1. The Human Genome and Normal Variation (1) Flashcards
What were the first cells?
Prokaryotes
What are the features of prokaryotes?
All living organisms have a genome. What is a genome?
The complete set of genetic information present in an organism or cell.
Genomes contain a number of defined genetic units called genes. What are genes?
A DNA sequence that codes for a functionally
relevant molecule.
Mechanisms by which prokaryotic genomes increase in size over evolutionary time: (5)
- Gene duplication
- Whole genome duplication (polyploidisation)
- Transduction
- Insertion of new genetic material
- Gene duplication, followed by mutation, creates
new genes
- Size of prokaryotic genomes is directly related to
their _______ _______. - the more genes, the more proteins and enzymes they
make
metabolic capabilities
True or false:
Genomes can also reduce in size – organisms
lose genes that they no longer need/use
True
- The human genome arose at a series of stages in _____
- 37% of human genes originated in ______
evolution
bacteria
Steps of genome evolution: (6)
- Small strands of nucleic acids (RNA and then DNA) floated about in the primordial soup
- The first life forms on earth were prokaryotic cells
- Single cells arose, in which DNA was protected by a cell membrane
- DNA amount expanded through various mechanisms
- Single cells worked together to form multicellular organisms
- Humans are currently at the end of that chain of evolution and thus our genome is a modified version of DNA sequences already observed in other organisms
- As genome size increased, it became impossible for a cell to maintain its DNA complement as a single, _______ thread
- Larger genomes are broken up into more manageable bits: chromosomes
continuous
The human genome comprises 25 distinct molecules:
Nuclear genome:
* 22 _______
* 2 ____ chromosomes
* Diploid (2n)
autosomes
sex
- Mitochondrial genome
- One complete sequence of the mitochondrial genome (although there are up to _____ mitochondria per cell!
2000
What is the size of the human genome? (4)
- If you stretched out all the DNA in a single human
cell, it would be about 2 meters long - 3 088 286 401 nucleotides in length
(3.1 billion bases of DNA per haploid genome) - The longest chromosome was designated ‘1’ and so
on.. - The shortest human chromosome is chr 21
How many genes do humans have? (5)
- Humans have about 20 000 genes
- (estimate is 19,969 protein-coding genes; Aganezov et al., 2021)
- Some genes are transcribed in numerous different ways. Thus one gene = many different functional molecules (alternative splicing)
- Some gene transcripts are joined together
- Small genes next door to each other can combine to form a larger gene
Gene distribution in the genome:
* Random!
* Gene deserts: regions >_____ kb with no ORF -
about 20% genome
* Gene islands: ____-_____ regions
* Some chromosomes carry more genes than
others
500kb
gene-rich
Does size of genome correlate with complexity? (2)
- Genome size is positively correlated with complexity among prokaryotes and lower eukaryotes
- However, after mollusks and all the other higher eukaryotes above, this correlation is no longer effective
Most of the genes that are unique to vertebrates are concerned with the _______ or nervous systems and have transmembrane or_____ functions.
immune
extracellular
What proportion of the human genome is coding? (3)
- Only ~ 1.5% is protein coding (exons)
- Genes (introns plus exons) occupy only about 25% of the human genome
- > 50% of the human genome consists of repetitive DN
How do we study human genetics? (3)
Cytogenetics:
- Karyotyping
Molecular Cytogenetics: (3)
- FISH
- Microarray
- Gene Panels
- Next Generation Sequencing
Molecular: (2)
- Sanger Sequencing
- PCR
The human genome can be investigated at different levels. You would choose a laboratory technique appropriate to the ______ and _____ of the mutation you are looking for.
type
size
Summary:
* All life is connected by DNA
* The total amount of DNA an organism possesses (its genome) is no indication of how _______ the organism is
* The number of genes an organism ______ is no indication of how complex the organism is
* The human genome shares much of its ______ with less complex organisms
* Human genetics is studied at different levels. Each level of study is characterized by the information it can provide. Different lab techniques need to be utilized
depending on level of ________.
complex
sequence
interrogation
- > 10 million species on Earth
- Most living organisms are _____ cells
– Single cells can multiply quickly - In both unicellular and multicellular organisms, the single cell is the vehicle for the _______ information of that species
single
hereditary
All cellular organisms have double-stranded DNA genomes:
- The ________ information in ALL living cells is stored in the linear chemical deoxyribose nucleic acid (DNA)
- DNA performs the same basic functions across all species
heriditary
What does the genome comprise of?
- The genome comprises all the genetic material that an
organism possesses
What is the main function of genetic material?
The main function of genetic material is to store
information required to produce an organism
– Reproduction
– RNA/protein synthesis
In unicellular organisms, it is typically a single
_____ chromosome.
circular
What is the genome?
The genome is the complete set of sequences in
the genetic material of an organism. It includes the sequence of each chromosome plus any DNA in organelles.
What is the transcriptome?
The transcriptome is the complete set of RNAs present in a cell, tissue, or organism. Its complexity is due mostly to mRNAs, but it also includes noncoding RNAs.
What is the proteome?
The proteome is the complete set of proteins that is expressed by the entire genome. Because some genes code for multiple proteins, the size of the proteome is greater than the number of genes.
Two Major Types of Cells:
The nucleus represents a major _______ transition
* As a consequence of separating translation from _____ many new functions arose, which likely contributed to the remarkable success of eukaryotic cells
* “the origin of the eukaryotic cell has long been
recognized as the single most profound
change in the cellular organization during the
evolution of life on earth”
evolutionary
transcription
How did the nucleus evolve?
What are the differences between PROKARYOTES and EUKARYOTES? (6)
The tree of life
3 main branches:
Multicellularity enables functional ______ and _______.
But remember: all the different cells in an individual arose from a single cell, so ALL cells carry the same DNA complement.
specialization
complexity
Bacterial Genome Arrangement:
- Bacterial chromosomal DNA is usually, a _______ molecule that is a few million nucleotides in length
- To fit within the bacterial cell, the chromosomal DNA must be compacted about a _____-_____
- This firstly involves the formation of loop domains
– compacts the chromosome ~ 10-fold - DNA ____ _____ within loops is the second important way to compact the bacterial chromosome
circular
1000-fold
super coiling
Eukaryotic Genome Arrangement:
- Eukaryotic species contain one or more sets of chromosomes
- Each set is composed of several different ______ chromosomes
- Chromosomes are located in the nucleus
- To fit in there, they must be highly ______!!
linear
compacted
What is the packaging issue with DNA? (4)
What are histone proteins? (2)
- The scaffold around which the DNA coils is a unit
of 8 proteins, called histone proteins - Histones are a family of small, positively charged
proteins termed (H1,) H2A, H2B, H3 and H4
How do histones bind?
DNA is negatively charged, due to the phosphate
groups in its phosphate-sugar backbone, so
histones bind with DNA very tightly.
What is the nucleosome? (2)
How can histones be enzymatically modified? (2)
How are adjacent nucleosomes connected? (2)
Beads on a String:
* Packaging of DNA into ______ shortens the
fiber length about 7X
– 1 meter long will become a “string-of-beads” ______
fiber just 14 cm
* Further compaction required
nucleosomes
chromatin
What are the different levels of DNA packaging?
Chromatin is the combination of: (3)
Chromatin Condensation
* Two types of chromatin:
What does chromatin structure influence?
Chromatin Structure Influences Gene Expression.
What is the difference between heterochromatin and euchromatin?
Chromosomes in the 3-D nucleus:
- Chromosome arrangement in the nucleus is not random
- Chromosome _________
- ________ chromosomes occupy a distinct part of the
nuclear space - Inter and intra-chromosome interactions are specific and affect nuclear ________, including gene expression
territories
Interphase
functioning
How do human genomes differ? (3)
- We know that any two randomly selected humans
share 98-99% of their DNA sequence - Put differently, the sequence of your genome is 98-99% identical to the human reference genome
- What sorts of sequence changes are seen in the
remaining 1-2%?
Types of Human Genetic Variation: (4)
What are the features of deletions and insertions? (3)
What are the features of Variable Number Tandem Repeats?
What are the types VNTRs? (2)
What are Microsatellites?
What are some examples of microsatellites? (3)
What are Copy Number Variants? (3)
Can CNV cause diseases? (3)
- Most CNV are benign variants and will not directly cause disease
- Some examples where CNV (deletion or duplication of certain genes) affect
critical developmental genes and cause diseases: - Nervous system diseases (incl Parkinson and Alzheimer) can result from copy number
variation - Autism
- CNV can be more common in cancer cells
- EGFR copy number can be higher in non-small cell lung cancer and breast cancer
Single Nucleotide Polymorphisms:
Single nucleotide polymorphisms:
- A SNP occurs 1 in every 1000 __________
- 0.1% of 3 billion is however a huge number (3 million per individual!)
- Most common type of variant in the human ______
- Most of our SNPs occur outside of gene (coding) _______
nucleotides
genome
sequence
- The knowledge of how human genomes differ can be
used to our advantage in the laboratory: (3)
- Human Identification (Forensics)
- Relationships between humans (Paternity, Kinship)
- Understanding disease susceptibility
Why is SNP useful?
- As SNPs are the most abundant type of variant in the
genome, they are popular with laboratory scientists. - SNPs are a useful tool for identifying and examining different genomes
Normal vs pathogenic variation: (3)
- A single nucleotide difference can also be disease-causing, usually if it occurs within a gene
- Short tandem repeats can became unstable in size
- CNVs can misalign during recombination leading to deletion or duplication of a gene, which can cause disease
- In other words: the ways in which normal human genomes differ can also become a source of ______.
disease
What is the Human Genome Project? (2)
Variation at the population level
* In a population context, a variant can be common or
rare
* Low frequency (<0.01) – ____ _____
* High frequency (>0.01) - __________
rare variant
polymorphism
What is a Polymorphism?
A locus that has two or more alleles in a population,
where the frequency of the rarer allele is greater than
0.01 (1%), is said to be polymorphic
(If two or more alleles occur in a population but the rare allele occurs very infrequently, i.e. less than 1% of the time, then - by definition - this locus is not polymorphic. The rare allele is then termed a ‘rare variant’ as opposed to a polymorphism.)
Variation between populations - Numbers of SNPs:
(3)
What is a locus?
- Locus is the genetic word for “position”
- The locus of a single nucleotide (nucleotide position 44 367 on chromosome 4)
- The locus of a gene (it’s on the long arm of chromosome 10)
- The locus of a mutation/polymorphism (it’s a 72 nucleotide deletion on the X chromosome)
- Plural = loci
What is an allele? (4)
- An allele is an alternative form of a DNA sequence found at the same locus
- A SNP occurs at a particular locus. At this locus, we either find an A nucleotide or a G nucleotide. A and G are the two alleles of this SNP
- The gene for your ABO blood type occurs at a particular locus. At this locus, we will either see the A gene, the B gene or the O gene. These are the 3 possible alleles of that gene locus in the population
- An STR occurs at a particular locus. At this locus, the STR repeat unit is commonly seen either 3,4,5,6 or 7 times. Thus, this STR has 5 possible alleles
- Because humans are diploid, we have two copies of each of our autosomes. The DNA sequence on our Dad’s copy of a chromosome is similar, but not identical to the DNA sequence of our Mom’s copy.
- At a particular locus, if you have the same allele on both copies of your chromosome, you are ________ at that locus, for that allele (a homozygote)
- If the alleles are different to each other, you are ________ at that locus (a heterozygote)
- Males can only ever have one copy of X chromosome and Y chromosome loci. Males are thus ______ for genetic variants on their X and Y chromosomes
- Individuals who have a ______ on one chromosome and therefore only one allele (on the normal chromosome), will also be referred to as being hemizygous at that locus
homozygous
heterozygous
hemizygous
deletion
What is a phenotype?
- Your phenotype is the observable characteristics of your genotype. In other words, it is the identifiable physical features you present with (eye colour, hair colour, height, weight etc.)
- Phenotype and genotype are often not perfectly correlated
What is a genotype? (4)
- The combination of your alleles at a specific locus
is termed your genotype - At the ABO locus, you have an A allele and a B
allele. Your genotype is thus A/B. You are a heterozygote - At a particular SNP locus, you have alleles T and G. Your genotype is thus T/G. You are a heterozygote
- At a particular VNTR locus, you have 4 repeats and 4 repeats. Your genotype is 4/4. You are a homozygote
