Tracking the evolution of complex traits over space and

Iain MathiesonDepartment of Genetics

Perelman School of MedicineUniversity of Pennsylvania

mathi@upenn.edu

Tracking the evolution of complex traits over space

and time with ancient DNA

Lascaux cave paintings, France ~15,000 BCE Image: Wikipedia user “Prof Saxx”

Images:

: Wikipedia(user Kurt Stueber)

: Czekaj-Zastawny 2008L. Wojcik

: Bartosiewicz et al 2006

Reconstruction of an LBK house ~5,400 BCE

Varna man, buried ~4,500 BCE with more gold than has been found in the entire rest of the world, up to that date.Image: Raiko Krauß

The Bronze Age brings dramatic changes in lifestyle and culture

What are the genetic changes associated with these shifts?

Olalde et al. 2018, Mathieson et al. 2018, Lipson et al. 2017 Fu et al. 2016, Mathieson et al. 2015, Allentoft et al. 2014, Haak et al. 2014, & many others

Steppe Ancestry < 4500 BPEarly Farmer 8500-4500 BPHunter-gatherer 14000-5000 BPUpper Paleolithic > 14000 BP

Bramanti et al. 2009, Skoglund et al. 2012, Lazaridis et al. 2014, Haak et al. 2015Allentoft et al. 2015, Mathieson et al. 2015, Lipson et al. 2017, Olalde et al. 2018

Early Farmers~8500 BP

Steppe Ancestry~4500 BP

Lazaridis et al. 2014, Haak et al. 2015

LCT

TLR1

SLC45A2

SLC22A4

MHC

ZSCAN31

DHCR7NADSYN1GRM5 ATXN2

OAS1

CHR13:31MbHERC2

CYP1A2

14 genome-wide significant signals of selection

Mathieson et al. 2015

LCT: Lactase persistence

NADSYN1/DHCR7: Vitamin D metabolism

FADS1/2: Decreased triglyceride levels

ATXN2/SHD2B3: Associated with celiac disease, Type 1 diabetes

SLC22A4: Ergothioneine uptake, celiac disease, IBD

CYP1A1: Metabolism of exogenous substances; caffeine.

SLC45A2, GRM5: Light skin pigmentation

HERC2/OCA2: Blue eye color

TLR1/6/10: Immunity, leprosy, TB and other mycobacterial resistance

OAS1/2/3: Viral resistance; Neanderthal introgressed haplotype

ZSCAN32: Autophagy

MHC: Immunity, everything.

Diet

Pigmentation

Immunity

Adaptation to agriculture

Figure: Gil McVean

West African

NorthernEuropean

Mathieson & Mathieson 2018

Lactase persistence postdates cattle domestication

LP allele appears~6500 years ago

LP allele starts to become common ~3000 years ago

Cattle domesticated> 10,000 years ago

First evidence of dairying ~8500 years ago

FADS1 variants post-date agriculture

Agriculture in Europe~8500 years ago

Derived allele not selected Until ~3000 years ago

Mathieson & Mathieson 2018

Mathieson & Mathieson 2018

SLC22A4 selection post-date agriculture

Agriculture in Europe~8500 years ago

Derived allele not selected Until ~4000 years ago

Mathieson & Mathieson 2018

Amylase copy number pre-dates agriculture

Evolution of pigmentation

Jablonski & Chaplin 2009

VLDLR-AS1

SMARCA2

MFSD12

SNX13

HERC2

SLC24A5DDB1

TMEM138

KITLG

TYROCA2

MC1R

IRF4

BNC2

ASIP

SLC45A2FLNB

SLC24A4

DUT

SLC12A1

MYEF2

ATP8B4

SHC4 CEP152

SST-RTP2

BEND7-PRPF18

54 pigmentation-associated variants

Dan Ju

Population* Based on 1KG

Score

African 0.61East Asian 0.59South Asian 0.50European 0.36

Score: proportion of pigmentation-increasing variants

Dan Ju

Variation in pigmentation in Europe 10,000 BP

Mathieson et al. 2018

HERC2 [OCA2] Eye color–associated rs12913832

Dan Ju

Evolution of stature

Differences in genetic height among ancient populations (N=1107)

∆SP = 0.4 s.d.P = 3 × 10-12

Hunter-gatherer

Early Farmer

Steppe Ancestry

025005000750010,00012,500

Date in years BP

Nor

mal

ized

poly

geni

c he

ight

scor

e

+2

-2

0

Steppe ancestry predicts present-day height

Skoglund & Mathieson 2018

R2 = 0.64

Collaborators & Funding

PennDan Ju

Other institutionsSara Mathieson (Swarthmore)Pontus Skoglund (Crick Institute)David Reich (Harvard)Christopher Ruff (Johns Hopkins)

Questions?