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Review
. 2014 Aug 28;10(8):e1004601.
doi: 10.1371/journal.pgen.1004601. eCollection 2014 Aug.

Human social genomics

Steven W Cole  1
Affiliations
Review

Human social genomics

Steven W Cole. PLoS Genet. .

Abstract

A growing literature in human social genomics has begun to analyze how everyday life circumstances influence human gene expression. Social-environmental conditions such as urbanity, low socioeconomic status, social isolation, social threat, and low or unstable social status have been found to associate with differential expression of hundreds of gene transcripts in leukocytes and diseased tissues such as metastatic cancers. In leukocytes, diverse types of social adversity evoke a common conserved transcriptional response to adversity (CTRA) characterized by increased expression of proinflammatory genes and decreased expression of genes involved in innate antiviral responses and antibody synthesis. Mechanistic analyses have mapped the neural "social signal transduction" pathways that stimulate CTRA gene expression in response to social threat and may contribute to social gradients in health. Research has also begun to analyze the functional genomics of optimal health and thriving. Two emerging opportunities now stand to revolutionize our understanding of the everyday life of the human genome: network genomics analyses examining how systems-level capabilities emerge from groups of individual socially sensitive genomes and near-real-time transcriptional biofeedback to empirically optimize individual well-being in the context of the unique genetic, geographic, historical, developmental, and social contexts that jointly shape the transcriptional realization of our innate human genomic potential for thriving.

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Conflict of interest statement

The author has declared that no competing interests exist.

Figures

Figure 1
Figure 1. Social regulation of human gene expression.
Social environments can influence human gene expression via physicochemical processes (e.g., toxins, pollutants, and microbes) and psychological processes (e.g., experiences of threat or uncertainty) that trigger neural and endocrine responses (e.g., activation of the sympathetic nervous system). In both cases, biochemical mediators engage cellular receptor systems, which activate intracellular signal transduction pathways culminating in the activation (or repression) of transcription factors that proximally regulate the transcription of genes bearing response elements for that particular factor. The gene regulatory “wiring diagram” that maps specific biochemical signals to specific gene expression responses represents an evolved genomic program that was presumably adaptive under ancestral conditions but may have distinct maladaptive effects in the very different social environments of contemporary human life.
Figure 2
Figure 2. Social signal transduction and recursive network genomics.
(A) A simple (acyclic) social signal transduction pathway maps adverse social conditions onto activation of the conserved transcriptional response to adversity (CTRA) in leukocytes. Brain-mediated perceptions of social threat activate the sympathetic nervous system (SNS), leading to release of norepinephrine (NE) at SNS nerve terminals, activation of β-adrenergic receptors on adjacent cells, and stimulation or repression of specific transcription factors in response to the cyclic 3′-5′ adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway. β-adrenergic-responsive transcription factors induce the CTRA gene expression program by stimulating transcription of genes encoding proinflammatory cytokines and suppressing transcription of genes encoding Type I interferons and IgG antibodies. CTRA gene expression programs prepare the body to respond to wounding injury and bacterial infections but may promote chronic illnesses such as cardiovascular disease (CVD), Alzheimer disease (AD), Type II diabetes (T2D), and metastatic cancer while undermining host resistance to virally mediated infectious diseases (ID). (B) Superimposed effects of reciprocal endogenous and exogenous recursive feedback on the social signal transduction pathway can propagate the impact of a transient adverse environmental shock. In this system, a transient environmental threat activates the core social signal transduction pathway to stimulate transcription of proinflammatory cytokine genes, as part of the CTRA. Arc 1 shows an endogenous biological feedback loop in which the proinflammatory gene products signal the brain to activate a programmed set of sickness behaviors that include reduced social motivation, fatigue, anhedonia, and negative emotional states. Arc 2 shows how the resulting reductions in individual social behavior and altered social niche selection evoke less supportive and more hostile responses from the surrounding social network and thereby create a more adverse social environment. Effects of the exogenous social recursion loop (Arc 2) are propagated via the core social signal transduction cascade into continued CTRA activation and continued endogenous biological recursion (Arc 1). Reciprocating feedback may thus maintain the system in a new dynamic equilibrium that maintains altered endogenous inflammation and exogenous social influence long after the initiating transient shock has passed. Similar recursive feedback can occur at every level of the social signal transduction cascade, resulting in complex systems dynamics that can trigger persistent sequelae such as PTSD and biological embedding of early life social conditions without requiring any durable genomic modification (e.g., mutation or epigenetic marking). Abbreviations: CHD, coronary heart disease; CNS (central nervous system); IRF, interferon regulatory factor.
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