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