with study of the structure and function of the cell and chromosomes
Routine analysis of BANDED chromosomes
Uses FISH and CGH
Chromosomal vs Metaphase vs Prophase Karyotypes
Chromosomal: photgraph of chromosomes arranged in homologous pairs in descending order of size and relative position of the centromere
Metaphase: analysis of metaphase chromosome used in cytogenetics and cancer studies
-chromosomes are condensed, thick, and coiled so are easily seen. Cells are arrested via mitotic inhibitor. Staining of slidies with Giemsa (G banding) or Quinacrine. Used for FISH and CGH
Definition: number of sets of chromosomes in a cell
ie) Tuner's syndrome (46 XO)
ie) Down syndrome
isochromosome: lost one arm and replaced with exact copy of the other arm
reciprocal translocation: exchange of material between nonhomologous chromosomes
Sex Chromosome Abnormalities
Turner Syndrome (Females)
Klinefelter Syndrome (male)
3 Types: Non disjunction, Mosaicism, Translocation
Diagnosis: 2 tests: the Quadruple Test and Triple Test
An exponential positive relationship after the age of 35 in mothers who have children.
Flat facial profile
poo moro reflex
hyperflexibility of large joints
loose skin on the back of neck
slanted palpebral fissures(seperation btw upper and lower eyelids)
small round ears
single palmar crease
ear rotates out
hypoplasia of small finger
Congenital Heart Defects
-found in 40-50% of indiv with downs
-overpresentation of endocardial cushion
-left sided lesions and aortic stenosis are RAR
-atrioventricular canal, ventricular septal defect, atrial septal defect, patent ductus arteriosus
crossed legs is the preferred position
feet with round bottom
low birth weight
low set ears
micrognathia (small jaw)
unusual shaped chest
mentally and motorly challenged
holoprosencephaly (forebrain not divided properly)
Effect on Fertility?
low set ears
ovaries dont work
one x chromosome is missing.
in females: oocytes degenerate and ovaries atrophy during neonatal and fetal periods bc the loci are located on that missing chromosome even though it would normally be inactivated.
Congenital Heart Defects:
-biscuspid aortic valve
-dilated aortic root
Normal UNTIL PUBERTY then shit hits the fan
tall, thin with long legs
no medical problems
boys have increased growth
Quadruple Serum Test for Down's Syndrome
15-18 weeks of pregnancy
AFP/ uE3: reduced by 20-30%
hCG/ inhibin A: 2x high
Triple Serum Test for Down's Syndrome
15-22 weeks of pregnancy
AFP, uE3, hCG
Maternal Serum Tests fro Down Syndrome
done in Second trimester
made in yolk sac, GI, liver of fetus
better for detecting NTD
decreased in Downs and NTD
if too elevated can mean a different kind of trisomy
made by placenta from fetal adrenals and Liver
normally is increased
but decreases in trisomy 21 and 18
glycoprotein made by fetal cells
peaks at first 8 weeks but then decreased until 20 weeks
MOST SENSITIVE FOR DETECTING TRISOMY
high levels: trisomy 21
low levels trisomy 18
alone diagnosis 25-50% of the time
hCG and AFP brings diagnosis to 40-50%
Inhibin A: increased in downs
Nondisjunction Trisomy 21
A typical gamete (either egg or sperm) has one copy of each chromosome (23 total). When it is combined with a gamete from the other parent during conception, the child has 46 chromosomes. However, with nondisjunction, a gamete is produced with an extra copy of chromosome 21 (the gamete has 24 chromosomes). When combined with a typical gamete from the other parent, the child now has 47 chromosomes, with three copies of chromosome 21. The trisomy 21 karyotype figure shows the chromosomal arrangement, with the prominent extra chromosome 21.
The majority of the cases.
Mosaicism Trisomy 21
When some of the cells in the body are normal and some cells have trisomy 21.
Translocation Trisomy 21
not inherited but occurs at the same time as conception.
The long arm of chromosome 21 is attached to the long arm of another chromosome, often chromosome 14 or itself in which we would then call it an iso-chromosome.
Defintion: sex determining region Y on the p arm of the y chromosome
embryo develops by default into the female fetus if there is no SRY inflence.
SRY-: no expression of the SRY gene
SRY+: expression of the SRY gene
SRY can be silent but present.
Fragile X Syndrome
What's the molecular mutation?
trinucleotide repeat of CGG in the promoter region of the FMR-1 gene on the x chromosome.
full mutation is a 200 repeat which leads to the abnormal methylation of the FMR-1 gene which is needed to be normal in order to have normal neural growth development.
carrier range: 50-230 repeats
normal range: 6-52 repeats
FMR: fragile X mental retardation 1 gene
macroorchidism: CT disorders
FISH: Fluorescent In Situ Hybridization
Used to identify specific mRNA in tissue sample and sequence the DNA for genetic counseling purposes
a cytogenetic technique used to detect and localize the presence or absence oof specific DNA sequences on chromosomes. probes only bind to parts of the chromosome with which they show a high degree of sequence complimentarity.
1) break Hbonds and expose chromosomes
2) fluorescent probe used to bind the parts of chromosome that is highly complimentary
3) use in metaphase chromosomes bc you want the DNA to be in the single copy phase
What are microdeletions and some microdeletion syndromes?
Microdeletion Syndromes: extrememly small deletions of genetic material sometimes only visible under FISH. Can be hidden in cryptic translocation of carrier parents.
13q with retonoblastoma
Cri-du-chat microdeletion syndrome
more in females
difficulty in swallowing and sucking
low birth weight and porr growth
speech and motor delays
congenital heart defect
del 18p and del 18q
cardio septal defect
cleft lip and palate
involuntary eye movement
del band p13 of chromosome 11
and Trisomy 18
13q with retinoblastoma
del 13 and q14
short nenck and lateral folds
low set large ears
Miller Dilker Syndrome
chromosome 17 del p13.3
arrested neuronal migration in the cerebral migration in the cerebral cortex
profound mental retardation
Amyloid Precursor Protein (APP)
Relationship to Downs and Alzheimer's
Definition: mother of amyloid plague which a beta rich protein.
APP gene located on chromosome 21. Normal indiv only have 2 copies of this gene while Down'd patients have 3.
Down's patients are more likely to get Alzheimer's due to the extra APP that can be synthesized and availbale to be fragmented into amyloid plaque.
FISH used on which microdeletion syndromes
Criteria for ordering a karyotype
1) suspected aneuploidy
2) unexplained mental retardation
3) sexual ambiguity
4) female that is really short
5)history of unexplained birth defects in close relatives
6) major anomalies in 2 or more systems
7) more than one mendelian disorder
8) history of 2 or more miscarriages
9) x linked recessive disease in female
10) x linked dominant lethal disease in a living male
11) suspected mosaicism
Process of proto-oncogene--> oncogene
usually a missense mutation to see a gain in functionn
DO NOT see frameshifts, nonsense, or deletion mutations
amplification rsultsi n increased # of gene copy number and increased gene expression
chromosomal rearrangemnets cause oncogenes to be abnormally activated.
Who is at risk for breast cancer and what are the risk factors of developing breast cancer? What are the features of possible breast cancer patients?
-late age with first birth
-benign breast disease
-hormone replacement therapy
HIGHEST RISK IS BRCA-1 and 2
BRCA1: 1/300 chance 20-40%
BRCA2: 1/800 chance
Ashkenzai jeews 1/40 chance 10-30%
Percentage of breast and ovarian cancers are hereditary
What type of tunor genes are BRCA 1&2
Tumor suppressor genes
Components of a risk assessment for breast cancer?
How many generations should a family history or pedigree be?
at least 3 generations
personal medical history
determine likelihood of mutation in cancer causing gene present
genetic testing if indicated
What risk factors could have a woman have that would make her think she was susceptibe for ovarian/breast cancer?
2 or more close relatives have cancer
early age diagnosis,
multiple primary tumors, bilateral or multiple cancers
autosomal dominant transmission
Misconceptions about the genetics of breast/ovarian cancers?
Opposites of the following are misconceptions:
1) 1/2 of women with hereditary risk inherited it from father
2)age of onset is more important than the # of women with disease in family
What is the 2 Hit Hypothesis and who proposed it?
Knudson's 2 hit-hypothesis
Definition: a hereditary mutation is inherited first and the second mutation is acquired somatically
IE) a cell can initiate tumor only when it contains 2 mutant alleles. A person who inherits a mutant allele must experience a second somatic mutation to initiate tumorgenesis.
Molecular basis is that is associated with loss of heterozygosity.
Li Fraumeni Syndrome
80% of the time it is a p53 mutation.
characterized by several kinds of cancers appearing at a young age and frequently thoughout life.
What is the relative importance of inherited vs somatic mutations in cancer?
Family history can give insight into possible inherited disorders and allow early detection.
Is the risk of developing malignancy in inherited forms of cancers always 100%?
No they can be prevented from genetic testing.
Genetic and phenotypic features of Neurofibromatosis 1 aka Rechinghausen's disease?
most common AD heritable disease
cafe au lait spots
nodules on iris
Loss of functional neurofibromin could result in unregulated Ras activity.
What cancers are due to DNA repair defects or chromosomal breaking defects?
Fanconi panytopenia syndrome
What is the philadelphia chromosome? What disorder is it associated with?
Balanced translocation between chromosome 9 and 22 which creates a hybrid gene that translates into proteins with increased tyrosine kinase activity.
CHRONIC MYELOGENOUS LEUKEMIA
Rb gene produces a phosphprotein involved in the control of cell cycle. The normal allele prevents retinoblastomas.
Familial Adenomatous Polyposis Syndrome
each offspring have 50% chance of getting
FAP gene is in chromosome and causes it.
if you have this then you have a lifetime risk of developing colorectal cancer.
What is the genetic mechanism that has been proposed to occur in prostate cancer, multiple endocrine neoplasia, and basal cell carcinoma?
Which oncogene is commonly involved in melanoma?
CDKN2 gene aka p16 tumor suppressor gene.
Compare and contrast tumor suppressor genes to oncogenes?
tumor suppressor genes cause cancer when they are turned off.
oncogenes are cells that can cause cancer when they are made from pro-oncogenes
What is the genetic cause of Lynch Syndrome aka HNPCC: hereditary non polyposis colerectal cancer? Which genes are involved?
a type of inherited cancer of the colon and rectum
Autosomal dominant trait
DNA mismatch repair defect
What is teratology? What are some examples of teratogens?
Definition: study of malformation or serious deviations from the normal type in developing organisms. It is the relationship of maternal exposure to an agent or disease potentially harmful to the fetus.
thalidomide (for morning sickness)
Epigentics: what are factors in it and how does it happen?
Definition: the study of heritable chagnes in gene expression or cellular phenotype due to mechanisms other than changes in the DNA sequence.
phosphorylation of histone
high fat diets
reveratrol in red grapes or wine ***may help against cancer
What conditions are associated with paternal epigenetics and outcomes of offspring?
advanced age of a father is correlated with high rates of
3) birth defects
limited diet of pre-adolescent father linked to reduced risk of cardio death in his children & grandchildren.
paternal obesity is linked to enlarged fat cells, changes in metabolic regulation, diabetes, development of brain cancer.
psycho-social stress on father is linked to defective behavioral traits in his offspring.
paternal alcohol use leads to decreased newborn birth weight, marked reduction in brain size and impaired cognitive function.
T box genes and Holt-Oram Syndrome
group of transcription factors involved in limb and heart development.
clinical application: defects in TBX5 gene expression can lead to finger like thumbs and ventricular septal defects where there is no separation between the right and left ventricle of the heart
genes important in the development of testis, CNS olidendrocytes, and neural crest formation.
PAX genes and Waardenburg Syndrome
genes important for the formation of tissues and organs during embryonic development and for maintaining the normal function of certain cells after birth.
They are called transcription factors as well bc they provide instructions for making proteins that help control activity and expression of particular genes.
they are usually turned off/inactivated but in some tissues they can help tissue regrow and protect against cell death.
Clinical application: mutation in the PAX gene leads to disorders that involve incomplete development of tissues where the Pax gene is expressed.
Waardenburg syndrome: congenital hearing loss
heptic phenylalanine hydroxylase which converts phe->tyr is mutated so you get a build up of phe and its metabolites which results in mental retardation and pale coloring
treatment: restrict diet to no meat
Gal-1-phosphate uridyl transferase deficiency in infants.
Sx: large liver, jaundice, hypotonia
Death can occur from sepsis
Galactose accumulates and cannot be converted to glucose
Treatment: eliminate lactose from diet
random X chromosome inactivation early in stages 32-128 of cell stage.
What test can be used to identify CF?
70% have the 3bp deletion mutation
30% have on of the several random mutations
Allele-Specific Oligonucleotide (ASO)
-probe analysis provides rapid and simple way to screen for common CF mutation in the general population.
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