Lecture 10

Question 1

Meiosis stages

Answer 1

1. Chromosomes become shorter and thicker; chiasmata are prominent
2. Homologous chromosomes repel; they are held together by chiasmata
3. Bivalents align on the metaphase plate
4. Homologous chromosomes separate
5. Chromosomes align on the metaphase

Question 2

What happens when bivalents lack the chiasmata

Answer 2

They are prone to nondysjunction where you don’t get proper segregation of the chromosomes into the gametes at the end, you don’t get recombination

Question 3

Why is meitotic recombination of fundamemental importance

Answer 3

• It generates new combinations of genotypes which is essential for adaptation/ natural selection
• Determines to what extent loci residing in different genomic locations are associated with one another (linkage)
• Crossover is critical for correct segregation of chromosomes during meiosis but its also really important for mixing genetic material between the maternal and the paternal genomes so the gametes aren’t identical to the parental genome

Question 4

What is linkage disequilibrium

Answer 4

The extent to which the allele frequencies at two loci are correlated.

Question 5

What does recombination do to LD

Answer 5

It breaks down LD which makes selection more efficient because it allows new and more favourable mutations to be more integrated into the population together and it allows selection to eliminate deleterious combinations

Question 6

What is background selection

Answer 6

Selection is going to act to purge those from the population. All the black lines (chromosomes are going to be lost from the population because they have a lower fitness leaving behind deleterious mutations.

Therefore in the next generation, this means that mutations can occur and become weakly linked with the deleterious mutation.

So therefore we get fixation of this bad mutation because you can’t have recombination to shuffle the mutations between the different chromosomes in order to create a mutation free chromosome .

Question 7

Mullers Rachets

Answer 7

there’s no recombination so there’s no shuffling of mutations between different chromosomes - what happens is there’s this stochastic loss of mutation free chromosome (purely by chance) - your population then starts to accumulate these deleterious mutations

Question 8

Genetic hitchhiking

Answer 8

deleterious mutations along with a beneficial mutation, there’s selection for the strongly beneficial mutation (positive fitness effect) however, its in LD with a deleterious mutation so as well as the beneficial mutation getting fixed, the deleterious one also does as well - can separate that linkage between the beneficial and the deleterious mutation.

Question 9

Ruby in the Rubbish

Answer 9

Opposite of the last where you get beneficial mutations that have been lost from the population simply because they’re linked with a really deleterious mutation that’s going to be eliminated from the population (lose those deleterious mutations)

Question 10

What’s the variation of recombination rates like across species

Answer 10

There’s huge recombination rate variations

This is strange because recombination is fundamental so why are some species doing it more and some doing it less? This may have implications for how efficient selection

Its important that we start to measure the intensity of recombination and its evolutionary significance due to the variation

Question 11

Where are the variations in recombination

Answer 11

Across a species

Across males and females of a species (between individuals

Across the genome

Across the chromosomes

Question 12

What is the genetic distance and how is it measured

Answer 12

The degree of genetic linkage between two loci is measured by the frequency of recombination between two loci

• c ranges between 0
  (complete linkage) to 0.5 (independent
  assortment or unlinked)
  – The standard unit is cM (centi-Morgan)
  – 1 cM = 1% probablilty of producing a recombinant

Question 13

What do we need to consider

Answer 13

• The genetic distance between locus A and locus B is 17cM, and so is that between locus C and locus D. (you can work out genetic distance by dividing the genetic distance by the physical distance- related but there’s no direct correlation between the two )
• But the physical distance between the the first pair of loci is 10 Mb, and that between the second pair is 50 Mb

Question 14

What is the recombination rate

Answer 14

• Standard unit: cM/Mb (or cM Mb-1)
• A measure of recombination
  propensity per genomic length unit

Question 15

Example calculation for genetic distance

Answer 15

• Between A and B: 17cM/10Mb = 1.7cM/Mb- recombination rate is higher which makes sense because they’re closer together (not a linear correlation)
• Between C and D: 17cM/50Mb =
  0.34cM/Mb
• The average rate is higher between A and B

Question 16

Iceland case study

Answer 16

• 5,136 microsatellite markers (as genetic markers)
  – 869 individuals in 146 Icelandic families (pedigree-based)
• Were able to measure 1,257 meioses
• Obtained recombination rates by mapping the markers to the genome
  sequence (there are 3billion base pairs in the human genome, calculated the recombination rate- divided genetic distance by the physical distance)
• The total length of the sex-averaged genetic map: 3,615 cM (22
  autosomes and the X)
• Genome size ≈ 3×109 = 3,000 Mb
• Mean sex-averaged rate ≈ 1.205 cM/Mb

Question 17

Variation in recombination rate between chromosomes

Answer 17

-Shorter chromosomes tend to have high recombination rates
– E.g., the average rates of chr 21 and 22 are twice as high as those of
chr 1 and 2.
– Each bivalent usually has at least one chiasma for proper disjunction
during meiosis
- Sex-averaged recombination rates tend to be higher towards telomeres and lower at centromere-

Question 18

Also see huge variation - not specific to humans

Answer 18

• Sperm crossovers occur across the region at 0.9 cM/Mb
• The great majority (about 94%) of crossovers lie within hotspots, with 72%
  in hotspot DNA3 (narrow 1-2kb regions)
• Hotspots are not randomly distributed but fall into clusters 60–90 kb apart
• Hotspots vary considerably in peak intensity

Question 19

Myers et al. (2005; Science)

Answer 19

A human genome-wide data set with ~1.6 million SNPs
– The fine-scale recombination landscape is dominated by
recombination hotspots
– 80% of the recombination occurs in 10 to 20% of the sequence

Question 20

Kong et al., Nature, 2010

Answer 20

The Basonuclin-2 gene on chromosome 9
* Recombinations in this region are dominated by those resulting from male
meiosis.

Males and females are recombing at different extents- females aren’t recombining huge amounts

Whereas there’s a lot of recombination in males- can see these big hotspots

Males and females- very striking difference in recombination.

No recombination is happening when eggs are produced in females

Question 21

Recombination variation on chromosomes in males and females

Answer 21

the location of these hotspots differs in males and females

Recombination is higher in females but females recombine evenly across the whole chromosome

In males there’s a really strong effect of physical location, so they recombine more highly towards the ends of the chromosome than the centromere in the middle - don’t know why this variation exists

Question 22

Humans versus chimps (Auton et al. 2012; Science)

Answer 22

Overall genome-wide divergence = 1.23%
– The genomes of 10 Western chimpanzees
At the level of entire chromosomes, recombination rates are very similar in
humans and chimpanzees, with the exception of chromosome 2
– Human chromosome 2 which originated from a telomeric fusion of chimp
chr2a and chr2b in the human ancestral lineage
- No evidence of sharing of hotspots between species

Question 23

What determines the location of a hotspot

Answer 23

Search for specific sequence features (motifs) in hotspots

Recombination is important for determining the efficacy of selection

Question 24

Myers et al. (Nat Genet, 2008)

Answer 24

This study mapped a recombination rate across lots of different individuals

They Identified 22,599 autosomal and 608 X-linked hotspots
– They found a A degenerate 13-mer CCNCCNTNNCCNC highly enriched in recombination
hotspots
– 41% (±1.4%) of all human hotspots is determined by the
presence of the motif- plays an important role in the determination of these hotspots

Question 25

Myers et al. (Science, 2010)

Answer 25

Hotspots aren’t conserved between humans and chimps

22 loci orthologous between humans and chimps
– Hotspots in the human orthologues
– The 13-mer hotspot motif exists in both species at these loci
– The 13-mer does not recruit hotspots in chimps

They searched for genes that interacted with this 13- base pair motif and what they found was a zinc finger protein that could bind to the motif

A computational algorithm was used to search for zinc finger proteins in the
human genome that bind specificity for the 13-mer motif and match the
degeneracy pattern
– PRDM9 was predicted to be a highly probably candidate

Question 26

Oliver et al. (2009, PLoS Genet)

Answer 26

Rapid rate of functional sequence divergence between chimp
and human exceeds neutral expectations by 10x
– The rapid evolution of these PRDM9 zinc finger coding sequences is exceptional, with a nucleotide divergence of
7.1% – over fivefold higher than the overall genome-wide
divergence (1.23%)
– Amino acids positions that contact DNA bases have undergone frequent recurrent episodes of positive selection
Humans and chimpanzees don’t share hotspots because of the rapid rate of evolution of the PMRD9

Question 27

Losses of PRDM9 across vertebrates

Answer 27

Investigated 225 species of invertebrates to see whether there was the presence of PMRD9- found that even distantly related species have genes that produce the equivilent of this protein - broadly conserved gene even though its evolving very quickly - some species have lost PMRD9 completely and in other species bits of it have been lost/ deleted.

There has been a minimum of 6 partial and 3 converted losses - have important consequences for variation in recombination rate - if there are losses there might be different motifs in the species (hotspots will change- big variation in this species might be mediated by this rapidly evolving protein PMDR9