What does the human genome tell us? + The Human Genome & Disease Flashcards
What is comparative genomics used for?
To discover what is in common and what is different
What are things in common called?
Conserved
What may conserved things encode?
Biology in common between species
What may things that are different encode?
Organism specific biology
What do you learn by comparing genes?
A little bit about which bits of the genome do what
How do you compare sequences?
By lining them up next to each other and marking each point where sequences are the same and different
What is the method for comparing sequences called?
Aligning
What does it mean when there are more differences between DNA sequences?
The further apart the organisms are in time
What may differences in individuals be associated with?
Disease, characteristics of an individual or evolutionary history
What can we learn about an organism if we compare its genome with others?
What sort of genes they have, how differences between species arise and relationships between species
How long does DNA from dead things remain in the environment?
For up to 1 million years
What happens to DNA in the environment?
It degrades and is masked by more modern DNA which may also show up when sequenced
When can ancient DNA be extracted?
In very special circumstances (for example if it is preserved in a cold environment such as a cave)
How many neanderthal nucleotides were found?
4 billion
What was done with modern contamination of the Neanderthal bits?
It was identified and discounted
How many neanderthals were sequences gathered from?
Probably 3 individuals
How much neanderthal sequence was obtained?
Enough sequence to compare with modern human genome sequences from around the world
What was identified from the neanderthal sequencing?
Bits of DNA that differ between Neanderthals and us
What was the most amazing finding from the neanderthal DNA sequencing?
Some of us carry neanderthal DNA
Which humans carry neanderthal alleles?
Modern humans from Europe and asia while those from Africa show no sign of these alleles
What is the most likely cause of africans showing no neanderthal DNA?
Neanderthals and homo sapiens have a common ancestor but Neanderthals left Africa before Homo sapiens. Then when Homo sapiens left Africa they interbred with neanderthals when they met
What does it mean that humans have some neanderthal DNA?
It doesn’t mean that those of us with Neanderthal DNA have a different set of genes, it just means that our DNA holds variants that arose in neanderthals
How much of the genome of non-africans is made up of variants that arose in neanderthals?
2-4%
What does Neanderthal DNA do?
Add to our variation in our genome and might be related to our phenotype
What was also found in Denisova?
A finger bone whose mitochondrial DNA doesn’t match Neanderthal or modern human DNA (Denisovam)
What was the genome from the species of archaic human sequenced from?
A tooth found in the same cave in 2010
How much Denisovans variation is found in the human genome?
4-6% in present day melanesians
What has sequencing our genomes helped?
Us to better understand who we are and where we came from
What is the key technology?
Being able to compare genomes
What can we do by comparing genomes from multiple species?
We can start to understand where our characteristics came from
What is this the same approach to?
Modern disease genetics- data rich and statistically intense analysis
What are our extinct relatives?
Not just fossils in our museums, but they also live on as variants in our genomes which affect our biology
What can mutations be?
Inherited or acquired
What are mutations?
Permanent changes to the DNA sequence
What are inherited mutations called?
Germline mutations
How are germline mutations passed on?
Via the gametes (eggs and sperm)
How can mutations be acquired?
If DNA gets damaged or is copied incorrectly
Are acquired mutations inherited?
No, these mutations are not passed on to the next generation
What is the driving force for evolution?
Genetic variations and mutations
What effects can mutations have?
They can have a beneficial effect, have no effect or a deleterious (damaging or harmful) effect on the organism
What effect do majority of mutations have?
No effect at all
What does the outcome of a mutation also depend on?
Environmental effects and other genes
What is not consistent?
The molecular basis of a mutation
What do we talk about when thinking about mutations?
Alleles
Why do we talk about alleles rather than genes?
Because mutations in a single gene can have different effects
What are the two ways of thinking about mutations?
Dominant vs Recessive and Loss of function vsGain of function
What can mutations (alleles) be?
heterozygous (one mutant, one wild type allele) or homozygous (both alleles mutant)
What is a dominant mutation?
One that causes a phenotype when heterozygous
What is a recessive mutation?
One that causes a phenotype when only homozygous
What must a mutation do to have a phenotype?
Affect the function of a gene
What can a mutation do negatively to a gene?
Break a gene to cause it to not work as well as normal, or not work at all
What is the mutation that breaks a gene to cause it to not work as well as normal or not work at all called?
Loss of function
What are loss of function mutations often?
Recessive mutations
What are loss of function mutations often recessive?
Because a normal copy of the gene exists on the other chromosome which can replace the lost function
What can a mutation do positively to a gene?
It can cause a gene to work too well, or to do something unexpected
What is a mutation called that can cause a gene to work too well or to do something unexpected?
Gain of function
What are gain of function mutations often?
Dominant
Why are gain of function mutations often dominant?
Because having an allele that works too well or does something novel will not be replaced by the normal copy of the gene
Gain of function doesn’t always mean it is…
something good
What can we do by examining the inheritance pattern of something?
Determine if it is dominant or recessive. Also if it is x-linked, y-linked or autosomal
What are examples of autosomal recessive mutations?
Inability to taste PTC, cystic fibrosis
What are characteristics of autosomal recessive mutations?
Typically not seen in every generation of an affected family, passed on by two asymptomatic carriers, males and females are equally likely to inherit
What are examples of autosomal dominant mutations?
Widows peak, Huntington’s disease
What are characteristics of autosomal dominant mutations?
Occurs commonly in a pedigree, affected individuals have an affected parent, males and females equally likely to inherit.
What are examples of x-linked recessive mutations?
Haemophilia A and Haemophilia B
What are the characteristics of x-linked recessive mutations?
Fathers can not pass on x-linked traits to their sone, no male to male transmission, most often affects males
How do we determine the inheritance pattern? Step 1
Examine the pedigree and look for individuals that break the rules to find out some possibilities
How do we determine the inheritance pattern? Step 2
Identify carriers who do not have the condition, if there are none, this might mean the condition is dominant
How do we determine inheritance pattern? Step 3
Find the inheritance pattern that explains all the disease occurrence in a pedigree
How do we find potential disease genes?
Sequence genome»>Map to the human reference»>Find common and novel variants»>Work out if novel variants are predicted to be harmful or benign»>validate and test the variants predicted to be harmful
How do most disorders appear?
To have a genetic basis but do not follow straight forward inheritance patterns
What do polygenic disorders involve?
Several genes acting together or environmental factors interacting with genes
What is identifying polygenic genes?
Very hard
How are polygenic genes identified?
Cases (10-100K) and controls (10-100K) are compared to identify variation
What is identified when caring cases and controls?
Common variants and shared variants which are in cases but not controls are identified
What happens after common and shared variants are identified?
The shared variants in cases not in controls are validated and tested to decide if variants in genes are likely to be associated with the disease
What does having a disease-related variation mean?
For most diseases it doesn’t mean you will get the disease
How do diseases come about?
Through a combination of variants and the environment
Different sufferers have…
different disease mechanisms
What are most genetic disorders?
Probabilistic, not deterministic
What is also probabilistic, not deterministic?
Most traits with a genetic component, your genes do not direct your destiny
