final exam Flashcards
endosymbiont hypothesis + evidences in mitochondria & chloroplasts
suggests organelles were once free-living bacteria that were engulfed by ancestral cells
- overtime formed symbiotic relationship
- proposed by Lynn Margulis and was controversial at first
evidences, both mitochondria & chloroplasts:
- have their own chromosomes
- divide by fission (similar to bacteria)
- have circular chromosomes
- their genomes look more like bacteria than eukaryotes
- also encode tRNA and ribosomes that look much more like prokaryotes than eukaryotes
3 genes that are not part of the main genome
- mitochondria
- transposons
- retrotransposons
transposons & retrotransposons
transposons: “jumping genes,” DNA pieces that can move from one place to another within the main genome, “copy and paste genes”
- importance: can influence function of other genes, sometimes causing mutations or helping w/ evolution by adding new DNA
retrotransposons: type of transposon that move different, instead of jumping around, they copy themselves into RNA and use reverse transcription to insert the copy back into DNA at a new spot
- importance: make up significant part of genome and can create new genetic material, but can also disrupt important genes if they jump into the wrong spot
extranuclear inheritance
inheritance of genes that are not located in the nucleus
- primarily uniparental, almost exclusively maternal inheritance (mitochondrial inheritance)
mitochondrial-inherited diseases
diseases caused by mutations in mitochondrial DNA
- passed from mother to children since maternal mitochondria is passed
- is dose-dependent (depends on how many normal mitochondria are given): ex. 80% defective mitochondria = lethal, whereas <20% means healthy still
- UK approves 3 parent IVF to prevent mitochondrial disease (basically egg has 2 moms- nuclear and mitochondrial)
Barbara McClintock
discovered “jumping genes” (transposons) & won the Nobel peace prize
- worked with corn plants (maize) and studied the colors of kernels
- noticed unusual patterns in the kernel colors- like spots or streaks- and wanted to figure out why
experiment:
- saw that some kernels changed color over generations in ways that didnt follow menders laws
- found certain pieces of DNA could move to different locations in the genome
- ex. gene responsible for kernel color could be “turned off” when jumping gene landed in it, causing patches of different color
Barbara McClintock’s experiment + findings
- noticed a maize strain that frequently showed chromosome breakage at a specific location on chromosome 9
- this strain produced kernels with unusual spotting patterns = some were purple, while others were a mix of purple & yellow
- she identified 2 genetic factors associated with this phenomenon: Ds (dissociation) and Ac (Activator)
- when she mapped them, Ds always mapped to the break but Ac was in a different spot every time
- Ds gene WAS the fragile location (it was a nonautonomous transposon, while Ac encodes transposase that can move Ds around)
- proposed that Ac was located elsewhere in the genome and triggered breaks at the Ds site = purple mostly but has a little bit of yellow
- when Ac activated movement of Ds in and out of C gene, pigment production was restored= purple spots
C = purple pigment made
c = no pigment, yellow
F-Factor Mediated Gene Transfer + Hfr strains
process where genetic material is transferred from one bacterium to another through direct contact
- made possible by the F-factor (plasmid that can exist independently)
Hfr strains: have the F factor integrated into their main chromosome
- during conjugation, can transfer portions of their chromosomal DNA along with the F factor
how do transposons move around + transposase
they excise themselves from the genome, find a new location, and splice into it
transposase: enzyme encoded by some transposons (like Ac) that can cut and paste transposon into new locations
- DNA sequenced called inverted repeats (IR) is recognized by the transposase enzyme and thats where it cuts and pastes
integrase
enzyme that inserts viral DNA into host cell’s genome
- process is crucial for retroviruses like HIV to establish permanent infection
mechanism of retrotransposon integration is very similar to that of retroviruses
retrotransposons + example
like retroviruses, move by first being transcribed into RNA
- RNA is then reverse transcribed into DNA, which is integrated into new location in the genome = like sending copies of your genome everywhere, leaving copy behind wherever you go
example: classic white mutation found in TH Morgan’s flies is a result of retrotransposon insertion (retrotransposon went in and broke the red gene = white eyes)
2 main types of transposes in the human genome
LINEs (long interspersed sequences): can encode transposase and reverse transcriptase, type of retrotransposon, repeated many times in the human genome
SINEs (short interspersed sequences): non autonomous (cant move on their own), require LINE enzymes for movement
- Alu family
significance: create genetic diversity by moving around genome, serve as evolutionary markers to trace genes (transposition in germline), but ARE MUTAGENIC
genes that came from transposon insertion can be detected by a region of altered %GC content
somatic transposition
transposons insert themselves into non-reproductive cells (somatic cells) leading to mosaics, where different cells within the same organism can have different genetic makeups
- could be useful (neural progenitor cells have higher levels of LINE transposon activity) or VERY BAD (rett syndrome)
VDJ recombination
process that generates antibody diversity in the immune system
- involves rearranging gene segments (V, D, and J) in a way that is similar to how transposons move (inverted sequence repeats)
enzymes that do the genomic editing are RAG-1 and RAG-2 that look just like transposons
TBXT gene
TBXT in all primates has an Alu SINE (transposon) in intron 5 but in tail-less primates, they have a second Alu element in intron 6 (AluY) causing a hairpin structure to form = skipping exon 6 during splicing = heterozygote (short/no tail mice)
- homozygotes for this are just DEAD (highly variable phenotype)
introns vs exons
introns: non-coding regions of the DNA that are spliced out
exons: coding parts of the DNA that are in the mature mRNA
Complete dominance, Co-dominance, & Incomplete Dominance
genes can come in multiple alleles, not just a single dominant or recessive
Complete Dominance: occurs when phenotypes of heterozygote and dominant homozygote are identical (Mendel)
- ex. purple flower is dominant so all the kids have purple flowers
Co-dominance: both alleles are expressed equally in the heterozygote
- ex. AB blood group, where both groups are present
Incomplete dominance: heterozygotes display intermediate phenotype b/w the 2 homozygotes
- ex. cross b/w red (CrCr) & white (CwCw) flowers produces pink (CrCw) showing neither is completely dominant
hypomorph allele (reduction-of-function) vs null alleles
hypomorph allele: mutation with reduced activity (works but not as well as the normal version)
null alleles (Lf- loss of function): mutations that eliminate activity (insertions, deletions, or frameshift usually result in LF alleles)
haploinsufficiency + example
one one functional copy of the gene is not enough for normal function
- usually, if one copy of gene is mutated, the other can compensate and everything functions normally but in haploinsufficiency, one working copy isn’t enough
example: cri du chat syndrome (cry of the cat): results from deletion on chromosome 5
- babies have intellectual disabilities, smaller head, and a high-pitched cry due to problems with larynx
- kids usually die early
still have intact copies of the deleted gens on the normal chromosome 5, but the phenotype is NOT the wild type
example: polydactyly (6 fingers) - several transcription factor loss-of-function alleles
dominant-negative mutation + example
mutation in one copy of a gene produces a defective protein that actively interferes with the function of the normal protein from the other copy
example: p53 tumor suppressor gene is a tetramer (meaning it works as a complex of 4 protein subunits so even 1 single mutant protein causes the entire thing to not work)
different from haploinsuffiency which is when 1 chromosome isn’t enough
blood groups & phenotypes
both A and B are co-dominant and they are both dominant over O
to be A you need to be: IAIA or IAi
to be B you need to be: IBIB or IBi
IAIB: AB blood type
ii: O blood type (double recessive)
trillium clover
follows incomplete dominance pattern in flower color
plant produces gradient of phenotypes depending on the levels of enzyme produced by Cr gene
- single gene w 7 possible alleles results in 22 combinations with diff phenotypes!!
more Cr enzyme = more cyanidin = deeper red
Cw coded enzyme is non-functional so CrCw have half the Cr enzymes as homozygotes for Cr!!
F2 ratio in incomplete dominance patterns
1:2:1 instead of the classic 3:1 mendelian ratio (neither allele is dominant)
2 is the intermediate color (like pink b/w red and white)
pleiotropy + 4 examples
pleiotropy: one gene can have multiple phenotypic effects (basically one gene gets deleted and theres a lot of symptoms of the disease)
examples:
- phenylketonuria (PKU): autosomonal recessive disease that leads to brain damage AND light skin, lack of phenylalanine hydroxylate → buildup of phenylalanine → damages neurons
- also less try available → less melanin made → light skin
- marfan’s syndrome: dominant deletion allele, result: tall stature, curved spine, elongated fingers, heart valve problems
- sickle cell anemia: heterozygotes for E6V mutation have normal looking cells and are not anemic but are resistant to malaria (two traits - anemia AND resistance to malaria but same gene)
- lamin A gene: single mis-spliced gene results in at least 4 distinct diseases, depending on the mutation
Complementation test
used to determine whether 2 mutations that produce the same phenotype are in the same gene or in different genes
“are the different dumpy strains mutated in the same gene or different genes?”
- if 2 mutations are in different genes = the 2 non-mutated copies (one from each parent) can “complement” each other to restore the normal phenotype
- if on same gene → no normal copy to compensate → mutant phenotype remains
corn snake skin example + what it demonstrates
corn snake skin color is determined by 2 genes:
R locus: orange pigment enzyme (R allele makes enzymes)
B locus: black pigment enzyme (B allele makes enzymes)
“In some cases, multiple genes act independently, and the observed phenotype is the sum of the products, similar to incomplete dominance at a single locus
both R & B = orange + black = red
both r and b = no orange and no black = albino
same with black and orange
additive effects of multiple genes
in some cases, multiple genes contribute to a single trait, acting independently and additively
- phenotype depends on sum of effects of individual genes, similar to incomplete dominance
- ex. corn snake skin color
different from epistasis which is when one worker paints over the work of another worker while additive effect is they both work together to contribute to wall without interference
epistasis + example
one gene masks or modifies the effects of another gene on particular phenotype
- often because genes are in the same pathway
example: coat color in Labrador retrievers
- B locus (determines pigment black or brown) = make black pigment from brown pigment
- E locus (determines pigment deposition, color visible or yellow coat) = make brown pigment from yellow pigment
- when epistasis occurs, observed phenotypic ratios in offspring will deviate from expected mendelian ratios (F2 = 9:4:3)
when is 9:3:3:1 classical mendelian ratio expected in additive relationships
IF the genes R and B in corn snake skin act independently and additively
- but this assumes no interaction between the genes
- but in additive inheritance, there is still some interaction because the effects are cumulative so the relationship is more complex (ex. 1:4:6:4:1)
continuous traits
additive effects of multiple genes can also be used to model continuous traits
- in these cases, phenotype is determined by the combined effects of many genes, each with a small effect
example: trait controlled by 3 genes, each w 2 alleles (one for brown and one for white). individuals with more brown have darker phenotype and more white have lighter phenotype
- result of continuous distribution of phenotypes from very dark to very light
MCR1R and TYRP1 (epistasis)
TYRP1 (B Locus): encodes enzyme involved in production of brown pigment
- B allele codes functional enzyme (black pigment), while b allele is non-functional (brown pigment)
MCR1R (E Locus): encodes receptor protein that plays crucial role in determining whether any pigment (black or brown) is produced at all
- E allele codes functional receptor (allowing pigment production), while e allele codes non-functional receptor (blocks pigment synthesis regardless of genotype at B locus)
therefore, e allele of MCR1R is epistatic to alleles at TYRP1 (B) locus
so 2 copies of e allele (ee genotype) = no pigment so yellow color irrespective of whether B or b
(labrador retrievers)
supressor mutations
mutation in another gene that reduces the effect of the first mutation
- often encode proteins that interact with the protein encoded by the first gene
- ex. gene m mutation so proper complex cannot be formed but mutation in s compensates, permitting complex formation
- but mutation in s without mutation in m cannot form active complex
suppressors in same pathway: reduce effect of original mutation by acting in the same pathway
- ex. gain of function mutation in suppressor gene can compensate for loss-of-function mutation in original gene, restoring normal phenotype
suppressors in parallel pathways: can also occur in genes that function in parallel pathways
- ex. mutation in gene A leads to mutant phenotype, suppressor mutation in gene B in parallel pathway can compensate and restore normal phenotype
opposite manner of synthetic mutations
3 applications of suppressor mutations
identifying genes in pathways: mutagenize organisms w/ mutations of interest and screen for suppressor mutations that restore the wild-type phenotype → identify genes w/ suppressor mutations that reveal other genes involved in the same pathway
drug target identification: suppressor screens are powerful ways to identify drug targets for genetic disease
- inhibit drug in parallel pathway → possible to suppress effects of a disease-causing mutation
understanding human disease: individuals found that have strong mendelian genetic disease but they’re very healthy due to unknown suppressor alleles
- investigation into these suppressor alleles could lead to novel therapeutic strategies for treating these diseases
synthetic mutants
2 mutations, which individually cause no or minor defects, together produce a severe phenotype
- mutant phenotype observed only when both genes are mutated
- act in manner opposite to the suppressor mutations
synthetic alleles and suppressor alleles working together in researched
Drosophila suppressor and synthetic alleles were used to map signaling pathways used by growth factors and the Ras oncogene (mutated causes cancer) to regulate cell division
C. elegans - both were used to study apoptosis
these pathways are conserved in humans so understanding them provides insight into diseases like cancer
phenotypic variability
even with identical genomes, individuals can exhibit range of phenotypes due to factors like penetrance, expressivity, conditional alleles, and genetic buffering
quantitative traits
these traits are determined by the combined effects of multiple genes, each with a small effect
what reasons can phenotypic variability come from?
sex differences: same genotypes for most genes, but different phenotypes
- ex. voice pitch, behaviors, and other secondary sexual characteristics are heavily sex-influenced
- variable penetrance
- variable expressivity
- environmental effects
- conditional alleles
- developmental noise
- somatic events: things like X activation
- transcription/translation variability: randomness in gene expression
- gene expression differences in heterozygotes: cells might express more of one allele than the other
3 examples of variable penetrance
osteogenesis imperfecta: autosomal dominant disorder, is 100% penetrant (everyone with the mutation exhibits some phenotype), but the severity of the phenotype can vary greatly.
- ranges from blue eyes to severe skeletal abnormalities or anything in between
BRCA 1 - heterozygote mutant women have 50% higher risk of breast cancer
neurodibromatosis: autosomal dominant disorder, exhibits incomplete penetrance (50-80%), meaning not everyone with the mutation develops symptoms
- but even among those who have it variable expressivity - ranges from skin splotches to massive tumors
variable expressivity vs variable penetrance
variable penetrance: not everyone with a particular genotype shows the associated phenotype (some individuals have the trait, others do not)
- ex. BRCA 1- heterozygote women have 50% higher risk of breast cancer, osteogenesis imperfecta, neurofibromatosis
variable expressivity: the extent to which a phenotype is expressed varies among people (all individuals have trait, but different amounts of it)
- ex. deleting exon 6 from mice TBXT results in heterozygote short/no tail mice (all have short tails but some have shorter tails than others)
environmental effect in phenotypic variability
genetical identical individuals in different environments have different phenotypes
- ex. risk of breast cancer alters by lifestyle
- himalayan rabbits have temp sensitive alleles of melanin producing enzyme (if temp less than 25ºC, extremities turn black while rest of rabbit is white)
conditional alleles in phenotypic variability
conditional alleles: alleles whose phenotype depends on environment
- auxotroph mutations are conditional alleles: genetic mutation that causes an organism to lose ability to produce vital nutrient for growth (in bacteria prevent growth in minimal media unless required nutrient is supplied)
ex. phenylketonuria (PKU): leads to brain damage but can be avoided is homozygous recessive individuals avoid eating phenylalanine
ex. (ts) alleles in Drosopholia- ts means temp sensitive, neurotransmission at high temperatures but no effect at lower temps - temp sensitivity makes them useful tools for studying the nervous system
development noise in phenotypic variability + paddington’s landscape
developmental noise: random fluctuations during development can affect phenotype
examples: inverted sides of face, identical twins with different fingerprints
waddington’s landscape: metaphor for development and phenotypic variability
- ball starts same but hills and valleys so rolling down ends up at different endpoint
- THE HILLS AND VALLEYS: explains things like mosaics (like McClintock’s maize), transcriptional/translational variability
X-inactivation in phenotypic variability
X-inactivation: process in female mammals where 1 of 2 X chromosome in each cell is randomly inactivated during embryonic development
- ensures that only 1 X chromosome is active per cell, preventing overdose of X-linked gene products
creates Barr bodies (the inactivated X copy)
example is calico coat color in cats, O allele is the inactivated one, so either orange or black fur expressed
genetic buffering & heat shock protein 90 (hsp90)
genetic buffering: ability of some genes to buffer (“mask”) the effects of mutations in other genes → reduces phenotypic variability
hsp90: highly conserved molecular chaperone that helps proteins fold correctly, stabilizes them, and assists in their proper functioning; some mutations lead to them misfiling and HSP90 rescues them, ensuring they still function properly
- under stressful conditions (like heat shock) → hsp90 ability reduced → previously masked genetic mutations are exposed → phenotypic changes
ex. FANFA (fanconi anemia - autosomal recessive anemia) protein interacts with hsp90 increasing severity of mild FANCA mutations
feedback & GFP expression in phenotypic variability
GFP: green fluorescent protein - used as marker to measure gene expression levels
- cells with more GFP glow brighter
TetR repressor: TetR is a protein that can bind to DNA and inhibit transcription of specific genes
- negative feedback loop: when TetR levels are high, suppresses its production and when TetR levels are low → resumes production
feedback reduces phenotypic variability because without feedback, the TetR gene (and GFP indirectly) is expressed freely and levels fluctuate randomly (“noise”)
- but when feedback is there, TetR levels are regulated, stabilizing GFP levels
qualitative vs quantitative traits
qualitative: either-or (binary traits) like yellow or green
quantitative: composed of multiple underlying distributions
- ex. height, “intelligence,” heart disease, hair loss, diabetes, personality traits
GWAS (genome-wide association study) + SNPs
GWAS: used to identify genes or genetic variants associated with specific traits or diseases
- involves genotyping thousands of people & comparing their genotype at different locations in the genome
- useful for genes that are variable and have small effects
SNPs (single nucleotide polymorphisms): common genetic variations that can be used as markers (should use markers that don’t have any effect on the gene itself and are put in b/w gene regions that do not bind transcription factors)
- microarrays & PCR are techniques used to genotype SNPs
- SNPs are crucial for GWAS = ex. if specific SNP is common in diabetes patients than those without, it might point to a gene related to diabetes risk
positional cloning
method for finding genes associated with a particular trait when the gene’s function is unknown
- relies on principle that genes located near each other on chromosome tend to be inherited together
- identify DNA markers that are known (polymorphic sites) - like SNPs or Microsatellites
- narrow down region to pinpoint approximate location of gene on chromosome by finding markers closely linked to the gene
- fine tune using markers near that gene
- candidate gene analysis
has to do with GWAS I think
