a novel fine-scale human recombination map reveals sex ...€¦ · map reveals sex differences...
TRANSCRIPT
A novel f ine-scale human recombinat ion map reveals sex dif ferences
Chenling Antelope, Graham Coop
University of California, Davis
Recombinat ion is an Important Process
Recombinat ion is a fundamental cel lular and molecular process
- Chromosomal segregation
- Hotspots (PRDM9)
Recombinat ion is a fundamental genet ic process
- Increase Genetic Variance
- Breaks up epistatic interactions
Sexual Dimorphism in Human Meiosis
MaleFemale
Sexual Dimorphism in Human Recombinat ion Rate
Number of crossovers per individual in the AGRE (Aut ism Genet ic Resource Exchange) pedigree
Fledel-Alon, A. et al. Variation in human recombination rates and its genetic determinants. PloS one 6, e20321 (2011).Fledel-Alon, A. et al. Variation in human recombination rates and its genetic determinants. PloS one 6, e20321 (2011).
Chromosomal Position Mb
Fine Scale Recombinat ion Rate
Sequence Specif icity -> Similar
Fine Scale Chromatin State -> Dif ferent
1. New method for inferring sex-specif ic f ine scale recombination rate
2. Amount of f ine scale recombination rate sharing
3. Fine-scale recombination rate around genes (as a proxy for chromatin state)
4. Interaction between large scale and f ine scale recombination variation
3774 Females, 3781 Males
Fledel-Alon, A. et al. Variation in human recombination rates and its genetic determinants. PloS one 6, e20321 (2011).Fledel-Alon, A. et al. Variation in human recombination rates and its genetic determinants. PloS one 6, e20321 (2011).
41745 Females, 30184 Males
Kong, A, Thorleifsson, G, Frigge, ML & Masson, G. Common and low-frequency variants associated with genome-wide recombination rate. Nature ? (2014).
Data & Method
Kong, A, Thorleifsson, G, Gudbjartsson, DF & Masson, G. Nature (2010).
We apply a Gibbs Sampler Method i terat ively in order to estimate the posit ion of of a recombinat ion event and recombinat ion rates in genomic windows simul taneously.
Male rate and female rate estimated using the same method independently.
Hotspot Sharing
Mal
e C
ateg
ory
Female Category
Hotspots are defined by the fold increase of a 10kb window compared to the 1Mb window (not including target window) around it.
Mal
e R
ecom
bin
atio
n In
tens
ity
Female Recombination Intensity
Hotspot Sharing
Mal
e C
ateg
ory
Female Recombination Intensity
Mal
e R
ecom
bin
atio
n In
tens
ity
Hotspot Sharing
Mal
e C
ateg
ory
Female CategoryFemale Recombination EnrichmentFemale Recombination EnrichmentMale Recombination Intensity
Fem
ale
Rec
omb
inat
ion
Inte
nsi
ty
Recombinat ion Rate Along Transcript
Female Male
Rec
omb
inat
ion
Rat
e cM
/Mb
5'U
TR1
st E
xon
1st
Intr
on2
nd E
xon
2nd
Intr
on3
rd E
xon
3rd
Intr
on4
th E
xon
4th
Intr
on5
th E
xon
5th
Intr
on6
th E
xon
6th
Intr
on7
th E
xon
7th
Intr
on8
th E
xon
8th
Intr
on9
th E
xon
9th
Intr
on1
0th
Exo
n1
0th
Intr
on3
'UTR
5'U
TR1
st E
xon
1st
Intr
on2
nd E
xon
2nd
Intr
on3
rd E
xon
3rd
Intr
on4
th E
xon
4th
Intr
on5
th E
xon
5th
Intr
on6
th E
xon
6th
Intr
on7
th E
xon
7th
Intr
on8
th E
xon
8th
Intr
on9
th E
xon
9th
Intr
on1
0th
Exo
n1
0th
Intr
on3
'UTR
Gold: Exon
Green: Int ron
Red: 5'UTR
Blue: 3'UTR
Distance (bp) from Transcription Start Site
Rec
omb
inat
ion
Rat
e cM
/Mb
Recombinat ion Rate Near Transcript ion Start Site
0.5
21
1.5
Variat ion Along Chromosome Arm
Distance (bp) from Transcription Start Site
Female 1/5 of Chromosome
Closest to Centromere
Rec
omb
inat
ion
Rat
e cM
/Mb
Variat ion Along Chromosome Arm0
.3-2
.0 c
M/M
b0
.7-2
.4 c
M/M
b
TelomericCentromeric
Conclusions:
- ~50% of recombination hotspots are shared.
Conclusions:
- ~50% of recombination hotspots are shared.
- Male and female rate are correlated in shared hotspots.
Conclusions:
- ~50% of recombination hotspots are shared.
- Male and female rate are correlated in shared hotspots.
- Recombination rate covaries with sequence function.
Conclusions:
- ~50% of recombination hotspots are shared.
- Male and female rate are correlated in shared hotspots.
- Recombination rate covaries with sequence function.
- Fine scale and broad scale recombination rate variation interact with each
other.
Conclusions:
- ~50% of recombination hotspots are shared.
- Male and female rate are correlated in shared hotspots.
- Recombination rate covaries with sequence function.
- Fine scale and broad scale recombination rate variation interact with each
other.
Further quest ions:
- What mechanisms are causing the recombination patterns we are seeing?
Thanks to
Coop Lab
Mol ly Przeworski
I will be moving to UC Berkeley next year to start my phD in the Computational Biology Graduate Group!
Hotspot Sharing%
Shar
ed
>1
>2
>3
>4
>6
>8
>1
2
>1
9
>2
6
>3
9
>5
8
>1
>2
>3
>4
>6
>8
>1
2
>1
9
>2
6
>3
9
>5
8
Simulat ion Using HapMap
Chromosomal Position Kb (Starting Chr1 99981 Kb)
Rec
omb
inat
ion
Rat
e cM
/Mb
Recombinat ion Rate in Annotat ion Categories R
ecom
bin
atio
n R
ate
cM/M
b
10 K rate / 1M background (Male)
Female Male
Hotspot Counts
187K 9998 4906 2867 2929 1492 1350 646 268 104 29 9 6
14K 2382 1335 826 776 404 344 52 14 1 0 0166
6243 1211 837 542 618 332 305 136 51 17 3 1 0
3207 677 491 400 552 317 278 55 21 2 0 0148
3261 625 582 484 756 449 525 265 85 25 7 0 0
1472 260 278 256 386 306 343 102 33 5 0 0244
1240 188 217 226 399 344 482 411 192 59 6 0 0
521 72 85 88 168 179 285 214 95 15 0 0349
183 13 15 14 37 48 100 130 115 20 1 0152
71 8 3 5 10 8 21 31 50 53 29 1 0
25 1 0 0 0 1 3 7 10 11 1 04
5 0 0 0 2 0 0 0 0 0 3 1 0
2 0 0 0 0 0 0 0 0 0 0 00
10
K r
ate
/ 1
M b
ackg
roun
d (F
emal
e)
10 K rate / 1M background (Male)
Correlat ion Between Expression and Recombinat ionTr
ansc
rip
t R
ecom
bin
atio
n R
ate
cM/M
b
Rank in Expression
Slope -5.15e-3
P value 2.58e-2
Slope -1.087e-2
P value 2.53e-06