Lecture 12

Question 1

Why is mutation important

Answer 1

Creates genetic variation between individuals and between species, producing this variation upon which evolution forces can act

Question 2

What do the differences in the rate of mutation produce

Answer 2

Different amounts of genetic variation which is important for evolvability

Question 3

What are some methods for studying mutation

Answer 3

Directly sequencing the genomes of individuals in family pedigrees

Sequence the genomes of both the parents then of the offspring, you can compare the offspring to the parents to identify mutations

If you see differences between the offspring genome and the parent genome, you know there are germ line mutations in the gametogenesis that is occurring in the parents

Once, you do this you can work out mutation rate

Question 4

How do you work out mutation rate

Answer 4

• Have to do a large amount of sequencing (have to sequence the trio multiple times with high throughput sequencing e.g. illuminia) to calculate the error rate
• You’re detecting new (de novo) mutations e.g. those found in the child and not the parents
• U = the number of de novo mutations found/ the number of nucleotide sites sequenced

Question 5

Kong et al (2012)

Answer 5

Study done from 2012 - looked at divergence between the human and the chimpanzee (for all of the 22 autosomes within the human genome)

Across all of these autosomes, there’s a little bit of variation in mutation rate (broadly chromosomes seem to have similar rates of mutations)

Question 6

Year of birth of the most recent common ancestory (MRCA)

Answer 6

They used the islandic pedigree genetic data set (because its very detailed)- lots of different genetic data for lots of different individuals.

From the common ancestor- can see lots of individuals have a G, clearly between the G -> A mutation occurred on the two generation branch

You can do this for all the sites on all the different sex chromosomes, can do that for the Y chromosome to estimate the Y specific mutation rate

Question 7

Helgason et al (2015, Nat Genet)

Answer 7

• 3.01x10-8 / site/ generation on the Y chromosome
• There was a much higher mutation rate on the Y chromosome compared to the autosomes - divergence on the Y chromosome is way higher than on the autosomes
• Divergence on the X chromosomes is lower than the average autosomal divergence and mutation rate

Question 8

Male-driven evolution

Answer 8

• Male mutation rate in humans is much higher than the female mutation rate because the male germ line has many rounds of cell divisions per generation than does the female germline
• Under this hypothesis, mutations arise mainly in males so evolution is “male driven” (Miyata)- evolution is being fuelled by processes that are happening in males

Question 9

Oogenesis

Answer 9

• Happens in the female germ line to produce eggs from this primordial female germ cell
• The primordial germ cell is essentially the precursor to the female egg
• Every time a germ line cell/ primordial cell divides, its DNA is replicated into a resulting daughter cell but this process is imprecise so mutations happen in that copying process to produce mutations
• In the females during oogenesis, there are about 22 cell divisions before meiosis
• For each of those 22 meitotic divisions, involves a DNA replication step, there’s the potential for a mutation, some of these cell divisions go onto produce polar bodies (dead ends)

This process of producing eggs/ precursor of the eggs happens during embryo development

This process in meiosis is arrested just before birth so after the female is born, there are no more cell divisions. When a female is born, she contains all of the eggs she can use to produce children and no more can be produced

Question 10

Spermatogenesis

Answer 10

In males, this cell division is a continual process (happening throughout life)

In males, there is a relationship between age and the number of chromosome replications that have happened in the germ line - males are continuously producing sperm - involves cell division and DNA replication

Because sperm undergo many more rounds of cell division, there’s this likelihood of mutations derived from sperm entering the genome of the next generation

Question 11

Male-driven evolution

Answer 11

• The Y chromosome is paternally inherited
• The autosomes spend an equal amount of time in both sexes
• The X chromosome spend 2/3 of the time in females and 1/3 of the time in males
• Predicted mutation rate: Y > autosomes > X

These sex differences in mutation rate are going to have an effect on how sex chromosomes evolve

Question 12

Why do we see differences in patterns of divergence

Answer 12

• In the female there are 22 cell divisions before meiosis and two during meiosis, giving 23 chromosome replications in total- as all the cell divisions are completed before birth, there is no increase with postnatal age
• Sperm are produced continuously throughout reproductive life - the number of cell divisions and chromosome replications that have occurred increases with age

Question 13

Kong et al al 2012 part 2

Answer 13

• Looked Fathers age at conception is strongly positively correlated with the number of de novo mutations the child has (paternally inherited)
• Mothers age at conception is not correlated with the mutation rate
• The best fitting model: the paternal mutations increase exponentially 4.28% per year (doubling every 16.5 years and increasing by 8-fold in 50 years)
• The number of mutations increases exponentially with age

Question 14

Rapid evolution of the Y chromosome

Answer 14

Extra factor for why we might see this rapid rate in turnover genes on the Y chromosome

Ampliconic gene families have huge variation in copy number within and across populations and how the broad structure varies dramatically across different priamtes- gains and losses of different genes

This is consistent with the Y chromosome having a higher mutation rate than the rest of the genome - rapid content in gene turnover on the Y and why it might degenerate quite quickly - higher mutational input

We think these big amplionic genes might be because they’re exposed to males who have this higher mutation rate

Question 15

Evolution of the W chromosome

Answer 15

Females have ZW

Males have ZZ

The W chromosome is female limited - inherited from mothers to daughters and therefore it has the lowest mutation rate because its never in males

It doesnt expeirence this elevated mutation rate (less mutational load/ less genetic drift) ZW chromosomes are more poorly studied - nice contrast to try and distangle the processes that drive sex chromosome evolution

Looked at the abundance, variability and evolution of ampliconic genes on the W chromosome within and across two different species (duck and the chicken) - separated by 90 million years of avian evolution - used nano strain (based on fluorescent probes)

Question 16

Deficit of ampliconic gene families on the duck W chromosome

Answer 16

There is one ampliconic gene family on the avian W chromosome that we know of- this is called hint W - present in about 40 copies in the chicken in the W chromosome and its also ampliconic across loads of different avian species apart from the ostrich and the emu (present in a single copy)

There has been this one family that has undergone this tandem genome duplication to produce this big gene family called HINTW

We don’t know what HINTW does and we don’t know why its present in so many different copies- we know its expressed in female ovary - female reproduction? but we don’t know- it was originally thought to be the sex determining gene in birds but now we know its a gene on the X chromosome that determines sex - interested in looking across different breeds to identify the variation in the copy number for both the duck and the chicken to see if we could work out why we get this gene is present in so many copies

Question 17

Evolution of HINTW

Answer 17

These were the breeds that were looked at - poultry were a nice study system - humans have applied lots of different artificial selection to produce different poultry breeds for different things - we have applied sex specific selection to these breeds

Malad - ancestor of all domesticated duck breeds

Humans have also selected for ducks - meat production

Looked at HINTW copy variation across all of these different breeds - hypothesis was that if HINTW was doing something important for female fertility - we should see more copies of it in the female selected lines then the male selected lines

Question 18

Evolution of avian HINTW

Answer 18

• Result for the duck breeds and the chicken breeds
• No variation in copy number across all of these different breeds- stark contrast for what we see for the Y chromosome across different human populations - consistent with the idea that the W has a lower mutation rate and that has led to stronger purifying selection to conserve size of the gene families - less mutation causing random gain/ loss of these different gene families - the breeds that layed more eggs have higher numbers on the HINTW than the modern ancestor and the breeds that layed few eggs- advantage to having more copies of HINTW- might produce more eggs/ egg production

Male and female mutation rate varies a lot because there are fundamental differences between oogenesis and gametogenesis- sex chromsomes are inherited unequally between males and females so there are differences in mutation rate