Genetics Flashcards by Raeann Whitney

What is apparently the main factor influencing de novo mutations?

Father’s age

Positive correlation

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What is the difference between SNV and SNP?

Single nucleotide:
Variant - any frequency
Polymorphism - commonly different (>1-5%)

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What is the difference between functional and non-functional SNVs?

Functional: aa change

non-synonymous (missense)
stop gain (nonsense)
stop loss
splice site

Nonfunctional: no aa change

synonymous (silent)
intronic
intergenic

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What are short tandem repeats/ microsatellites?

Repeat of 2,3, 4 or more NTs 10-100x
Highly polymorphic (used in forensics, linkage studies)
Generated though error during replication (slippage of DNA pol - DNA melts and reanneals incorrectly)

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What are retrotransposons?

RNA intermediate required to copy, then jump around
Repetitive sequences in genome
LINE-long interspersed repetitive elements (makes copies)
SINE-short interspersed repetitive elements (Alu sequence around 300 bp)
LTR-long terminal repeats
Total ~40% of genome

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What are copy number variants (CNVs)

Deletions/duplications

longer (can be millions of bases long)
usually fine until 2 million bp range, then start to see phenotypic problems

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What effects do inversions and translocations have?

Impact depends on break point

Inversions can sometimes be harmless, but can cause problems other times

Reciprocal translocations (switching) less likely to cause problems, but reproduction can be a problem

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Describe the map-based (indirect) strategy to finding genetic variants that influence disease?

Used to narrow down portion of genome responsible for trait
Use a set of markers (variants) spread throughout genome
Markers themselves not expected to influence trait

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Describe the direct strategy to finding genetic variants that influence disease?

Test potential causal variants

previously in canditate genes with biological plausibility (often flawed)
now by complete genome or exome sequencing (difficulties in correct interpretation)

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What are examples of indirect causal variant identification strategies?

Linkage studies (rare variant) 
Canditate genes (frequent variant)

Both used with there is a large effect on phenotype

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For what kind of diseases would you map using linkage?

Mendelian

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How would you map using linkage?

Genotype 300-400 microsatellite markers for affects and unaffected family members
Identify makers that cosegregate with the disease
Get down to ~10mB region
(now cheaper to use SNPs instead of microsatellites)

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What can you NOT find with linkage?

Dominant variants compromising reproduction
Atypical presentations

(use exome or genome sequencing)

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Describe mapping using common variants through Genome-Wide Association Studies (GWAS).

Designed to interrogate all common genetic variation (tagging SNPs)
Large sample sizes (1000-100K or more)
Unrelated individuals
Genotype cases and controls (or continuous trait)
Strict statistical procedures

Have largely not found variants of medical importance

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What is a main difference between map-based and direct methods?

Map-based focus on variants that can identify the genomic region of interest and do not usually affect the trait themselves.

linkage
GWAS

Direct focus on causal variants themselves

candidate gene studies
whole-gemone or exome sequencing

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What is G banding?

Pattern obtained using protease pretreatment of chromosomes followed by staining with Giemsa
Dark bands AT rich, heterochromatin, late replication
Light bands GC rich, euchromatin, early replication
Resolve 3-10 Mb

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Short arm

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Long arm

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Centromere at the end. Only genes in p arm are for rRNA (non-coding)

Acrocentric

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Centromere in center

Metacentric

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Centromere off-center

Sub-metacentric

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What determines how many bands you will see?

How compressed DNA at the time
Resolution
-Landmarks can show up at different resolutions
-Can appreciate smaller abnormalities with higher resolution

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________ is the organized image of an individual’s chromosomes. ________ is how you would describe it.

Karyogram

Karyotype

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Loss/gain of entire chromosome set

Euploidy

Haploid, diploid, triploid, tetraploid

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Loss/gain of entire less than an entire chromosome set

Aneuploidy Monosomy, Trisomy

Presence of more than one cell line

Mosaicism Often function of trisomy rescue (some cells have 3, some have normal 2)

Triploidy often results in:

Spontaneous abortions

Possible origins of triploidy

Egg has 46 - didn't release polar body Sperm has 46 Two sperm fertilize one egg (most common)

Protein structure that forms mediating chromosome pairing

synaptonemal complex

Physical points along chromosome where crossing over has occurred

chiasma | at least one per chromosome arm is required for normal segregation

Where is recombination more likely to occur?

Increased near telomeres, decreased near centromeres | More in females

Two causes of aneuploidy in meiosis and mitosis

Nondisjunction | Anaphase lag

Failure of chromatids (mitosis or meiosis II) or chromosomes (meiosis I) to separate at anaphase

Nondisjunction

Failure of a chromatid of chromosome to attach to the spindle and segregate into a daughter cell

Anaphase lag

Contributing factor in all human trisomies

Abnormal recombination

Tips of the X and Y chromosomes - identical regions | Only place where X and Y can pair to each other for recombination

Pseudoautosomal regions

How is incidence of aneuploidy related with maternal age?

Advanced maternal age (33-34) is correlated with increased risk of abnormal oocytes and Down syndrome -associated with most human trisomies

What is the two hit theory for why aneuploidy increases with maternal age?

1. Some eggs are produced with missing or mislocated chiasma (this happens during prenatal development) 2. As women age, meiotic proteins lose the ability to resolve these mishaps

Small, cell free fetal DNA sample from maternal blood compared to control chromosome Very sensitive Postive predictive value depends on a priori risk Positive results should be followed by diagnostic testing

NIPS | Non Invasive Prenatal Screening

Labeling of probe DNA with fluorescent dye, denature and hybridize Can show copy number, position Dual color dual fusion design for malignant translocation s

FISH | Fluorescence in situ hybridization

High resolution tool for copy number analysis Pieces of DNA hybridized to chip Quantitative - Is the amount of DNA more or less than expected? (compare pt to reference)

Microarray | Yellow if hybridized equally red or green if unequal

What are some limitations of microarray CGH (Comparative Genomic Hybridization)?

Doesn't tell you policy, location of rearranged sequences responsible for copy number change Can be of unknown clinical significance Mosaicism can be difficult to ditch if

phenotype is result of inappropriate dosage for a critical gene with a genomic segment - interstitial (low copy number repeats, more consistent breakpoints) - terminal (may not have breakpoints)

segmental aneusomy syndromes

Balanced rearrangement of chromosomes de novo carry a 5-10% chance of abnormal phenotype Carrier risk of unbalanced offspring related to size of segments

Reciprocal translocation

Fusion of the long arms of two acrocentric chromosomes Lose two p arms Increased risk of +13, +21 conceptions

Robertsonian translocation

Individual with only one representative of a chromosome or chromosome segment

Hemizygous

Single gene disorder | Simple

Mendelian

Mechanism is through haploinsufficiency or a gain of function

Autosomal dominant

Mechanism is typically loss of function (but could also be gain of function) Haplosufficient

Autosomal recessive

Pedigree includes mating between individuals with common ancestors

Consanguinity

Males express phenotype because they are hemizygous

X-linked

Both alleles at a given locus, when in heterozygous state, are expressed

Co-dominance

Expression/severity of mitochondrial disease may be extremely variable because of ______________, which is the concept that not every mitochondrial genome is the same with a cell.

Heteroplasmy

Proposed mechanism of expansion of triplet repeats

Replicative slipping

Multiple genes + environment

Complex disease

Proportion of population with a particular genotype that express a phenotype

Penetrance

What classification of disease has low frequency, high penetrance, and causative alleles?

Mendelian

What classification of disease has high frequency, low penetrance, and susceptibility alleles?

Complex

Two disease patients with indistinguishable disease phenotype, even within a single pedigree, but the underlying cause of disease is different

Phenocopies

Susceptibility genes: Ch 1 complement factor H, ch. 10 ser peptidase HTRA1 Risk increased with smoking Vision loss

Macular degeneration

Sequencing only the coding regions of genes

Exome sequencing

Very distinct phenotype Autosomal recessive Extremely rare Was able to determine cause through exome sequencing

Miller syndrome | more realistic, but complicated for Dominant Muscular Dystrophy