Topic 1 - Cellular and Molecular Basis of Inheritance Flashcards
Revise and refresh ¥ DNA, packaging and chromosomes ¥ Gene structure ¥ DNA to RNA to protein ¥ Genetic variation (111 cards)
1
Q
The beginning of life
A
Sperm fertilised egg cell (ovum) to form a zygote.
Ovum and sperm are haploid germ cells.
Zygote is diploid
2
Q
Heredity
A
early scientists - hereditary characteristics transmitted by proteins.
1944 - bacteria work, DNA responsible
3
Q
Why was there skepticism by the scientific community about DNA transmitting hereditary characteristics?
A
DNA was considered a very simple molecule - only 4 bases
4
Q
Structure of hereditary material needed to be:
A
versatile to account for variety.
Be able to reproduce to form an identical replica
Structure described by Watson + Crick and Franklin + Wilkins fulfilled these requirements
5
Q
Deoxyribonucleic acid (DNA)
A
- twisted double helix
- made up of 4 bases (chemicals)
6
Q
Adenine and Thymine
A
2 H bonds
7
Q
Guanine and Cytosine
A
3 H bonds
8
Q
Bases are attached by
A
2 phosphate backbones
9
Q
DNA is
A
tightly packed, takes up less space
10
Q
How many bases in the whole human genome?
A
3.2 billion bases
11
Q
DNA packaging chromatin =
A
DNA + RNA + protein
12
Q
Main protein in chromatin are
A
histones
13
Q
DNA wound around histones to form
A
nucleosomes
14
Q
Nucleosomes organise into
A
solenoids
15
Q
Solenoids
A
loop up into structure of chromatin (tightly packaged fibre)
16
Q
Histones
A
DNA would round 2 each of histones H2A, H2B, H3 and H4
17
Q
Histones core particles connected by a
A
short stretch of linker DNA, forming a structure resembling beads on a string
18
Q
Histone 1 is NOT
A
part of the nucleosome bead
19
Q
Histone 1 =
A
linker histone
20
Q
Histone 1 binds to the
A
entry/exit sites of DNA on the surface of the nucleosomal core particle and completes the nucleosome
21
Q
Types of chromatin
A
Euchromatin + heterochromatin
22
Q
Euchromatin
A
open chromatin, prevalent in parts of the genome that’s being regularly used + in cells that are active in the transcription of many of their genes (active part of the genome)
23
Q
Heterochromatin
A
condensed form of chromatin made up of tight loops, most abundant in parts of genome not in active expression + cells that are less/not active
24
Q
Condensed DNA is packaged into
A
chromosomes
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Human genome
22 autosomes + sex chromosomes
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Human chromosome structure
2 identical chromatids, each contains 1 DNA molecule, centromere in middle.
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Chromosomes vary in size, which is longest?
Chromosome 1
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Genetic Makeup of Human cells Haploid
23 chromosomes: 1 copy of each autosome and 1 sex chromosome (X or Y)
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Genetic Makeup of Human cells Diploid
46 chromosomes: 2 copies of each autosome 1-22 and 2 sex chromosomes (XX / XY)
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Gene ->
Basic physical and functional unit of heredity
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Gene is made up of
DNA, acts as instructions to make proteins
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Genes vary in
length; few hundred bases - 2.5 million+
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How many genes in the human genome?
20,000 - 23,000
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Less genes in the human genome than expected, why?
due to alternative splicing
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DNA to RNA to protein
- central dogma of molecular biology
- DNA to RNA - transcription
- RNA to protein - Translation
Each triplet codon codes a specific amino acid
- non overlapping
- more than 1 codon per amino acid - degenerate code
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Nonsense mediated control
?
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Transcription
- RNA polymerase binds to a promoter sequence (near beginning of gene - directly/helper proteins)
- RNA polymerase uses the DNA template strain to make new/complementary RNA molecule (primary RNA)
- Transcription ends in termination (depends on sequences in RNA, STOP codon)
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what is the main transcription enzyme?
RNA polymerase
39
RNA vs DNA
RNA - ss, uracil, less stable than DNA
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RNA processing: before primary mRNA molecule leaves the nucles it's modified:
Splicing (removing introns)
Capping (5' end)
Polyadenylation (3' end)
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RNA capping
- 5' cap added to 5' end of newly synthesised mRNA using modified nucleotide 7-methylguanosine (to protect from degradation)
- capping occur after initiation of synthesis of mRNA and precedes other modifications that protect mRNA from degradation by RNases
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closer look at 3'UTR
- 3'UTR begins at Translation Termination Codon
- part of mRNA and signals end of translation of the nucleotide code into a protein
- Polyadenylation of 3' end occur before mRNA leaves nucleus
- 100-200 nucleotides long, protects mRNA from degradatory action of phasphatases + nucleases
- Export of mRNA from nucleus into cytosol relies on polyadenylation (adding of polyA tails)
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Splicing
- Spliceosomal proteins bind to pre-mRNA template (has introns)
- Intron removed in the form of lariat and 2 exons ligated (spliced out) to make mature mRNA
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Spliceosomal proteins
U1, U2, U4, U5, U6)
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Translation
- mRNA used as template to assemble amino acids to produce polypeptide
- occurs in cytoplasm within ribosome
- Initiation - ribosome connects mRNA with the first tRNA so translation can begin
- Elongation - amino acids brought to ribosome by tRNAs and linked together to form a polypeptide chain
- Termination - finished polypeptide released to be folded into mature protein
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CFTR protein
goes to surface of cell, insert into membrane and allows chlorides and water in/out of cell
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Other Nuclear DNA
Genes represent less than 2% of total nuclear DNA
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Other nuclear DNA, rest of the genome is mostly repetitive DNA sequences
- vary from short repeated segments to repeats thousands of bases long, can repeat from a few to several hundred times
- previously known as junk/garbage DNA
- Recent evidence shows that this plays role in regulation of gene expression (base change around 10,000 bases away from promoter sequence was discovered to cause disease in a family)
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Introns (intragenic regions)
non coding regions found within genes - few hundred to several thousand bases long + some contain regulatory elements
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Intergenic regions
regions of genome that don't contain protein coding sequences - between the genes. CAn contain regulatory elements that may be involved in the regulation fo gene expression
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Mitochondrial DNA
- 16.6 kb circular double stranded DNA molecule (mtDNA)
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mt DNA codes for
37 genes (on this loop of DNA, many to do with electron transfer chain.
- 2 types of ribosomal RNA
- 22 transfer RNAs
- 13 protein subunits for enzymes - cytochrome b + cytochrome oxidase
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mtDNA genetic code
differs slightly from nuclear DNA
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Mitochondrial DNA encodes
genes necessary for optimal mt function
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Mitochondria inherited almost exclusively from
oocyte, leading to maternal pattern of inheritance that characterises many mitochondrial disorders
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After fertilisation
- rapid cell division leading to adult human with 1x10^14 somatic cells
- cell division = Mitosis
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Mitosis
2 identical diploid daughter cells formed from single diploid cell
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Mitosis (somatic cell division
Prophase, Metaphase, Anaphase, Telophase
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Prophase
- chromosome condensation,
- spindle formed
- nuclear envelope
- organelles disappear
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Metaphase
- chromosomes connect to spindle fibres and align on metaphase plate in centre of cell
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Anaphase
- centromeres split + chromosomes separate
| - Chromosomes move to opposite poles of cell
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Telophase
- chromosomes form clusters at opposite poles of cell
| - Nuclear envelope and organelles reform
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Cytokinesis
- cytoplasm divides into 2 parts following furrowing of plasma membrane
- cell divide, gain separate memrbanes and become independent
2 identical daughter cells formed
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Reproductive Cell Division - Meiosis
- gametes ready to produce new organism upon fertilisation
- 2 step division process produces 4 genetically different daughter cells
- reduction division
- gametes - haploid cells (single set of 23 chromosomes)
- Spermatogenesis + Oogenesis
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Meiosis
2 steps
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Meiosis 1
- reduction division, 46->23 chromsomes
- prophase 1
- metaphase 1
- anaphase 1
- telophase 1
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Meiosis 2
- equational division, duplicating what you've made, so generate 4 different daughter cells
- metaphase 2
- anaphase 2
- telophase 2
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Introducing variation during meiosis
Crossing over, independent assortment and errors in replication
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Classification of GEnetic variation
- size (large and small scale)
- DNA structure (substitution, insertion, deletion)
- Protein structure (Synonymous, non-synonymous)
- Coding, non-coding
- Protein function (loss/gain, dominant negative)
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single gene
CF / Huntington disease
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Chromosomal disorders
Down Syndrome
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Synonymous
has changed the amino acid being coded for
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Non-Synonymous
hasn't changed the amino acid being coded for
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DNA repair mechanisms and when they go wrong
- if DNA damage occurs in both somatic and germline cells
- changes in germline cells = heritable defects
- changes in somatic cells = nonheritable local changes
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Mutations drive
evolution
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Mutation can be
pathogenic (disease)
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Mutations in the Mismatch repair mechanisms can cause
colorectal cancer
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Crossing over
- Homologues chromosomes exchange genetic material at chiasma (prophase 1)
- Resultant chromosomes consist of combinations of parts of the chromosomes - genetic variation
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Independent assortment
- Anaphase 1, centromeres don't duplicate or divide
- only 1 member of each pair of chromosomes migrate to each daughter cell (maternal or paternal)
- paternal and maternal chromosomes are randomly sorted due to independent segregation, so mix of chromosomes different from cell to cell
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When Meiosis goes wrong
- Turners syndrome XO
- Down Syndrome Trisomy 21
- Edward Syndrome Trisomy 18
- Patau Syndrome Trisomy 13
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Cell destiny
- zygote will grow by mitosis to 8 cell stage (embryonic stem cell) then they undergo cellular differentiation (nerve, blood, muscle etc)
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Cell destiny - - all cells have 3 possible destinies all controlled by the cell cycle
1 - remain alive and function withought dividing (neurons)
2 - grow and divide (epithelial cells, liver cells)
3 - Die (necrosis or apoptosis)
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Cell Cycle
alternation of cell division (mitosis and cytokinesis) and interphase
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Interphase
G1, S and G2
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G1
synthesis of RNA and proteins (growing)
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S
DNA replication
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G2
DNA repair takes place, cell prepares for mitosis. Cell contains 2 identical copies of each of the 46 chromosomes
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G0
when cell stops dividing for a long time, length o time varies
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Rapidly dividing (epithelium) G0 =
10 hours
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Liver, G0 =
1 year
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Muscle and nuerones
do not divide, permanent G0
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Cell cycle, cells divide in response to
internal and external stimuli
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Checkpoints at
G1, S, G2 and M
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Tumour suppressors
act ot inhibit cell proliferation
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oncogenes
act to stimulate cell growth
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Cyclins and Cyclin Dependent Kinases (CDKs)
- transition between stages triggered by increased phosphorylation activity of specific CDKs
- CDK activity in turn is regulated by specific cyclin binding as well as multiple intracellular signalling pathways
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DNA replication - S phase
- DNA helicase unwinds DNA template
- ss binding proteins stabilise unwound DNA
- leading strand synthesis in the 5' to 3' direction by DNA polymerase
- Lagging strand, RNA primase adds RNA primer, then extended by DNA polymerase to form Okasaki fragment
- DNA ligase joins Okasaki fragments to form continuous strained
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When Cell Cycle Control goes wrong?
- uncontrolled cell division - cancer
99
Due to a series of changes in activity of cell cycle regulators, through mutation of i.e.
- tumour suppressors becoming inactive
| - oncogenes becoming over-active
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Retinoblastoma (eye cancer in children) caused by
mutation in tumour suppressor gene RB1
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Li Fraumeni
multi-organ cancer syndrome caused by mutations in the tumour suppressor p53
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Lung cancers
mutation in kras (oncogene)
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Cell destinies, all cells have 3 possible destinies
1 - remain alive + functioning without dividing (neurons)
2 - grow and divide (epithelial, liver cells)
3 - die (necrosis or apoptosis)
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Cell Death - Apoptosis
- programmed cell death
- cell suicide
- triggered by normal, healthy processes in body, almost always normal + beneficial (removing webbing between fingers of babies)
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Necrosis
- uncontrolled cell death
- necrosis - cell death triggered by external factors/disease - trauma/infection
- abnormal and harmful
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combination of apoptosis and proliferation responsible for
shaping tissues and organs in developing embryos
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apoptosis has a role in the
immune system - any ineffective/self-reactive T cells removed through induction of apoptosis
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Cancer
disease often characterized by too little apoptosis
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too much apoptosis
contribute to neurodegenerative diseases - Parkinsons/Alzheimers, progressive loss of neurons
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Necrosis
cell injury results in premature death of cells in living tissue by autolysis
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Necrosis caused by
toxic chemical/physcical events
- toxins
- radiations
- heat
- trauma
- lack of oxygen due to blockage of blood flow
