Learning Objectives (not comprehensive) Flashcards by Megan Kalata

autosomal dominant pedigree

i. One copy of disease allele needed to express phenotype
ii. 50% chance offspring will inherit disease allele
iii. all affected individuals have at least one parent who carries disease allele
iv. males and females equally affected
v. male-to-male transmission observed
vi. ie: muscular dystrophy, Huntington’s

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autosomal recessive

i. Two copies of disease allele needed to express phenotype
ii. 25% change offspring inherits disease allele (has phenotype); 50% chance offspring inherits one copy of disease allele (carrier); 25% chance offspring inherits no copies of disease allele (not carrier)
iii. Parents of affected individual are not typically affected but are gene carriers
iv. Males and females equally affected
v. Often seen in consanguineous couples (related by blood)
Ie: sickle cell anemia, CF

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x-linked dominant

i. One copy of disease allele on x-chromosome required for individual to be susceptible
ii. 50% chance for offspring to inherit disease allele from affected female
iii. affected male: all daughters will be affected but none of his sons
iv. Males and females affected (may be more severe or lethal in males)
Ie: Fragile X syndrome

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x-linked recessive

i. Two copies of diseased allele on X chromosome are required for female to be affected; one copy for male
ii. Females are usually carriers because they have one copy of diseased allele
iii. Carrier female: 50% chance that sons will inherit disease from mom and 50% chance that daughters will be carriers
iv. Affected female: all sons will be affected, all daughters will be unaffected carriers
v. Affected men transmit disease to all daughters (who are then carriers) but none to sons
Ie: Duchenne muscular dystrophy, hemophilia A

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What is mendel’s first law?

segregation; alleles segregate at meiosis into gametes

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What is mendel’s second law?

law of independent assortment; segregation of each pair of alleles is independent (except linked genes)

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How is penetrance like a light switch?

on/off (affected/unaffected)
i. Could have mutation but not be affected (no visible phenotype)
ii. 80% penetrance: 80% of individuals with mutation are affected
Fraction of individuals with trait (disease) genotype who show manifestations of disease

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What is age-dependent penetrance?

likelihood of manifesting disease in mutation carriers depends on age

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How is expressivity like a light switch?

light is on but you’re trying to figure out how severe (dimmer function)
i. Affected individual (gene mutation led to disease) looking at severity
Degree to which trait is expressed in an individual (severity)

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What is the influence of sex on Mendelian inheritance patterns?

manifestation of a trait depends on individual’s sex

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What is the influence of stochastic effects on Mendelian inheritance patterns?

random effects can influence expression of phenotypes

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What are modifier genes?

genetic factors that influence phenotype

Ie: one gene affects eye color but another also influences it by changing amount or distribution of pigment in iris

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What are phenocopies?

same phenotype (as a genetic condition) due to non-genetic factors
Ie: some animals change fur color (phenotype) depending on temperature where they live

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What is pleiotropy?

Some mutation leads to multiple and different phenotypes (different organ systems); genes that have multiple effects within the body

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How frequent are SNPs?

1 per 1,000 base pairs between any human genomes

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What are insertion-deletion polymorphisms?

lots of variation in genome comes from variation in these large blocks of small repeating segments instead of variation between important genes

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Mini-satellites are tandem repeats of ________ base pairs of DNA

10-100

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How many base pairs does the haploid human genome have?

3x10^9

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Evolution and adaptation are fueled by __________

random genomic variation

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How do individuals get new mutations?

shuffling of regions during meiosis (recombination)

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VNTR (variable number of tandem repeats) are found in _________

minisatellites

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Microsatellites contain ________ repeats

2-,3-,4-bp

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STRP (short tandem repeat polymorphisms) are found in ____________

microsatellites

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What is the primary type of structural variation in the human genome?

copy number variation

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Genomic DNA copy numbers are measured using _____________

array comparative genomic hybridization (array CGH)

What protein coding sequence exhibits the greatest human specific copy number expansion?

DUF1220

Gene-rich genome

Chr19 | how many genes (expressed segments) each contains

Gene-poor genome

Chr13,18,21

____% of the genome is G-C rich

38%

____% of the genome is A-T rich

54%

Euchromatic has (more/less) repeats and makes up (more/less) of genome

less, more

Categories and frequencies of genomic DNA sequences

a. 1.5% translated (protein coding) b. 20-25% represented by genes (exons, introns, flanking sequences involved in regulating gene expression) c. 50% “single copy” sequences d. 40-50% classes of “repetitive DNA”

Tandem repeats are the basics for ________ techniques

cytogenetic banding

Tandem repeats are often found on _________ (hotspots for evolutionary change)

Chr1,9,16,Y

"Alpha satellite" repeats are found near the _________ region of all human chromosomes

centromeric

"Alpha satellite" repeats may play a role in _________ during mitosis and meiosis

chromosome segregation

What do retrotransposon elements in DNA do?

copy their own sequences into other locations in DNA (can cause inactivation of genes)

Two examples of dispersed repetitive elements are ...

- Short interspersed repetitive elements (SINES) | - Long interspersed repetitive elements (LINES)

Short interspersed repetitive elements (SINES) are part of the ______ family

alu

Long interspersed repetitive elements (LINES) are part of the _________ family

Alu's and L1's can lead to non-allelic homologous recombination (NAHR), which is ___________

aberrant recombination events between different copies of dispersed repeats leading to diseases

How many human genes are there?

25,000-30,000

The three types of human genes are...

- protein-encoding - RNA-encoding - pseudogenes

Gene families arise through __________

gene duplication

Meiotic recombination involves ________ crossing-over between _________

homologous; non-sister chromatids

What is the most common contiguous gene syndrome in humans?

del 22q11 (overexpression of multiple loci next to each other)

Methylation binding proteins attract ________ to _______ transcription and compact ________

HDACs, silence, chromatin

DNA methylation marks are established in the _______

gamete

DNA methylation is stably maintained in ______ cells after fertilization

somatic

Methylation in somatic cells is maintained by ____________

methyltransferase

Prader-Willi and Angelman Syndromes involve deletions in long arm regions of chromosome _____

Prader-Willi causes (%s)

- 70% deletion of paternal chromosome - 28% maternal uniparental disomy - 2% mutation on imprinting center

Angelman Syndrome causes (%s)

- 70% deletion of maternal chromosome - 4% paternal uniparental disomy - 18% (ish) imprinting center mutation on maternal allele - 8% mutated gene

FISH Probe: Centromere (name, use, example)

Name: cen Use: enumeration of chromosomes Example: ALL panel, prenatal dx

FISH Probe: Locus specific identifier (name, use, example)

Name: LSI Use: deletion/duplication of gene (loci) Example: p53, cancer

FISH Probe: Fusion (name, use, example)

Name: F, DF Use: detecting translocation Example: BCR;ABL, PMR;RARa

FISH Probe: Break apart (name, use, example)

Name: BAP Use: detecting translocation and rearrangement Example: MLL (cancer)

FISH Probe: Whole chromosome point (name, use, example)

Name: WCP Use: identifying translocations or markers Example: WCP 1-22, X, Y

The target DNA in chromosomal microarray is ...

a single-stranded oligomer

CMA can only detect ________ and _________

gains, losses

CMA cannot detect _________________

balanced rearrangements (limited mosaicism)

The CYP450 enzyme is active in the _______ and ___________

liver, intestinal epithelium

Cyclosporine is a(n) ________ of _______ gene.

immunosuppressant, CYP3A

Grapefruit juice and ketoconazole are _________ of CYP3A gene

inhibitors

Rifampicin is a(n) ________ of CYP3A gene

inducer

tricyclic antidepressants and opioids such as codeine act on _______ gene

CYP2D6

Warfarin acts on _______ gene

CYP2C9

Proton pump inhibitors and fluoxetine act on ________

CYP2C19

__________ drugs act on NAT gene

isoniazids for TB

TMPT gene experiences _______ mutations that destabilize the genome

missense

If you give kids with ALL a standard dose of ________, it will kill them.

6-mercaptopurine (for TMPT gene)

Butyrylcholinesterase hydrolyzes _________, which acts on BCHE gene

succinylcholine

G6PD is a ________ enzyme

x-linked

people are susceptible to hemolytic anemia after exposure to _________ drug

sulfonamide, dapsone

Rare mutations in RYR1 lead to _________

malignant hyperthermia

Warfarin acts on the _______ gene by reducing vitamin K so it can be recycled and used to make more coagulation factors

VKORC1

Hardy Weinberg assumptions

- large population, random mating - constant allele frequencies - no mutation rate - all genotypes equally fit - no significant immigration/emigration

Turner and Klinefelter's syndromes are normally driven by ____________

meiotic nondisjunction

Centromeres (are/are not) repeat rich

are

The classes of DNA include __________ and _________________

tandem repeats, dispersed repetitive elements

Types of DNA variation (3)

- insertion/deletion polymorphisms - SNPs - copy number variation

Increases in DUF1220 copy number led to an increase in _________ instability

1q21.1

1q21.1 duplications lead to ________ and _________

macrocephaly, autism

1q21.1 duplications lead to _______ and __________

microcephaly, schizophrenia

Aneuploidy can occur...(3)

- meiosis I - meiosis II - post-zygotically

What percent of Turner's Syndrome karyotypes are pure 45X?

50%

75% of Klinefelter Syndrome comes from errors in _____________

maternal meiosis I

Mosaicism is most commonly caused by ___________

nondisjunction

In chromosomes, which are more common: structural rearrangements or numerical aberrations?

numerical aberrations

75% of Robertsonian translocations involve chromosomes ____ and ____

13, 14

Inversions with chromosomes 1,9,16, and Y are almost always ______ in nature

familial

Pericentric inversions give rise to ___________

two complementary recombinants

Imprinted genes make up less than ___% of the human genome

10%

During crossing over, deletions are caused by __________________

low copy repeat misalignment

Cytogenetics are important in diagnosing ________ while CMA are important in diagnosing __________

leukemia, lymphoma; children with delays

APML is caused by gene fusion of ___________ and CML is caused by gene fusion of ____________

PML-RARalpha (t(15;17)) | BCR-ABL (t(9;22))

CML is treated with ___________

Gleevec

Gleevec (CML treatment) binds at the ____ binding site in the BCR/ABL ___________ and the effect is __________

ATP, tyrosine kinase, inhibited cell proliferation

DS infant and children have a _______ increased risk for developing AML or ALL and a _______ increased risk for developing AMKL

20-100 fold | 500x

Cytogenetics detects ____________ while CMA detects _____________

balanced rearrangements, runs of homozygosity

CMA determines the _________ and _________ of deletions/duplications

size, location

T/F You can see mutations in FISH

false (identifies number of a specific chromosome or translocation)

What is inverted duplicated isodicentric 15Q (IDIC15)?

autism, not dysmorphic, often hypotonic seizures

What are 15Q interstitial duplications?

- maternally inherited - within one arm of chromosome - autism, not dysmorphic, hypotonic seizures

Pharmacogenetics looks at variable responses due to ____________

individual genes

Pharmacogenomics looks at variable responses due to ____________

multiple loci across the genome

Pharmacokinetics describes the ___________ of drugs

absorption, distribution, metabolism, and excretion

Pharmacodynamics describes the relationship between ___________

concentration of a drug (at active site) and biological effects

Expected DNA mutations for poor metabolizers (4)

- frameshift - missense - nonsense - splicing

Expected DNA mutations for ultrafast metabolizers (2)

- increased copy number | - missense

Mendelian disease looks at the _____ of genetic effect and population genetics looks at the _________ of disease

size, frequency

What can NextGen DNA sequencing determine?

if estimates of mutation rates from Hardy-Weinberg are correct

Genes present for development of testes

SRY, SOX9, SF1, DAX1

SF1/NR5A1 cause the genital ridge to differentiate into ___________ and __________

- sertoli cells (AMH, spertm) | - Leydig cells

Production of anti-mullerian hormone (AMH) is stimulated by...(2)

SRY, SOX9

________ is important for differentiation of the testes

FGF9

WNT4 protein is important in females for __________

differentiation of ovary

WNT4 is inhibited by _______

SOX9

CYP2D6 inhibitors (3)

- quinidine - fluoxetine - paroxetine

How are imprinting patterns maintained in offspring?

maintain methylation

_______% of babies with DS have congenital heart defects

30-50

Copy number variations are often enriched with __________ and __________

- specific duplications | - sequence gaps

First degree relatives include __________

parents, siblings, children

Patau syndrome is trisomy ____

Edwards syndrome is trisomy ____

In adjacent 1 segregation, homologous centromeres go to _________ daughter cells

different

In adjacent 2 segregation, homologous centromeres go to _________ daughter cells

the same

Individuals with androgen insensitivity have _____________

extra female genitalia with male gonads

The incidence of inversion is as high as ___%

Leydig cells produce _________ and Sertoli cells produce ________

testosterone, anti-Mullerian hormone

Androgen insensitivity syndrome is caused by a _______________ gene

x-linked

What is 5-alpha reductase deficiency?

inability to convert testosterone to dihydrotestosterone

5-alpha reductase deficiency is caused by a ________________ gene

autosomal recessive

allelic heterogeneity

existence of multiple alleles of a single gene causing a similar phenotype

compound heterozygote

person who carries different mutant alleles at the same gene locus

Alpha1-antitrypsin deficiency (ATD) is (early/late) onset

late

Tay-Sachs has a defect in the ability to get rid of ___________, which makes up 5% of brain mass

ganglioside

Qualitative hemoglobinopathies (3)

HbS, HbC, HbE

Quantitative hemoglobinopathies (4)

alpha, beta, gamma, delta thalassemias

Patients with Denys-Drash and Frasier Syndromes are genetically ______ but exhibit sex reversal because of a mutation in the _____ gene

male, WT1

WT1 is a ____________ for the SRY gene

transcription factor

Salt wasting in the first few weeks of life and metabolic stress are symptoms of ____________

congenital adrenal hyperplasia

What is a genetic linkage study?

search genome for segments disproportionately co-inherited along with diseases in multiplex families

What is log of odds?

a statistical measure of the likelihood that loci are linked together given the inheritance/disease pattern

Gene linkage studies are most powerful for...

uncommon risk alleles with strong effects

most commonly used DNA polymorphisms for finding genes (3)

- microsatellites - SNPs - CNVs

Candidate gene association studies are best for...

common risk alleles with small to moderate effects

In sickle cell (HbS), the amino acid change is _______ to _________

glu(-) to val(neutral)

In HbC, the amino acid change is ________ to ____________

glu(-) to lys(+)

Alpha-thalassemias are usually caused by ________ and beta-thalassemias are usually caused by __________

deletions, point mutations

4 main characteristics of epigenetic phenomena

- different gene expression pattern/phenotype, identical genome - inheritable through cell division - on/off switch - erase-able (therapeutic potential)

In a person with PWS, treatment with GH should be started....

at onset of excessive eating symptoms

Paternal errors in meiosis I result in ...

XXY (Klinefelter's)

What is the recurrence risk for Trisomy 21?

1/100 + maternal age risk

Learning Objectives (not comprehensive) Flashcards

(154 cards)