mutations -genomics (unit 4) Flashcards
1
Q
mutation
A
statistically random events that change the base composition of a genome (code)
2
Q
deletion mutation
A
one or more nucleotides are removed
-large deletions usually form null alleles
3
Q
missense mutation
A
a nucleotide change that results in a codon change
4
Q
nonsense mutation
A
nucleotide change that results in a stop codon
5
Q
frameshift mutation
A
an insertion/ deletion that changes the open reading frame
6
Q
genotype affecting mutations (terms= 4)
A
deletion M, missense, M, nonsense M, frameshift M
7
Q
phenotype affecting mutations (terms= 4)
A
hypomorphic M, null alleles, gain of function M, dominant negative M
8
Q
hypomorphic mutation
A
gene product has less function than normal
-usually recessive alleles
9
Q
null alleles
A
(loss of function) caused by mutations including deletions and early stop codons- usually recessive alleles
10
Q
gain of function mutation
A
gene product has new and abnormal function- often hyperactive or overexpressed
11
Q
dominant negative mutation
A
gene product interferes with function of normal protein
12
Q
marfan syndrome
A
caused by dominant negative mutation
- tall individuals with long digits and often heart and bone disorders
- usually heterozygous (the defective fibrillin protein antagonizes the normal fibrillin
13
Q
temperature sensitive mutations
A
some enzymes for pathways are blocked at certain temperatures- result in completely functional proteins at the permissive temperature and non-functional proteins at wrong temps
14
Q
mosaicism
A
results when a patch of cells differ genetically from other body cells (somatic cell mutation)
15
Q
generation of mutations
A
transposons, chemical mutagens, radiation, and errors in replication
16
Q
transposons
A
lots in human genome- most are inactive
1/600 mutations in human genome= caused by transposon
17
Q
chemical mutagens
A
mechanisms: chemically altering base pairs or looking enough like base pairs to be incorporated into DNA
18
Q
nitrous acid
A
chemically alters base pairs causing them to pair with the ring base during DNA replication (HNO2)
19
Q
5-bromouracil (5BU)
A
can be incorporated into DNA instead of thymine… especially bad because 5BU can pair with A or G
20
Q
radiation
A
UV mutagenesis= UV irradiation causes cross links to form between thymines (thymine dimers)
21
Q
thymine dimers
A
inhibit transcription and can cause problems in DNA replication
-can be repaired by too many increase the risk of skin cancer
22
Q
ionizing radiation
A
when IR interacts with H2O, highly reactive ions (free radicals) form and these can directly, chemically damage DNA
23
Q
common DNA repair mechanisms
A
mismatch repair
base-excision repair
nucleotide excision repair
double strand break repair
24
Q
mismatch repair
A
repairs replication errors (A-c, or G-T pairs)
1) MutS protein recognizes the mismatch and recruits MutL which stimulates Much protein which cuts the 5’ end of GATC
2) exonuclease degrades the daughter strand to just beyond the site of mismatch and DNA polymerase corrects match and DNA ligase seals cut w/ DNA
3) DAM methylase methylates A in GATC in daughter strand
* mismatch repair pathway removes the newer, unmethylated strand
25
base excision
abnormal/ missing bases are detected and repaired (also removes any U incorporated in DNA)
26
abasic sites
sites in which the base has been lost by hydrolysis
- base loss can occur spontaneously or can be result of removal of damaged bases buy enzyme uracil glycosylase
* AP endonuclease repairs nucleotide sites at abasic sites
27
nucleotide excision repair
works on variety of bulky DNA adducts
- UV damage can induce the formation of covalent bonds between adjacent pyrimidines (like thymine)
- in humans, pyrimidine dimers are recognized as bulky DNA lesions and removed by nucleotide excision repair
28
Xeroderma pigmentosum (XP)
autosomal recessive genetic disorder
- deficient ability to remove damage caused by UV light
- leads to multiple skin malignancies- usually caused by loss of nucleotide excision repair enzymes
29
Double strand break repair
if double strand breaks and is unprepared, will lead to lost pieces of chromosome
- homologous repair (HR)= similar to recombination and requires an intact hom chrom (builds from older copy)
- non-hom end joining (NHEJ)= just sticks the broken pieces back together
* *HR>NHEJ
30
RB
retinoblastoma protein= critical targets of CDK/cyclin
| -rb is required to keep cell at G1 until the cell is large enough for S phase
31
DNA damage checkpoint
if DNA is damaged, cells can arrest at checkpoint in G1, S, or G2
32
centrosome duplication checkpoint
occurs at the end of G2, makes sure there are two separate chromosomes
- monitors spindle formation
- functions to maintain the normal complement of chromosomes
- coordinates with spindle checkpoint qnd exit from mitosis
33
spindle checkpoint
occurs in mitosis and ensure the chromosomes are correctly attached to the spindle
- monitors assembly of spindle and attachment to kinetochore
- keep anaphase promoting complex from being active (when active APC degrades the proteins that keep chroms together)
- if checkpoint fails, aneuploidy can result
34
oncogenes
mutant genes that promote cancer progression- usually gain of function
-before they become mutant= photo oncogenes
-ex= Ras
===mutant gene capable of causing the transformation of normal cells into cancerous cells
35
tumor suppressor genes
genes that when mutant fail to prevent cells from becoming cancerous
- loss of function
- p53 or RB
36
hyperactive growth stimulation
mutations that activate growth factor receptors like EGFR trigger this
-mutations that activate Ras
-overexpressing cyclin D
-mutations that inactivate pRB
= all result in inappropriate activation of G1 to S
37
Ras
acts as switch, stimulating cell proliferation in presence of growth factors
* GTP-bound state= on state
* *oncogene Ras= constitutively active in GTP bound state and leads to unrestrained cell proliferation
38
GAP
rapidly inactivates ras-gtp (on) complex by activating hydrolysis
39
GEF
activation brings ras to active form
40
Rb protein
keeps cells in G1- can lead to tumors in mutant form
41
loss of heterozygosity (LOH)
result of somatic mutations= hallmark of cancer
42
li-fraumeni syndrome
inherited disorder in which p53 is mutant and homozygotes do not survive, heterozygotes are at risk to develop wide variety of different tumors
-missense mutations in p53 are often dominant negative
43
dominant negative
acts antagonistically to wild type allele= mutant protein interferes with WT protein (heterozygotes are affected)
44
p53
critical factor in preventing cancer because it controls cell cycle arrest, apoptosis and inhibition of angiogenesis
= transcription that is activated when DNA is damaged
= turns on genes that stop the cell cycle so DNA can be repaired or led to apoptosis
45
genetic instability
loss of the centrosome and spindle checkpoints can cause loss of chromosomes = drastic change in genome
46
rRNA
central component of ribosome- essential for catalysis of peptide bond
47
horizontal (lateral) gene transfer
transfer of large segments of DNA between different species
48
endosymbiosis
collection of microorganisms living inside another- selection acts on the superorganism
49
new genes can arise from...
mutations, gene duplications, transposable element "domestication", lateral gene transfer, DNA rearrangements (fission and fusion), de noro organization
50
non synonymous organization
does change the resulting amino acid sequence
51
synonymous mutation
does not change resulting amino acid sequence- accumulate in the population since they are not selected against
52
gene duplication
most common way of making new genes
53
homolog
genes related by descent from a common ancestral DNA sequence
-can be in same or diff species
54
paralog
genes related by duplication within a genome- evolve new functions even if they are related to the original
**the similar gees are used in new tissues or in combinations to build new body plans and generate new orgs
55
orthologs
genes in different species that evolved from a common ancestral gene from speciation- normally retain same function over course of evolution
56
mtDNA
can be used to trace evolution -transmitted along female lineage
-different genes can evolve at different rates (gestation and lifespan timing)
57
population
group of organisms of the same species living in a geographical area
58
subpopulation
local populations, actings occur within each sub pop
59
gene pool
all of the alleles available in the population
60
allele
specific form of a gene (sequence variant)
| -genetic composition of a pop can be described in terms of frequencies or relative abundancies
61
genotype frequency
proportion of organisms that have a particular genotype
62
allele frequency
proportion of all alleles of specific type
63
hardy Weinberg principle
method for calculating the genotype frequencies expected at equilibrium with random matings in a pop
*allele frequencies add up to 1
64
HW assumptions
mating is random
males and females have same allele freq.s
no mutations or migrations to intro new alleles
pop large enough that allele frequencies do not change by chance
***the rarer the allele, the greater the ratio of heterozygotes to homozygotes
65
linked X genes in HW
males: H= p, h=q... the more rare the x-linked recessive allele, the more likely an affected individual will be male
66
inbreeding with HW
in most species inbreeding Is harmful because the frequency of recessive homologous individuals increases
AA= p^2(1-F)+pF
Aa=2pq(1-F)
aa=q^2(1-F)+qF
**the bigger the F, the stronger the inbreeding is and the faster the population loses heterozygosity
67
genetic drift
causes loss of alleles in small populations
- based on the random sampling effect
* strength of genetic drift is directly related to population size (small pop= large variance from gen drift)... the average effect of gen drift is about the same between large and small pops, but the VARIANCE range is much larger in small pop
68
bottleneck effect
causes loss of alleles= transiently small pop with new allele frequencies
-form of genetic drift- usually environmental catastrophe
69
founder effect
small portion of pop leaves and founds new pop with different allele frequencies
70
natural selection
can act to maintain genetic diversity by conferring advantages to heterozygotes
71
multifactorial/ complex traits
do not show complete 1:1 correspondence between genotype and phenotype
- influenced by gen and envi
- 75% of inherited human disorders are multifactorial
72
binary/ dichotomous trait
two states (affected and unaffected)
73
continuous trait
measurable feature that spans a range of values (height)
74
stochasticity
chance
75
natural selection routes
stabilizing selection- cuts extreme variations
directional selection- shifts mean of distribution
diversifying selection
76
variance
measure of the spread if distribution- estimate of the variance of a sample pop
**the greater the variance, the broader the distribution
77
standard deviation
the square root of the variance
| -68% of a normal distribution is within one st dev of the mean.... 95% within 2 (less than .15% greater than 3 st devs)
78
modifier genes
other genes that alter the phenotype produced by the main responsible gene
79
genotype variance
variance in phenotype caused by differences in genotype among individuals
-combined genetic and environmental effects on variance= total
80
pop differences with variance
in genetically uniform pop- all of the variance comes from environment (" highly inbred" or "highly homozygous")
in genetically diverse pop, the real/ total variance can be measured
81
genotype by environment interaction
the environmental effects on phenotype differ according to genotype
= environment effects on individual phenotypes do not affect all genotypes equally
82
heritability
amount of phenotypic variance within a group of individuals that is due to genetic variation
83
broad sense heritability
takes into account all of the ways that genetics can affect phenotypes- additive affects of alleles, epistasis
= importance of genetic variation relative to environmental variation in the phenotype of interest
H2= gen variance/ total variance
84
twin studies
used to determine genetic contribution to complex traits- tend to overestimate genetic contributions to variance bc the environment experienced by twins is usually very similar
85
covariance
measure of the relationship between two variables in group
86
correlation coefficient
tells us how much variance of one trait depends on the other
- positive value= two factors vary in the same way relative to each other
- negative= two factors vary in different ways
87
genomics
genetic study of multifactorial disease
88
multifactorial disease
affected by combination of genetic, environmental, and lifestyle factors
89
quantitative trait locus
region of DNA correlated with genetic environmental or lifestyle factors
usually alleles but can also be cluster of genes
-QTL alleles that contribute to complex traits tend to be common and have low-penetrance effects on the trait
90
quantitative traits
phenotypes that vary in degree and can be attributed to multiple genes and their environment
91
candidate gene method
basically taking educated guess and seeing if the gene you think is involved has alleles correlated with the trait
92
QTL mapping
simple sequence repeats (DNA polymorph) can be used to map QTLs
93
SSRs
alleles differ in the number of copies of a short repeated nucleotide sequence
- SSRs are tenderly expressed DNA sequences common in the human genome- ACACAC repeats- variance person to person
* ***the closer the SSR is to your gene of interest, the less/ smaller the % recombinants
94
copy number variants CNV
duplications and deletions
95
GWAS
goal is to identify single nucleotide polymorphisms that are associated with traits and diseases
96
Haplotype
set of linked alleles (or SNPs) close together on a chrom and tend to be inherited together
97
single nucleotide polymorphism (SNP)
single base variation between two identical genetic sequences- most occur in noncoding regions
98
important
* speciation gives rise to orthologs
* rRNA is part of ribosome and allows for peptide bond catalysis
* new genes= gene duplication+ mutation, DNA rearrangements, lateral gene transfer, transposable element domistication
* proliferation of cancer cells could be promoted by a peptide based compound that activates EGFR
