2. Non-mendelian Inheritance Chromosomal Abnormalities Flashcards
Continuous variation • Range of an \_\_\_\_ phenotype • Normal traits: – \_\_\_\_, weight, \_\_\_\_ intensity • Likely due to Caused by \_\_\_\_ in multiple genes
• A trait that's among a \_\_\_\_; usually within an average range • Height and BP • Pathologic - there is a large number of people that we would consider to be above healthy BP ○ But there are extremes • Weight - strong environmental influences • Skin pigment - 6 genes necessary in order to make, and deposit > variability
observable height color allelic variation continuum
Mitochondrial Inheritance
- Matrilineal
- Both ____ are affected
- Mitochondria in zygote are all from ____
- Mitochondria have own ____
- Severity depends on # of defective mitochondria inherited (____)
- i.e ____ Neuropathy• Mitochondria use a lot of nuclear genomes but have own genome
○ May not all be identical within cell > heteroplasmy (only 30-60% may be affected)
• ____ - all mitochondria come from mother
○ Male has no affected offspring
• Things that require heavily on energy > ____ and ____ are usually affected
sexes egg genome heteroplasmy leber hereditary optic
matrilineal
muscles
neurons
Genomic Imprinting • \_\_\_\_ process – DNA \_\_\_\_ • Maternal vs Paternal inheritance of an autosome • Prader-Willi vs Angelman syndrome • Other disorders: – \_\_\_\_ disease – Neurofibromatosis – \_\_\_\_ Dystrophies
• Same deletion on chromosome > some are only expressed on paternal allele (active, and imprinted ones - inactivated)?; and on maternal side it's the opposite (Angelman vs. prader-willi) ○ Same genetic loci are affected???
epigenetic
methyltransferases
huntington
myotonic
15q11-15q13
• Paternally expressed genes – \_\_\_\_ • Small nuclear ribonucleoprotein- associated protein N – \_\_\_\_ • necdin
• Maternally expressed gene
– ____
• Ubiquitin protein ligase E3A
• Within this region ○ Paternal: SNRPN and NDN ○ Maternal: UBE3A • Inherit deletion of mom > do not express \_\_\_\_, but only SNRPN and NDN; and vice-versa
SNRPN
NDN
UBE3A
UBE3A
Prader-Willi Syndrome
• Deletion on ____ inherited from ____
• ____, obesity ,small ____, mild mental retardation, ____
• Missing information: ○ Believed to be due to loss of SNRPN and NDN on paternal chr 15/inactivation on maternal chr 15 § Only express \_\_\_\_ • Low muscle tone, obese (\_\_\_\_ to eat, insatiable) • Stubborn and manipulative • If pass on chromosome, as a boy, brings down Prader-willi syndrome • If you have angelman/prader-willi as a female, will always pass on angelman syndrome ○ Has to do with parent \_\_\_\_ and not the phenotype
chromosome 15 father hypotonia hands hypogonadism
UBE3A
desire
sex
Angelman Syndrome
• Same deletion on Chromosome ____ inherited from Mother
• Ataxic ____, inappropriate ____, severe mental retardation, and seizures
• Missing information: ○ Due to UBE3A deletion on maternal chr 15/silencing on paternal ch15 § Expressing \_\_\_\_ and \_\_\_\_ • More severely \_\_\_\_ retarded and are prone to seizures
15 gait laughter NDN SNRPN mentally
Presence of a mutation in a population
• Heterozygous advantage
– Advantage of heterozygous state
– e.g. ____ – malaria; ____ – tuberculosis
• Founder Effect
– Sudden ____ in population leaves an increase in ____ among survivors
– ____ disease
• HA - disorder that while being heterozygote isn't as good as homo good, but not as bad as homo bad ○ SCA - resistant to \_\_\_\_ (allows people to live in malarial belt to survive) (higher rate in Africans) ○ Tb - heterozygous for cystic fibrosis gene is resistant to \_\_\_\_ (higher rate for European descent); but then a higher rate of allele to lead to \_\_\_\_ • FE - Tay Sachs (asokonizi Jews) > population that came to America during the Holocaust (higher rate in the initial \_\_\_\_ of that group)
sickle cell anemia cystic fibrosis decrease mutant tay sachs
malaria
Tb
CF
founding group
Trinucleotide repeat diseases
• Expansion in the # of ____ nucleotide repeats
• Low #’s of repeats are ____
• # of repeats above threshold lead to disease
• Pre-mutation- repeats between these 2 threshholds
• ____ disease, Fragile X syndrome, ____ disease
* Transcription/replication machinery is slippery > expansion of repeats > development of disorder * Expansions in the \_\_\_\_ region of the genes, leading to a repeated AA structure * Short \_\_\_\_ example
3
normal
huntington’s
kennedy
coding
CNV
• HD > occurs within a gene • There are a number where they can occur in other parts: ○ FGX > UTR in the \_\_\_\_ ○ Myotonic dys > \_\_\_\_ end ○ Myoclonus epilepsy > \_\_\_\_ ○ Friedrecih ataxia > \_\_\_\_ region
5’
3’
promoter
intron
Multifactorial Inheritance
• AKA ____
• Co-inheritance of modest effect, low-penetrant genetic variants
– Risk factors vary in importance
• 22 risk factors for ____ , 6-7 are most important
– Some risk factors are specific to disease others are common to multiple diseases
- ____ may influence
- Family has higher risk than population, but not ____
- Compare concordance between ____ and dyzygotic twins• Multifactorial > a number of genes working together to lead to the phenotype
○ Some disorders are polygenic
• Each gene has a tiny amount of risk > inherit together > develop the disorder
polygenic type 1 diabetes environment mendelian monozygotic
TABLE!
• How to determine whether something is a risk allele and something that is causing the disease
○ Look at monozygotic and dizygotic twins
§ If something is causing the disorder > should be 100% in ____ twins, and should the same as with a sibling in dizygotic twins
• CLP > ____% mono twins both develop (not 100% genetic); dizygotic is ____%
• IDDM (insulin dependent diabetes) is similar to CLP
• Use the twins, growing up in as close to same ____ as you can get
monozygotic
35
5
environment
Cleft Lip/Palate • 1/700 • \_\_\_\_ expressivity • RARa, \_\_\_\_, Folic Acid metabolism, fetal alcohol syndrome, malnutrition • \_\_\_\_ and \_\_\_\_ decrease cleft lip
* Some people have more minor, and some have a more severe disorder (VE) * Environmental things: nutrition (put on folate and B6 when \_\_\_\_)
variable TGFB3 folate B6 pregnant
Next Frontiers
• Genetic Risk Identification
• Genome wide association studies
• Pharmocogenomics
• ID genetic risk factors > who has the greatest \_\_\_\_ of developing disorders > then can start preventing ○ Can cure AD in mice bc we know which mice get the disorder; and risk would help us start therapies at the right time (for preventative therapies) • GWAS > \_\_\_\_ > looking at them across genome of 1000's ○ In AD > 22k people and look at what genes cause risk > look at all genes together you can see who's at greatest risk; also looking at how they're expressed • PG > based on my \_\_\_\_, what is the best medicine for me? ○ Women > have been \_\_\_\_ for majority of medicines bc dosage was based on \_\_\_\_ of male
risk SNPs genes misdosed average weight
Chromosomal Abnormalities
• Background • Structural abnormalities • Numerical abnormalities – \_\_\_\_ – Sex chromosomes • 1/200 newborn infants have \_\_\_\_
• Structural abnormalities > gross changes
autosomal
chromosomal abnormalities
Background • DNA is packed into \_\_\_\_ • Centromere • p – \_\_\_\_ – \_\_\_\_ arm • q–\_\_\_\_ arm • G-band (Giemsa stain)
• Chromosomes depicted at time of replication when form two sister chromatids and paired at the centromere ○ Middle - \_\_\_\_ ○ Sub-metacentric ○ Acrocentric - at the \_\_\_\_ ○ Where centromere falls has some implications for where can form abnormalities • P - petit - small • Q - long arm (after P) • Can look at chromosomes with \_\_\_\_ stain > stains active \_\_\_\_ and heterochromatin differently > can see a banding pattern based on difference of \_\_\_\_; can be used to tell which chromosomes are the same
chromosomes petit small long metacentric end giemsa euchromatin methylation
Karyotype • Picture of stained \_\_\_\_ chromosomes • 46 chromosomes – 22 pairs of autosomes – 1 pair of sex chromosomes
• Can compare \_\_\_\_ > get a sense of abnormalities
metaphase
g-banding
Spectral Karyotype (SKY) • Each Chromosome labeled with unique \_\_\_\_ signature • Pseudocolor • Visualize \_\_\_\_ • Comparative Genomics
fluorescent
chromosomal abnormalities
Translocations by SKY
• Mouse treated with ionizing radiation
• SKY of bone marrow cells reveals 2 ____
• T(2:14)andt(2:19)
• Important for cancer as well as for people who are trying to have children and are wondering why they cannot \_\_\_\_ • Green chromosome > has bits of 2 on it; and then 2 has parts of 14 on it > translocations > important in cancer ○ These events in cancer cells > drivers of blood cancers
translocation
conceive
Structural Abnormalities • \_\_\_\_, duplications, insertion, • Translocations • \_\_\_\_ • Inversions • \_\_\_\_
* Prader-willi is a \_\_\_\_ * Translocations > \_\_\_\_ information • Isochromosomes > one arm gets mixed > get two copies of \_\_\_\_ arm ○ Two \_\_\_\_'s instead of p/q • RC > \_\_\_\_ get locked off and you form circles
deletion isochromosomes ring chromosomes deletion exchange one p telomeres
Microdeletions – Williams Syndrome
- Chromosome deletion of ____
- ____ mouth, full lips, small chin, puffy eyes, and ____ iris
- wide-spaced, small teeth
- Thick, ____ hair
- ____disposition
- ____ learning deficit (____ test) – Normal verbal and ____
- ____ Valve defects• More similar features to other people with this disorder than with their own ____
• Dentally need extra care, but always extremely happy
• Unique learning disability > normal on verbal/social skills; but a spatial learning deficit
○ D of y test > took a D and make it out of y’s > they would say it’s a ____ instead of the BIG D
○ Draw a truck > box and wheel in ____ places > spatial constructs are difficult
7q11.23 wide starburst curly happy spatial D of y social cardiac
family members
y
random
Williams Syndrome
____ spaced teeth
Enamel ____ ,
– increased risk for ____ .
– regular ____ visits and good home care are required.
– Behaviorally, these patients are frequently ____ and easy to ____
wide hypoplasia caries dental hygiene pleasant manage
Balanced Translocation • All genetic material \_\_\_\_ • Not problem for \_\_\_\_ • Fusion of 2 acrocentric chromosomes – \_\_\_\_ Translocation • Problem in \_\_\_\_
* Equal exchange of information, but attached to wrong chromosome > you survive * Unless something happens at break point > people live normal happy lives * But if you have \_\_\_\_ > begins to be an issue * Robertsonian translocation > two \_\_\_\_ chromosomes > can attach to each other > and then depending on how it sorts during miosis > can end up with \_\_\_\_ copies of this chromosome * During miosis, take one chromosome as 13 with 14, and a regular 14, then you have \_\_\_\_ copies of 14 (when combining with the male) and then the normal two of 13 * Can pull apart chromosomes in various ways???
maintained
carrier
robersonian
gametogenesis
children
acrocentric
three
three
Balanced Robertsonian Translocation
• Robertsonian translocations can lead to abnormal chromosome # in offspring
* Chr 21 > acrocentric > can attach to \_\_\_\_ or \_\_\_\_ * Chr 21 > most common forms of \_\_\_\_ > \_\_\_\_ syndrome
13
14
trisomy
down’s
Abnormal Chromosome Number -Aneuploidy
• Extra chromosomes – Trisomy 21 – \_\_\_\_ – Trisomy 18 – \_\_\_\_ – Trisomy 13 - \_\_\_\_ – Sex Chromosomes
• Loss of chromosomes
– Monosomy – ____
• Only 3 are viable, and only \_\_\_\_ survives past first couple of years
down syndrome edward syndrome patau syndrome turner syndrome trisomy 21
Trisomy 21- Down Syndrome
• 92–95% have ____ chormosomes (3 copies of ____)
• Incidence increases with maternal age of ____
• As eggs mature, and women don't get new eggs as they age > increase risk of eggs to develop \_\_\_\_, damage and translocations ○ Every year after \_\_\_\_, your risk for DS continues to increase
47 21 conception mutations 35
Down Syndrome • Leading Cause of mental retardation • \_\_\_\_ Folds and \_\_\_\_ facial profile • Simian Crease • 40% have \_\_\_\_ malformations • Increased risk of \_\_\_\_ • Increased risk of \_\_\_\_ disease
* Common facial features * Simian crease > the crease goes all the way across hand and \_\_\_\_ * fAD > one of those genes is encoded on chr \_\_\_\_
epicanthic flat cardiac leukemias alzheimer connect 21
Abnormal Sex Chromosome Number • 45 X to 49 XXXXY are \_\_\_\_ • 45 X – \_\_\_\_ • XXY, XXXY, XXXXY – \_\_\_\_ • XYY or XYYY - \_\_\_\_ • XXX, XXXX – \_\_\_\_ hypothesis, 1 active \_\_\_\_
• Monosomy X - turner's syndrome > sometimes need two copies of X • Men > the Y still makes them male, but having an extra X causes issues ○ Multiple Y's makes you \_\_\_\_ • Extra X's, totally fine > you \_\_\_\_ the extra ones
viable turner syndrome klinefelter syndrome normal lyon X
Klinefelter Syndrome • Male \_\_\_\_ • Increased \_\_\_\_ length • \_\_\_\_ atrophy • Gynecomastia • \_\_\_\_ • Mild mental impairment
* Two X and a Y * The person is \_\_\_\_, and feminine features develop (\_\_\_\_ formation)
hypogonadism body testicular sterility sterile breasts
Turner Syndrome • \_\_\_\_ neck • Low \_\_\_\_ hairline • Widespread \_\_\_\_ • Growth \_\_\_\_ • Failure to develop \_\_\_\_ sex characteristics • High arched \_\_\_\_ • \_\_\_\_ and kidney malformations
• Only one X with female ○ Need the second X during development • No \_\_\_\_
webbed posterior nipples retardation secondary palate aortic breasts
