Evidence of Selection on Circadian Regulation of the Immune System in Ancient Iberia Open Access

Abstract

Various components of the immune system oscillate in a time-of-day dependent manner, a phenomenon that has been attributed to the circadian clock. Circadian regulation of the immune system is one of many mechanisms that allows the gradation of immune responses, likely timing immune robusticity to meet the demands of infection while limiting damage to tissues. Increased exposure to pathogens as human settlements adopted Bronze age technologies likely placed a distinct selective pressure on this regulatory system. Utilizing genome-wide SNP data of ancient Iberians during the Bronze age shift, this study aims to identify evidence of selection upon genes participating in immune system/circadian rhythm crosstalk. Specifically, allele frequencies at these sites of interest are compared before and after the historical shift through two differentiation statistics, FST and DAnc. Of six significantly differentiated SNPs, five observed frequencies fail to be explained by a Wright-Fisher model of evolution under genetic drift. The Wright-Fisher models are re-implemented with varying selection coefficients to determine the average strength of selection acting at these loci. Signals of positive selection are reported for two Class II MHC variants, suggesting potential constraints on foreign antigen presentation. Signals of negative selection are reported for a regulatory variant of KIR3DL2 known to decrease susceptibility to autoimmunity. Notably, this thesis reveals likely selection on two variants, one of the clock gene BMAL1 and the other of chemokine receptor CCR7, known to be involved in the time-of-day dependent trafficking of lymphocytes to the lymph nodes. Future studies into the functional relationship between these two variants may provide insight into disease phenotypes correlated with differences in the timing of peak T-cell activation. Overall, this thesis demonstrates how archaeological data and advancements in ancient DNA sequencing can complement human niche construction hypotheses during times of large-scale cultural change, helping us understand how cultural environments can be embodied in our genomes and identify potential therapeutic targets. 

Table of Contents

Introduction.....................................................................................................1

Literature Review.............................................................................................4

A. Circadian clocks carry temporal information................................................4

B. Autonomous circadian clocks exist in cells of the immune system.......................8

C. Pathogens affect circadian control of immunity.............................................15

D. Hypotheses regarding evolution in the human immune system...........................28

E. Previous aDNA studies into immune system regulation....................................24

F. Archaeology of the Iberian Peninsula.........................................................31

Methods........................................................................................................36

A. Description of dataset...........................................................................36

B. Establishing genetic continuity in temporally separated populations.....................37

C. Identifying candidate variants for selection simulation....................................37

D. Establishing evolutionary scenarios using SLiM3..........................................38

Results.........................................................................................................40

A. Mid-to-late Neolithic and Bronze age Iberia form a single continuous population.....40

B. One circadian rhythm and five immune system polymorphisms are highly differentiated.........................................................................................41

C. Selection likely explains differentiation of HLA, KIR3DL, and CCR7 variants.........42

Discussion.....................................................................................................44

A. Selection on immune system/circadian rhythm variants is a window to the past.......44

B. Future directions.................................................................................49

Conclusion....................................................................................................52

References....................................................................................................54

Figures

1: Levels of peripheral clock entrainment..................................................................7

2: Simplified stages of information transfer during recruitment of adaptive immune response...10

3: Pathogens alter information transfer in the immune system through disruption of the circadian clock............................................................................................................14

4: Inferences of natural selection require fewer assumptions about evolutionary trajectories when using a time transect...........................................................................................24

5: Geographic distribution of collection sites in the Iberian Peninsula (Olalde et al, 2019, Figure 1A)...............................................................................................................34

6: SLiMgui interface and Eidos script for a neutral selection scenario................................39

7: PCA plot reveals tight clustering of MLN and BA single genomes in PCA space...............41

8: Expected distributions of BA allele frequencies under a drift and selection scenario...........43

Tables

1: Input Parameters for SLiM3 Neutral Selection Simulation..........................................39

2: Significantly Differentiated Immune System and Clock Variants during the MLN-BA Shift..42

3: Potential Ranges of Selection Coefficient in Purifying and Positive Selection Models.........44

Equations

1: The Fisher-Wright model of neutral evolution as the transition matrix of a Markov chain.....25

2: The fixation index, Fst, is a theoretical measurement of population differentiation due to genetic substructure..........................................................................................27

3: DAnc is a branching statistic that measures population differentiation for a given polymorphism................................................................................................28

4: DAnc can be used to infer extreme allele differentiation along a time transect.................28 

About this Honors Thesis

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School	Emory College
Department	Anthropology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Anthropology, Archaeology Anthropology, Physical Biology, Evolution and Development
Keyword	circadian rhythm natural selection simulation iberian peninsula bronze age neolithic immune system regulation snps
Committee Chair / Thesis Advisor	John Lindo, Emory University
Committee Members	Dietrich Stout, Emory University Michal Arbilly, Emory University

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