Genetic isolation in human populations

Genetic isolation in human populations part one: theory

“A population can be considered in genetic isolation if maintains itself in a relatively constant environment, if its gene pool remains unadulterated from the outside and evolves under the influence of the natural selection, mutation and drift and other stochastic processes” (Roberts, 1992)

Reproductive isolation drosophila pachea larus fuscus larus argentatus drosophila melanogaster ecological temporalbehavioral

euhadra quaesita – euhadra aomoriensishaliotis (5 specie) Reproductive isolation mechanicalgametic

Post-zygotic barriers reduced survival of hybrids reduced fertility of hybrids non-viable hybrids euhadra quaesita – euhadra aomoriensishaliotis (5 specie) Reproductive isolation mechanicalgametic

1928: Sten Wahlund takes into consideration geographical barriers as factors of within-population subdivision Geographical isolation

1928: Sten Wahlund takes into consideration geographical barriers as factors of within-population subdivision

1928: Sten Wahlund takes into consideration geographical barriers as factors of within-population subdivision... GENE FLOW BARRIERS! Geographical isolation

1928: Sten Wahlund takes into consideration geographical barriers as factors of within-population subdivision... GENE FLOW BARRIERS! … followed by GENETIC DRIFT Geographic isolation: geographical barriers prevent free genetic exchange among populations of the same species (Mayr 1963) Geographical isolation

A thorough understanding of the genetic structure of human populations cannot be achieved without identifying groups which depart from common backgrounds Genetic isolation in humans is often hypothesized to be associated with cultural diversity, which provides an opportunity to test the relations between cultural factors and population genetic structure Studies of human genetic isolates have proven to be extremely useful for mapping genes for rare monogenic disorders The importance of studying genetic isolation in human populations

The complexity of genetic isolation in human populations migratory patterns cultural, technological and scientific progress

Cultural Isolation Geographical isolation Isolation in human populations

Cultural isolation Language Mating strategies Social structures Ethnicity

Isolation in human populations Geographical isolation Islands Mountainous environments

Human isolates 1.tribal populations of presumably very ancient origin which since they emerged as distinct entities have had relatively little biological exchange with other similar groups; 2.relatively large ethnic groups that are sub sample of an established, national population formed by the coalescence of tribes in a period of two-four thousand years; 3.small populations that show a slow demographic expansion and minimum immigrant rate: the allelic profile about these populations is largely influenced by the case. (Neel, 1992) Isolation in human populations

1.offshoot populations in areas geographically distant from the main population; 2.communities isolated on account of a particular factor; 3.unique ethnic communities; 4.primitive populations of hunter-gatherers still living under conditions comparable with those during prehistoric times. (Yanase, 1992) Human isolates Isolation in human populations

Isolates originate as a consequence of some type of bottlenecks and remain in isolation (cultural, geographical or both) for many generations (Arcos-Burgos & Muenke, 2002) Isolates show more inbreeding and genetic drift of a wider population that cause a reduction of effective population size and genetic complexity in presence of reduced immigration rate (Peltonen et al., 2000; Varilo & Peltonen, 2004) Human isolates Isolation in human populations

Break-up of isolates Improvements of living conditions (welfare state policies, medical progress) End of Second World War 50s: the demografic revolution! Increasing of birth rates and decreasing of mortality rates Weakening of traditional endogamous mating strategies (Vogel, 1992) Isolation in human populations

Indirect approach Direct approach Intra- and inter-population genetic variation analysis Gene flow estimates Using unilinear (mtDNA and Y chromosome) and autosomal markers Detecting genetic isolation in human populations

Both direct and indirect Indirect approach Detecting genetic isolation in human populations

Indirect approach Detecting genetic isolation in human populations

Evaluation of genetic isolation analysing among and within group diversity levels Confounding factors: reduced sample size purifying selection differential admixture

Both indirect and direct approach Detecting genetic isolation in human populations Szekely n=178 Csango n=182

Both indirect and direct approach SZEKELY CSANGO ind./gen ind./gen. Detecting genetic isolation in human populations

Indirect approach Detecting genetic isolation in human populations 1310 campioni Illumina Human370CNV SNPs e CNV

Ancestry proportions of the studied 1008 individuals from 39 European and Near-Eastern populations (including the six FVG village populations) as revealed by the ADMIXTURE program with K=2 to K=10. A stacked column of the K proportions represents each individual, with fractions indicated on the y axis. From all non-FVG populations a subset of 24 randomly drawn individuals (if applicable) was used. Detecting genetic isolation in human populations

Genetic isolation in human populations part two: practice

Detecting genetic isolation in human populations 193 campioni mtDNA HVR 1 e 2

Detecting genetic isolation in human populations

Direct approach: gene flow estimates Isolation with Migration Model Priors Settings: -q (effective population size) -t (splitting time) -m (migration rate) Detecting genetic isolation in human populations

Isolate Neighboring Open Population Wide Open Population 0.71 copies/year 0.35 copies/year 0.42 copies/year copies/year

Detecting genetic isolation in human populations

610 campioni 17 STR e 50 SNPs

Detecting genetic isolation in human populations Y Chromosome Haplotype diversity of Alpine populations values based on 15 STRs

Detecting genetic isolation in human populations Multi-Dimensional scaling plot of Fst genetic distances (15 STRs; stress value=0.128)

Detecting genetic isolation in human populations Multi-Dimensional scaling plot of Fst genetic distances (15 STRs; stress value=0.128)

Detecting genetic isolation in human populations Analysis of molecular variance (AMOVA) within groups under study based on mtDNA sequences (hypervariable region 1) and 15 Y chromosome STRs. GroupPopulationsWithin groupp value EuropeAUS-CRO-POL-POR-SER-SPA Northern ItalyBRE-COM-CUN-SPE-TRE-VIC

Detecting genetic isolation in human populations Three main genetic patterns Italian speaking group Higher HD Lower inta-group diversity Low differentiation from surrounding genetic background German speaking group Lower HD Higher inta-group diversity High differentiation from surrounding genetic background Ladin speaking group Intermidiate HD Itermidiate inta-group diversity Itermidiate differentiation from surrounding genetic background

Detecting genetic isolation in human populations GroupPopulationsMean census size Within group diversityp value German speakersLES-LUS-SAP-SAU-TIM Linguistic islandsSAP-SAU-TIM CimbriansLES-LUS Italian speakers ADI-FER-FIE-GIU-NON- PRI-SOL Eastern TrentinoFER-FIE-PRI Western TrentinoGIU-NON-SOL Ladin speakersBAD-FAS-GAR Inverse correlation between within group diversity and census size Could our observations be the result of differences in the long–term effective size among groups, without any substantial effect of genetic isolation?

Detecting genetic isolation in human populations

The distributions obtained are incompatible (Ladins and Italians) or only marginally compatible (German speakers) with the observed Fst values. A scenario combining the effects of founding group size and continued genetic isolation seems, therefore, to provide the best explanation for the observed level of within group differentiation detected in both geographic and geographic/linguistic isolates

Genetic diversity among human populations Any role for cultural factors?

Two case studies 1. Local Ethnicity in Eastern Alps 2. “Geschlossener Hof” in Tyrolean populations Detecting genetic isolation in human populations

1. Local Ethnicity in Eastern Alps Genetic diversity among human populations: cultural factors

2. “Geschlossener Hof” in Tyrolean populations

Genetic diversity among human populations: cultural factors