Clinical Genetics Flashcards
What are genes?
Functional units encoded in double-stranded deoxyribonucleic acid (DNA)
Where are genes packaged?
As chromosomes in the nucleus of the cell
What type of cells do not contain a nucleus?
Erythrocytes and platelets
What are the four bases of DNA?
- Adenine (A)
- Cytosine (C)
- Thymine (T)
- Guanine (G)
What is the structure of DNA?
A double helix, a twisted ladder-like structure
How are the strands of DNA joined?
By hydrogen bonds between bases on opposite strands
Which bases pair in DNA?
- C pairs with G
- A pairs with T
What feature of DNA enables faithful DNA replication?
The complementary base pairing
What happens when the DNA double helix ‘unzips’?
One strand can act as a template for creating an identical strand
What comprises a single copy of the human genome?
Approximately 3.1 billion base pairs of DNA wound around proteins called histones
The human genome is the complete set of genetic information.
What is a nucleosome?
A unit consisting of 147 base pairs wrapped around four different histone proteins
Nucleosomes are the fundamental units of chromatin structure.
What are the two types of chromatin?
- Heterochromatin
- Euchromatin
Heterochromatin is tightly wound and densely packed, while euchromatin is open and less tightly wound.
What is the structure that chromatin is packaged into?
Chromosomes
Chromosomes are the condensed forms of chromatin visible during cell division.
What does it mean that humans are diploid organisms?
The nucleus contains two copies of the genome
Diploid organisms have two sets of chromosomes, one inherited from each parent.
How many chromosome pairs are visible microscopically in humans?
23 chromosome pairs
This is known as the human karyotype.
What are chromosomes 1 through 22 known as?
Autosomes
Autosomes consist of identical chromosome pairs.
What are the sex chromosomes in humans?
X and Y chromosomes
The 23rd pair consists of sex chromosomes, with females having two X chromosomes and males having one X and one Y chromosome.
What is the normal female karyotype?
46,XX
This indicates two X chromosomes.
What is the normal male karyotype?
46,XY
This indicates one X and one Y chromosome.
What are genes?
Functional elements on the chromosome capable of transmitting information from DNA template to proteins
Genes produce messenger ribonucleic acid (mRNA) for protein synthesis.
How many genes are in the human genome?
Over 20,000 genes
Many of these genes are inactive or silenced in different cell types.
What does variable gene expression reflect?
Cell-specific characteristics
Different genes may be active in different cell types.
What is the central dogma?
The pathway describing the basic steps of protein production: transcription, splicing, translation, and protein modification
This pathway is an over-simplification of gene expression processes.
What are the basic steps of protein production according to the central dogma?
Transcription, splicing, translation, and protein modification
These steps outline how genetic information is converted into functional proteins.
What is the relationship between gene expression and cell types?
Gene expression is variable and can be inactive or silenced in different cell types
This variability contributes to the unique characteristics of each cell type.
What is transcription?
The production of ribonucleic acid (RNA) from the DNA template
Transcription is a crucial process in gene expression.
What enzyme is responsible for transcription?
RNA polymerase
RNA polymerase binds to DNA to initiate the transcription process.
Where does RNA polymerase bind to initiate transcription?
At the promoter region of a gene
The promoter is a specific DNA sequence that signals the start of a gene.
What does RNA polymerase produce during transcription?
An RNA molecule complementary to the DNA template
This RNA molecule is synthesized based on the sequence of the DNA.
What is the RNA produced from protein-coding genes called?
Messenger RNA (mRNA)
mRNA carries the genetic information from DNA to the ribosome for protein synthesis.
What is the polyadenylation signal?
A DNA sequence that signals termination of the RNA transcript
This signal indicates where RNA polymerase should stop transcription.
What is the role of RNA polymerase II in gene transcription?
Binding to the promoter of genes being transcribed with transcription factors
What does the primary RNA transcript include?
Both introns and exons
What happens to introns during the transcription process?
They are removed within the nucleus by splicing
What are exons joined to form?
Messenger RNA (mRNA)
What modification is made to the 5′ end of the RNA before export from the nucleus?
A methylated guanosine nucleotide is added (cap)
What is added to the 3′ end of the RNA before it leaves the nucleus?
A string of adenine nucleotides (polyA tail)
Why is the addition of the methylated guanosine cap and polyA tail important?
It protects the RNA from degradation and facilitates transport into the cytoplasm
What occurs in the cytoplasm after mRNA is exported from the nucleus?
mRNA binds to ribosomes and forms a template for protein production
How does RNA differ from DNA?
RNA is single-stranded.
*The sugar residue within the nucleotide is ribose, rather than deoxyribose.
*It contains uracil (U) in place of thymine (T)
What regulates the activity of RNA polymerase?
Transcription factors
Transcription factors are proteins that bind to specific DNA sequences at promoters or enhancers.
How many different transcription factors does the human genome encode?
More than 1200
This indicates the complexity of gene regulation in humans.
What can mutations in transcription factors, promoters, and enhancers cause?
Disease
For example, alpha-thalassaemia can be caused by gene deletions or variants in enhancers.
What influences gene activity or expression?
Complex interacting factors
These include the accessibility of the gene promoter to transcription factors.
What is DNA methylation?
The addition of a methyl group to cytosine molecules
Methylation in promoter regions usually silences transcription.
as methyl cytosines are usually not available for transcription factor binding.
What is euchromatin?
Open chromatin
In euchromatin, gene promoters are accessible to RNA polymerase and transcription factors.
It is therefore transcriptionally active
What is heterochromatin?
Densely packed chromatin
Heterochromatin is transcriptionally silent.
What determines chromatin configuration?
The chromatin configuration is determined by modifications (such as methylation or acetylation) of specific amino acid residues of histone protein tails.
What are epigenetic modifications?
Changes that do not alter the primary DNA sequence but have biological signifcance in chromosomal function.
‘Epi-‘ means ‘above’ the genome and these changes have biological significance.
What role do abnormal epigenetic changes play in cancer?
They allow expression of normally silenced genes
This results in cancer cell de-differentiation and proliferation.
What is vorinostat?
A histone deacetylase inhibitor
It has been used to treat cutaneous T-cell lymphoma by re-expressing silenced genes.
What do the genes re-expressed by vorinostat encode?
Transcription factors that promote T-cell differentiation
This leads to tumor regression instead of proliferation.
What is the term for the RNA molecule that is a copy of the whole gene?
Primary or nascent transcript
This transcript undergoes further processing to become mature mRNA.
What process involves the removal of intronic regions and retention of exonic regions in RNA?
Splicing
splicing, whereby regions not required to make protein (the intronic regions) are removed while those segments that are necessary for protein production (the exonic region
This is essential for producing a functional mRNA molecule.
What is the name of the protein complex that carries out splicing?
Spliceosome
The spliceosome is a multimeric protein complex involved in RNA processing.
What happens to mRNA after splicing?
It is exported from the nucleus and used as a template for protein synthesis
This is a crucial step in gene expression.
What is the process called when genes produce more than one form of mRNA?
Alternative splicing
This allows for the production of different proteins from the same gene.
Can Different proteins from the same gene can have entirely distinct functions?
Yes!!
For example, in thyroid C cells the calcitonin gene produces mRNA encoding the osteoclast inhibitor calcitonin, but in neurons the same gene produces an mRNA with a different complement of exons via alternative splicing that encodes a neurotransmitter, calcitonin-gene-related peptide.
What is the segment of mRNA that directs the synthesis of a protein product called?
open reading frame (ORF)
The ORF contains the coding sequence for a protein.
What is a codon composed of?
three contiguous bases
Codons specify which amino acids are incorporated into proteins.
How many different codons are there?
64
This includes 61 codons for amino acids and 3 stop codons.
What are the three stop codons?
UAA, UAG, UGA
These codons signal the termination of protein synthesis.
What amino acid do ORFs in humans most commonly start with?
methionine
Methionine is often the first amino acid in newly synthesized proteins.
What are the regions before and after the ORF in mRNA called?
5′ untranslated region (UTR) and 3′ untranslated region (UTR)
These regions play roles in the regulation of translation and mRNA stability.
What structure at the start of the 5′UTR protects mRNA from degradation?
cap structure
This cap is critical for mRNA stability and translation initiation.
What is the function of the polyA tail in the 3′UTR?
regulates efficiency of translation and mRNA stability
The polyA tail is a stretch of adenine bases that aids in these processes.
What do mRNAs associate with after leaving the nucleus?
ribosomes
Ribosomes are the sites of protein synthesis.
What are the two subunits of a ribosome?
40S and 60S
These subunits consist of non-coding rRNA and proteins.
What is the role of transfer RNA (tRNA) during translation?
delivers amino acids to the ribosome
tRNA molecules have anticodons that are complementary to mRNA codons.
What is the structure that surrounds the nucleus and where ribosomes may be bound?
endoplasmic reticulum (ER)
The ER is involved in protein synthesis and processing.
What happens to proteins synthesized on ribosomes bound to the ER?
translocated into the lumen of the ER
Here, proteins undergo folding and processing.
What post-translational modification may occur in the Golgi apparatus?
glycosylation
Glycosylation involves the covalent attachment of sugar moieties to proteins to form the mature protein that can be exported into the cytoplasm or packaged into vesicles for secretion.
What are congenital disorders of glycosylation associated with?
severe developmental, neurological, haemostatic and soft tissue abnormalities
These disorders highlight the clinical importance of proper glycosylation.
What is an example of a gene variant that causes cystic fibrosis?
ΔF508
This variant results in an abnormal protein that cannot be exported from the ER.
How many genes in humans encode non-coding RNAs (ncRNA)?
Approximately 4500 genes encode non-coding RNAs.
ncRNAs are distinct from protein-coding genes, focusing on regulatory functions.
What are the categories of non-coding RNAs (ncRNA)?
Categories of ncRNA include:
* transfer RNA (tRNA)
* ribosomal RNA (rRNA)
* ribozymes
* microRNA (miRNA)
Each category plays a unique role in cellular processes.
What is the role of microRNAs (miRNAs) in gene expression?
miRNAs bind to mRNAs, typically in the 3′UTR, promoting target mRNA degradation and gene silencing.
This process is crucial for post-translational regulation of gene expression.
In what areas do miRNAs have important roles?
miRNAs have important roles in:
* normal development
* cancer
* common degenerative disorders
Their involvement in these areas is a focus of ongoing research.
What molecules provide the signal to activate the cell cycle in normal tissues?
Hormones, growth factors, and cytokines
These molecules are essential for initiating the controlled programme of biochemical events leading to cell division.
What is the cell cycle?
A controlled programme of biochemical events that culminates in cell division
The cell cycle is crucial for growth and repair in tissues.
What type of cell division do all body cells, except gametes, undergo?
Mitosis
Mitosis results in two diploid daughter cells.
What is the outcome of mitosis?
Two diploid daughter cells
Each daughter cell has the same number of chromosomes as the parent cell.
What type of cell division do sperm and egg cells undergo?
Meiosis
Meiosis results in four haploid daughter cells.
What is the outcome of meiosis?
Four haploid daughter cells
This process is essential for sexual reproduction.
What phase do cells enter if they are not committed to mitosis?
G0
G0 is a resting phase where cells are not actively preparing to divide.
What are the three phases of interphase that cells committed to mitosis must go through?
- G1 (first gap)
- S (synthesis)
- G2 (second gap)
Each phase serves a specific purpose in preparing the cell for division.
What occurs during the G1 phase?
Synthesis of the cellular components necessary to complete cell division
G1 is crucial for preparing the cell for DNA replication.
What happens during the S phase?
DNA replication producing identical copies of each chromosome called the sister chromatids
This phase ensures that each daughter cell will receive an identical set of chromosomes.
What is the primary function of the G2 phase?
Repair of any errors in the replicated DNA before proceeding to mitosis
G2 is essential for maintaining genomic integrity.
What are the four phases of mitosis?
- Prophase
- Metaphase
- Anaphase
- Telophase
Each phase plays a critical role in the separation of chromosomes.
What occurs during prophase?
The chromosomes condense and become visible, the centrioles move to opposite ends of the cell and the nuclear membrane disappears
Prophase is the first stage of mitosis where key structural changes occur.
What happens during metaphase?
The chromosomes line up at the equator of the cell and centrioles complete their migration to opposite ends
This alignment is crucial for ensuring correct chromosome separation.
What is the role of spindle fibers during anaphase?
Spindle fibres attach to the chromosome and pull the sister chromatids apart
This separation is critical for the equal distribution of genetic material.
What occurs during telophase?
The chromosomes decondense, the nuclear membrane reforms and two daughter cells are formed, each with 46 chromosomes
Telophase marks the near completion of mitosis, preparing for cytokinesis.
What is meiosis?
A special, gamete-specific, form of cell division
How many phases does meiosis consist of?
Four phases: prophase, metaphase, anaphase, and telophase
How does Meisosis differ from mitosis?
It consists of two separate cell divisions known as meiosis I and meiosis II.
It reduces the chromosome number from the diploid to the haploid number via a tetraploid stage, i.e. from 46 to 92 (MI S) to 46 (MI M) to 23 (MII M) chromosomes, so that when a sperm cell fertilises the egg, the resulting zygote will return to a diploid, 46, chromosome complement. This reduction to the haploid number occurs at the end of meiosis II.
*The 92 chromosome stage consists of 23 homologous pairs of sister chromatids, which then swap genetic material, a process known as recombination. This occurs at the end of MI prophase and ensures that the chromosome that a parent passes to his or her offspring is a mix of the chromosomes that the parent inherited from his or her own mother and father.
When does meiosis begin in females?
In fetal life
When does meiosis complete in females?
After ovulation
When does meiotic division begin in males?
At puberty
How long does it take for both meiotic divisions to complete in males?
A matter of days
What is the Hayflick limit?
The number of divisions a cell population can go through in culture before division stops and enters senescence.
What is senescence?
A state in which cell division stops due to the Hayflick limit.
What are progeric syndromes?
Rare human diseases associated with premature ageing that help identify the importance of DNA repair mechanisms.
What is Werner syndrome?
A condition where a mutated DNA helicase leads to failure of DNA repair and premature ageing.
What is apoptosis?
Programmed cell death that occurs in normal tissues and plays a role in development, tissue remodelling, and the immune response.
What triggers apoptosis?
A specific signal that varies by tissue or cell type.
What are caspases?
Enzymes activated during apoptosis that destroy cellular components, including chromosomal DNA.
What are apoptotic bodies?
Characteristic vesicles formed during cell death that are recognized and removed by phagocytic cells.
What is the role of macrophages in apoptosis?
They recognize and remove apoptotic bodies without provoking an inflammatory response.
What is necrosis?
A pathological process where the cellular environment loses components necessary for cell viability.
What is the most common cause of necrosis?
Hypoxia.
