Genetic Geography and Population Structure Oscar Lao - - PowerPoint PPT Presentation

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Genetic Geography and Population Structure Oscar Lao oscar.lao@cnag.crg.eu 16.11.2017 GENETIC SIMILARITY IN HUMANS All our social policies are based on the fact that their intelligence is the same as ours whereas all the testing

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Genetic Geography and Population Structure Oscar Lao

  • scar.lao@cnag.crg.eu

16.11.2017

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“All our social policies are based on the fact that their intelligence is the same as

  • urs — whereas all the

testing says not really,”

GENETIC SIMILARITY IN HUMANS

(FRO FROM A GE GENETIC POI OINT OF OF VI VIEW) GENE NETI TICALLY Y SI SIMI MILAR

HUMA UMANS

HUM HUMANS

Som

  • me sc

scie ientists

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a) c) b) d)

GUESS THE GENETIC ANCESTRY

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a) c) b) d)

GUESS THE GENETIC ANCESTRY (and be wrong!)

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Erased recent historical memory & Forensics

  • Colonization of Americas &

slavery

  • Romani Diaspora
  • Australian’s Stolen Children
  • Recent migrations
  • Bombing attacks
  • …

Tiger Woods calls himself "Cablinasian“

Caucasian, Black, American Indian, Asian

GUESS THE GENETIC ANCESTRY (if you dare!)

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  • Why is there population substructure?
  • How much population substructure in the human

genome? (Do races exist?)

  • How to detect population substructure? Available

methods & caveats

  • Some examples of population substructure
  • Final conclusions & suggestions

TOPICS TO BE DISCUSSED

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1) WHY IS THERE POPULATION SUBSTRUCTURE

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Mutation Recombination Selection Genetic drift Migration/Isolation Evolutionary parameters Population Sample Stochastic Evolutionary process

ATGCATGGGCTATTGGACCT ATGGATGGGCTATTGCACCT ATGCATGGGCAATTGCACCT ATGCATGGGCAATTGGACCT ATGGATGGGCTATTGCACCT

Stochastic Sampling process Inference

“Demographic” processes

METASOURCES OF GENETIC VARIATION

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Van Oven and Lao International Encyclopedia of Social and Behavioral Sciences 2nd Edition

  • Physical factors
  • Distance
  • Barriers
  • …
  • Cultural factors
  • Language
  • Religion
  • …

METASOURCES OF GENETIC VARIATION DEMOGRAPHY & POPULATION HISTORY

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Nature Reviews Genetics 13, 745-753 (October 2012)

METASOURCES OF GENETIC VARIATION DEMOGRAPHY & POPULATION HISTORY

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Green et al. 2010

~5% of Melanesian genome derive from Denisovans ~2.5% of non-African genomes derive from Neanderthals

Reich et al. 2010

METASOURCES OF GENETIC VARIATION DEMOGRAPHY & POPULATION HISTORY

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Mutation Recombination Selection Genetic drift Migration/Isolation Evolutionary parameters Population Sample Stochastic Evolutionary process

ATGCATGGGCTATTGGACCT ATGGATGGGCTATTGCACCT ATGCATGGGCAATTGCACCT ATGCATGGGCAATTGGACCT ATGGATGGGCTATTGCACCT

Stochastic Sampling process Inference

“Selective” processes

METASOURCES OF GENETIC VARIATION

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  • Adaptation to new environments
  • Food production – new diets
  • Population increase – new diseases

METASOURCES OF GENETIC VARIATION SELECTION

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HUMAN CULTURAL EVOLUTION

https://es.pinterest.com/

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Fan et al 2016

METASOURCES OF GENETIC VARIATION SELECTION

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  • Humans are

mammals

  • We consume milk

when we are babies

  • This is done thanks to

the enzyme LACTASE (LCT)

  • Milk is a complete

source of energy and proteins + defense METASOURCES OF GENETIC VARIATION SELECTION IN LCT

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  • The capacity to

metabolize lactose disappears at adult age in almost all the mammal species

  • LCT gene is not

expressed anymore because there is no more maternal milk to drink

  • Or is it not?

METASOURCES OF GENETIC VARIATION SELECTION IN LCT

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  • How to recognize if

you are lactose intolerant?

– Can be asymptomatic – Gas production – Diarrhea – Related to diseases such as inflammatory bowel disease – Usually lactose intolerant people “don’t like milk”

METASOURCES OF GENETIC VARIATION SELECTION IN LCT

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METASOURCES OF GENETIC VARIATION SELECTION IN LCT

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Yang et al (2012) Nature Genetics

METASOURCES OF GENETIC VARIATION SELECTION IN LCT

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METASOURCES OF GENETIC VARIATION SELECTION IN LCT

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CONSEQUENCES OF HUMAN EVOLUTION EVOLUTIONARY MISMATCH

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CONSEQUENCES OF HUMAN EVOLUTION EVOLUTIONARY MISMATCH

Stearns and Medzhitov, 2016

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  • Impairing disease & Fitness

Faraone, et al., 2015. Nat. Rev. Dis. Primers

EVOLUTIONARY MISMATCH ADHD

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PREVALENCE ~2.5% HERETABILITY (76%) SYMPTOMS

  • High energy
  • S pon tane ity
  • R is k - t a k i n g
  • I n n o v a t i o n
  • C r e a t i v i t y
  • …

ADHD… AN EVOLUTIONARY MISMATCH?

Theories:

  • Hunter-farmer theory
  • Response-readiness theory
  • Wader theory
  • Fighter theory

High motor activity Impulsive Hipervigilant Focused attention Low motor activity Non-impulsive

Adapted from Jensen et al., 1997. JAACAP

PAST ENVIRONMENT RESPONSE-READY CURRENT ENVIRONMENT PROBLEM-SOLVING IMPAIRING

EVOLUTIONARY MISMATCH ADHD

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Fu et al., 2016 dataset (initially 51 genomes) Lazaridis et al., 2016 dataset (initially 281 genomes)

Demontis et al., 2017

EVOLUTIONARY MISMATCH ADHD

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LAZARIDIS dataset

  • R = -0.26
  • P value = 1.37·10-3

FU dataset (robust regression)

  • R = -0.44
  • P value = 0.04

Esteller et al, in preparation

  • P value neutrality = 3·10-4
  • P value neutrality = 0.019

 ADHD risk alleles in ancient samples seem to be have been negatively shaped by selection.

EVOLUTIONARY MISMATCH ADHD

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SDS statistic (Field et al., 2016. Science)

Spearman correlation:

ρobserved = 0.198 P value = 0.0217  There is evidence of recent polygenic adaptation in the alleles that are protective for ADHD at a genomic level.

Pvalue association ADHD SDS (risk allele ADHD)

Esteller et al, in preparation

EVOLUTIONARY MISMATCH ADHD

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2) DO RACES EXIST?

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Barbujani, Current Genomics

Table 1. Lists of Human Races Author Races proposed

  • No. of races

Races proposed Linnaeus (1735) 6 Europaeus, Asiaticus, Afer, Americanus, Ferus, Monstruosus Buffon (1749) 6 Laplander, Tartar, South Asian, European, Ethiopian, American Blumenbach (1795) 5 Caucasian, Mongolian, Ethiopian, American, Malay Cuvier (1828) 3 Caucasoid, Negroid, Mongoloid Deniker (1900) 29 Weinert (1935) 17 Von Eickstedt (1937) 38 Biasutti (1959) 53 Coon (1962) 5 Congoid, Capoid, Caucasoid, Mongoloid, Australoid US Office of Management and Budget (1997) 5 African-American, White, American Indian or Alaska Native, Asian, Native Hawaiian or Pacific Islander Risch et al. (2002) Fig. 1 5 African, Caucasian, Pacific islanders, East Asian, Native American Risch et al. (2002) Table 3 5 African Americans, Caucasians, Hispanic Americans, East Asians, Native Americans

FACTS: TOO MANY CLASSIFICATIONS

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http://theadvancedapes.com/genetic-origins/

FACTS: NOT TOO MUCH VARIATION

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Pagani et al, 2016, Nature Mallick et al, 2016, Nature De Manuel et al, 2016 Science

FACTS: NOT TOO MUCH VARIATION

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Classifying individuals according to continental

  • rigin is not a good idea

Richard Lewontin

Lewontin, R "The Apportionment of Human Diversity," Evolutionary Biology, vol. 6 (1972) pp. 391-398

FACTS: NOT TOO MUCH VARIATION AMONG POPULATIONS

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Using data from G3 (Bethesda). 2013 May 20;3(5):891-907

FACTS: GENETIC VARIATION FOLLOWS A GRADIENT

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Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15942-7 Henn 2015 Using data from G3 (Bethesda). 2013 May 20;3(5):891-907

FACTS: GENETIC VARIATION FOLLOWS A GRADIENT

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Jay et al, 2012 MBE

FACTS: GENETIC VARIATION FOLLOWS A GRADIENT

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Maceda and Lao, in preparation

FACTS: GENETIC VARIATION FOLLOWS A GRADIENT

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3) HOW TO DETECT POPULATION SUBSTRUCTURE?

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snp

1

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2

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3

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4

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5

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6

… snp

n

I1 1 2 1 1 I2 2 2 1 I3 1 1 2 2 I4 1 2 1 2 I5 1 1 2 1 2 1 … Im 2 1 1 2 2

AA = 0 AB = 1 BB = 2

K = 4

α1 α2 α3 α4 Dim1 Dim2 Model-based ancestry estimation Algorithmic ancestry estimation Van Oven and Lao International Encyclopedia of Social and Behavioral Sciences 2nd Edition

METHODS FOR INFERRING POPULATION SUBSTRUCTURE

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snp

1

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2

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… snp

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I1 1 2 1 1 I2 2 2 1 I3 1 1 2 2 I4 1 2 1 2 I5 1 1 2 1 2 1 … Im 2 1 1 2 2

AA = 0 AB = 1 BB = 2 Spatial ancestry estimation Wollstein and Lao, under review

METHODS FOR INFERRING POPULATION SUBSTRUCTURE

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Wollstein and Lao, 2015 Investigative Genetics

METHODS FOR INFERRING POPULATION SUBSTRUCTURE

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Wollstein and Lao 2015

METHODS FOR INFERRING POPULATION SUBSTRUCTURE

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4) SOME EXAMPLES

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Novembre et al 2007 Nature Lao et al 2007 Current Biology Yang et al (2012) Nature Genetics

EXAMPLE I:POPULATION SUBSTRUCTURE IN EUROPE

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EXAMPLE I:POPULATION SUBSTRUCTURE IN EUROPE: DATA MASSAGE

“In particular, the Catalans have more genetic proximity with the French than with the Spanish; more with the Italians than with the Portuguese; and a little with the Swiss. While the Spanish have more proximity with the Portuguese than with the Catalans and very little with the French. Curious...”

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Mendizabal and Lao et al, Current Biology 2012

EXAMPLE II:POPULATION SUBSTRUCTURE IN EUROPE: THE ROMANI

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Mendizabal and Lao et al, Current Biology 2012 Philip IV of Spain, who declared that Romani did not exist (they are Spanish people who had made up an artificial language)

EXAMPLE II:POPULATION SUBSTRUCTURE IN EUROPE: THE ROMANI

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Mendizabal and Lao et al, Current Biology 2012

EXAMPLE II:POPULATION SUBSTRUCTURE IN EUROPE: THE ROMANI

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Mendizabal and Lao et al, Current Biology 2012

EXAMPLE II:POPULATION SUBSTRUCTURE IN EUROPE: THE ROMANI

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Mendizabal and Lao et al, Current Biology 2012

EXAMPLE II:POPULATION SUBSTRUCTURE IN EUROPE: THE ROMANI

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Mendizabal and Lao et al, Current Biology 2012

EXAMPLE II:POPULATION SUBSTRUCTURE IN EUROPE: THE ROMANI

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Sapfo-Malaspina et al, 2016 Nature

EXAMPLE III:POPULATION SUBSTRUCTURE IN ABORIGINAL AUSTRALIA

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Sapfo-Malaspina et al, 2016 Nature

EXAMPLE III:POPULATION SUBSTRUCTURE IN ABORIGINAL AUSTRALIA

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80 100 120 140 160 180 10 20 30 40 time since first contact with Europeans mean(generations since first contact) BDV CAI ENY NGA PIL RIV WCD WON WPA

”Australian” ”Europe” ”East Asian” ”Papuan”

Sapfo-Malaspina et al, 2016 Nature

EXAMPLE III:POPULATION SUBSTRUCTURE IN ABORIGINAL AUSTRALIA

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CONCLUSIONS

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  • Population substructure must be interpreted in

evolutionary terms

– Demographic – Selective

  • The amount of population substructure depends
  • n the genomic region we are considering

– Magnitude – Geographic distribution

  • The amount of population substructure we detect

depends

  • n

the assumptions we make

FINAL REMARKS

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  • The amount of population substructure must be

interpreted in the context of what we are studying

  • AVOID over-interpretation

FINAL REMARKS

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A “small” or “modest” amount of genetic diversity when compared with other species can be “big” when trying to detect extremely small effects

FINAL REMARKS

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Thank you very much!

  • scar.lao@cnag.crg.eu