Epigenetic this, epigenetic that: comparing two digital humanities methods for analyzing a slippery scientific term

Abstract

We compared two digital humanities methods in the analysis of a contested scientific term. “Epigenetics” is as enigmatic as it is popular. Some authors argue that its meaning has diluted over time as this term has come to describe a widening range of entities and mechanisms (Haig, International Journal of Epidemiology 41:13–16, 2012). Others propose both a Waddingtonian “broad sense” and a mechanistic “narrow sense” definition to capture its various scientific uses (Stotz and Griffiths, History and Philosophy of the Life Sciences 38:22, 2016). We evaluated these proposals by first replicating a recent analysis by (Linquist and Fullerton, Theoretical Medicine and Bioethics 42:137–154, 2021). We analyzed the 1100 most frequently cited abstracts on epigenetics across four disciplines: proximal biology, biomedicine, general biology, and evolution. Each abstract was coded for its heritability commitments (if any) and functional interpretation. A second study applied LDA topic modelling to the same corpus, thus providing a useful methodological comparison. The two methods converged on a discipline-relative ambiguity. Within such disciplines as biomedicine or molecular biology that focus on proximate mechanisms, “epigenetic(s)” refers to a range of molecular structures while specifying nothing in particular about their heritability. This proximal conception was primarily associated with the functions of gene regulation and disease. In contrast, a second relatively uncommon sense of “epigenetic(s)” is restricted to a small proportion of evolutionary abstracts. It refers to many of the same molecular structures, but regards them as trans-generationally inherited and associated with adaptive phenotypic plasticity. This finding underscores the benefit of digital tools in complementing traditional conceptual analysis. Philosophers should be cautious not to conflate the relatively uncommon evolutionary sense of epigenetics with the more widely used proximal conception.

Appendices

Appendix: Word lists and consensus labels for topic models

A total of eight topic models were generated in this study. For each of four disciplines (General biology, biomedicine, proximal biology, and evolutionary biology) both an earlier model (1990–2005) and a more recent model (2005–2019) were generated using using the Latent Dirichlet Allocation (LDA) (Blei et al., 2003) in the Python package Gensim (Rehurek & Sojka, 2011), with a lambda setting of 0.5. Below are the top 30 words in each topic for each of the eight models. See also the labels assigned by the three co-authors to topics for which we could reach consensus.

A: General biology 1990–2004

Topic #/label	% corpus	Word list
(1) The epigenetic regulation of genes	17.9%	Transcription, regulation, expression, involve, antisense, epigenetic, suggest, protein, mutant, mechanism, RNA, role, gene, silence, act, recently, implicate, require, chromosome, action, inheritance, maternal, plant, well, background, occur, sequence, state, highly, chromatin
(2) Development and evolution	15.3%	System, cell, group, drosophila, impact, biology, evolutionary, theory, activation, focus, conserve, physically, synthesize, mediate, genetic, review, developmental, yeast, influence, phase, functional, exist, study, exert, morphogenesis, future, critical, consistent, variant, homolog
(3) Environmental factors/disease/cell signalling/methylation	9.8%	Ecs, stress, exposure, decrease, degreesc, thermal, alteration, xist, even, weight, pre, respectively, temperature, congenital, survive, increase, disease, condition, methylation, affect, production, blood, later, reduce, compare, potentially, responsible, block, body
(4) Epigenetic effects on gene expression	7.7%	Post, transcriptional, link, rate, control, interesting, disrupt, originally, effect, mutation, bind, repression, expose, purpose, suppress, analyze, rapidly, gene, vivo, degree, level, usually, grow, dependence, specifically, silence, reversible, function, imprinted gene, emerge
(5) Effects of methylation on disease and evolution/cell differentiation	6.1%	Cancer, methylation, commitment, evolutionarily, year, demethylation, event, contribute, DNA, deficient, need, methylate, somatic, current, summarize, minority, precise, mechanistic, maintain, parental, biological, create, discuss, development, risk, normal, reprogramme, epigenetic, embryo, germline
(6) Methodological factors	5.7%	Initiation, genome, site, genomic, appear, replication, mammalian, DNA, human, study, frequency, recent, hypomethylation, principle, duplication, potentiate, suppressor, result, connect, interpretation, make, change, individual, simultaneously, important, region, understand, phenomenon, methylation, line
(7) Gene regulation	5.5%	Express, cytokine, gene, cell, raise, subject, possibility, receptor, damage, manner, terminal, fate, moreover, various, promote, report, class, apoptotic, allele, stimulation, repair, hematopoietic, stimulate, thus, induction, modulate, regulate, regard, variety, nore
(8) Methodological*	4.9%	Hat, activity, modification, histone, acetylation, multiple, tail, element, code, provide, replicate, protein, hypothesis, finding, evidence, finally, determine, rather, long, addition, domain, regulation, require, particular, important, new, prion, rich, yeast, maintenance,
(9) Development and cancer	4.7%	Growth, tumor, cell, cycle, factor, gata, signal, represent, nervous, differentiation, differentiate, maturation, intrinsic, helper, secrete, distinguish, guide, respond, program, dependent, treatment, confer, extend, time, heritable, work, form, interaction, smad, transcriptional
(12) Phenotypic plasticity and disease	3.2%	Liver, surprisingly, oxidative, alpha, oncogene, cytogenetic, alone, age, induced, genotype, plasticity, peak, mouse, increase, myc, tumorigenesis, hematopoietic, adaptive, environmental, developmental, irradiate, character, incidence, phenotypic, adult, landscape, cluster, strong, apoptosis, genetic
(17) Chromosome structure	1.3%	Kinetochore, satellite, cenp, centromere, plate, centromeric, inner, nucleosome, purify, segregation, alpha, organization, molecular, assembly, classical, reflect, recognition, sequence, enrich, together, antisera, tagging, location, carboxy, ultrastructural, trilaminar, cse, neocentromere, substructure, dicentric

B: General biology 2005–2019

Topic label	% corpus	Word list
(1) Regulation of gene expression and development	39.9%	Gene, expression, mechanism, methylation, epigenetic, variation, DNA, change, genome, stress, control, plant, social, genetic, associate, show, remain, telomere, role, use, silence, identify, term, express, demonstrate, result, find, animal, individual
(2) Regulation and genome architecture	7.4%	acquire, transition, composition, feature, code, nuclear, aspect, network, resistance, poise, paradigm, RNA, transcription, neural, facilitate, genotype, range, temporal, less, address, pre, architecture, ctcf, dynamic, chromatin, drug, pluripotency, principle, dispensable, depletion
(3) Adaptive phenotypic plasticity	6.8%	Inheritance, effect, organism, epigenetic, exposure, environmental, environment, adaptive, evolutionary, plasticity, parent, developmental, offspre, consequence, adaptation, evolution, biology, consider, utero, expose, population, phenotype, great, condition, life, summarize, experience, intrauterine, understand, generation
(4) Epigenetic effects on regulation and cancer/TE suppression	6.3%	Cellular, post, tumor, protein, functional, module, source, RNA, pcg, turn, suppressor, method, bring, diversity, family, small, piwi, defect, oncogenic, illustrate, tumor, quality, elucidation, quantity, certain, absent, parallel, opportunity, spermatogenesis, need
(5) Regulation and cancer	6.2%	LncRNA, mediator, focus, impact, include, therapeutic, various, investigation, cancer, diverse, potential, inflammatory, research, review, nutrition, physiological, shape, unique, highlight, putative, macrophage, acetylation, exception, example, inhibitor, technology, mechanism, conservation, emerge, tissue
(6) Regulation and centromere structure	4.9%	Kinetochoer, DNA, methylation, centromere, structure, progression, accumulation, mark, produce, identify, promise, responsible, detect, microtubule, attachment, approximately, retain, surprisingly, enable cenh, RNA directe, specificity, question, spindle, summary, efficient, hypomethylation, last, typical, mitotic
(7) Methylation and ageing	4.5%	Age, enhancer, motif, bind, stem, cpg, aging, demethylase, suppression, DNA, hematopoietic, coordinate, site, sra, maturation, rich, loss, kyp, asymmetry, ring, methylate, methylcytosine, domain, activity, substrate, cg, concurrent, attenuation, shorten, carefully
(8) Methylation, disease, and heritability	3.7%	Tet, reprogramme, somatic, lie, cell, convert, climate, autism, repair, erasure, differentially, brain, advance, poorly, ber, apply, line, scale, ability, correspond, excision, capture, supply, restrict, inactivation, base, subsequently, disorder, germline, inhibition
(9) Maternal effects	3.5%	Obesity, microRNA, onset, blood, placental, vertebrate, fetal, respectively, assumption, help, schizophrenia, patient, previous, epigenomic, testis, biomarker, alter, cortisol, cord, impair, promoter, programming, analyze, nmis, unprecedented, donor, prominent, select, marrow
(10) Disease	3.3%	Disease, health, oxidative, pathway, chronic, risk, sex, flux, radiation, non, bystander, adverse, communication, dohad, intracellular, incidence, involvement, metabolic, diet, generation, plasma, little, irradiated, effect, late, life, increase, moreover, postnatal, purpose
(14) Drug addiction	1.2%	Memory, ino, nuclear periphery, recruitment, activation, reactivation, bulk, fosb, detailed, repress, localization, recruit, addiction, yeast, drug, promote, transcriptional, reward, abuse, modern, set, gal, previous, require, conserve, promoter, nucleoplasm, periphery, regulating, underway
(15) Transposons and evolution	1.2%	Recombination, rate, transposon, organization, computational, subtelomeric, divergence, allopolyploid, create, meiotic, suz, family, add, subtelomere, evolve, progress, eukaryotic, fast, poorly, duplication, contain, respectively, newly, evolution, metabolism, functional, polyploidy, frequent, mal, disaccharide
(18) Neurons and cognitive disease	0.5%	Neuron, neuronal, ehmt, reversible, orchestrate, fly, cognition, behavioral, learning, body, requirement, dimethylation, predominantly, kleefstra, cognitive, writer, corrupt, intellectual, mushroom, associative, adulthood, larval, disability, classic, seq, dendrite, courtship, neuroscience, memory, mutant
(19) Meiosis and sex chromosomes	0.3%	Meiosis, sex, continue, spermatid, persist, spermiogenesis, postmeiotic, rabl, msci, xy, prophase, postmeiotically, autosome, configuration, thereafter, hand, clarify, preinactivated, inactivation, chromosome, spermataogenesis, spawn, comprehensive, similarity, abundance, meiotic, compartment, body, discover, mature
(20) Centromere structure	0.3%	Strategy, cenp, neocentromere, centromere, amount, mass, paucity, complementary, randomly, segregate, fold, assemble, similar, centromeric, action, position, enrichment, contain, mitosis, prevent, inheritance, quantitative, represent, stochastic, mechanistic, implication, nucleosome, number, sufficient, segregation

C: Biomedicine 1990–2004

Topic label	% corpus	Word list
(1) Epigenetics in cancer and regulation	43.7%	Methylation, cancer, gene, DNA, tumor, promoter, epigenetic, associate, protein, mutation, role, human, silence, control, specific, development, study, tissue, tumor suppressor, mechanism, change, lung, include, find, use, hypomethylation, risk, occur, metastasis, group
(2) Cellular mechanisms/progression of cancer	12.7%	Cell, adhesion, metase, stem, epithelium, serum, system, increase, adult, reduce, mouse, concentration, epithelial, progression, prolong, tumorigenicity, emerge, induce, effect, contact, fibroblast, potential, induction, characteristic, impair, treatment, breast, activity, single, phenotype
(3) Epigenetic mechanisms of cancer	8.2%	Arf, igf, imprint, deletion, patient, tumor, age, cdkn, wild type, esophageal, normal, loi, mucosa, hypomethylation, functional, loh, chromosome, glioblastoma, homozygous, mdm, loss, product, apply, etv, gene, wilm, completely, sense, often, heterozygosity
(4) Epigenetics in disease treatment and gene regulation	6%	Chromatin, modification, histone, understand, differentiation, drug, great, resistance, become, repress, agent, new, acetylation, maintain, state, advance, melphalan, activity, cytosine, diverse, genome, myogenic, therapy, promise, way, mammalian, regulate, causal, impact, toxicity
(5) Epigenetics and specific cancers	4.9%	Cadherin, prostate, mgmt, cpg island, methylguanine, almost, line, neck, head, deacetylation, thyroid, remove, hpec, replication, prb, transferase, glutathione, similar, light, pps, function, pathway, invasion, senescence, karyotype, show, peroxisome, inactivation, relation, associated
(6) Effects of nickel exposure on cancer in murine models	4.8%	Dose, week, rearrangement, liver, chain, nutrient, statistical, rat, elsevi, compound, carcinogenic, exposure, fashion, nickel compound, tcr beta, focus, thereby, epigenetically, tumor, hepatocellular, investigation, strain, hypomethylate, mouse, rodent, nickel, hepatocyte, reversion, unilateral, gavage
(7) Relationship between smoking and cancer	3.7%	Passage, hematopoietic, smoke, area, revertant, property, leukemia, competence, cd, stability, receive, concordance, cell, germline, acute, environmental, yield, follow, gamma, msp, neo, stimulation, strong, imply, deoxycytidine, myelogenous, later, mesenchymal, nucleotide, fragment
(8) Study of cancer	2.8%	Variant, review, begin, bha, assumption, immune, respect, cervical, sufficient, attempt, discussed, icc, sscp, emphasis, initially, survive, concentrate, adenocarcinoma, heterogeneity, generation, elimination, question, program, possess, cytokine, widespread, fade, differentiate, metastatic, cell
(9) Disease, regulation, and cell signaling in the intestines	2.7%	Escape, reactivate, acf, cytokine, member, block, diagnose, phase, crypt, spread, demethylation, family, activation, consist, concomitant, transcription, express, signal, metaplastic, inflammatory, probably, commonly, percentage, central, primarily, elucidate, proliferative, large, restimulation, instruction
(10) Intestinal cancer	2.5%	Catenin, regard, concept, immune, defect, newly, anchorage, regression, duodenal, ohe, protocol, proceed, elucidation, nontransgenic, transgenic, system, number, intestinal, end, spontaneous, promotion, regulate, transformation, mediation, unconjugate, pge, soft, agar, hydroxylation, ckmgmt
(11) Methodology in cancer studies	2.5%	Nonmalignant, line, reaction, mesothelioma, plasma, autoimmune, trial, score, design, breast, secrete, genetically, reflectance, factor viii, month, vector, testing, apparent, culture, biopsy, lung, endpoint, conclusion, method, adjuvant, independent, transfecte, prognostic, recipient, variability
(12) Nutritional/molecular deficiencies and disease	1.6%	Folate, normally, guanine, deficient, mp, supply, deficiency, part, donor, incorporate, mode, prevention, hypoxanthine, resistant, fragmentation, passive, mutagenic, medium, viability, salvage, pool, aa, cho, ham, aprt, presently, arrest, effective, uv, leukemia
(13) Cellular mechanisms	1.4%	Transporter, glutamate, prior, free, self, history, available, capacity, post, amino, lateral, translational, excitatory, persist, central, subline, passage, selection, agonist, carrier, affinity, alanine, variant, transform, spontaneous, confluence, transformation, individual, threonine, regional
(14) Cellular structure	1.1%	Toxic, intracellular, junction, specificity, restore, gap junction, organism, gap, metabolic, couple, evolve, differentiated, translational, matrix, multi, bring, dysfunction, molecule, extracellular, production, chemical, adaptive, toxicology, synchronization, dysfunctional, connexin, metazoan, speculate, maladaptive, reproductive
(15) Heat shock response in yeast	0.6%	Yeast, heat stress, currently, transient, mild, life span, divide, life, mortality, longevity, elucidation, ra, extension, lack, nonlethal, resumption, ignore, curtail, afford, manipulation, mitochondrial, thermotolerance, hsp, recovery, hinder, altogether, cerevisiae, petite, responsive, saccharomyce

D: Biomedicine 2005–2019

Topic label	Percentage of corpus	Word list
(1) Cancer treatment	15.6%	Cancer, tumor, cell, therapeutic, drug, heterogeneity, target, immune, therapy, discuss, lncRNA, progenitor, diagnostic, advance, resistance, anticancer, review, interaction, response, different, focus, strategy, stroma, transcriptional, agent, phenotypic, understand, include, hallmark, genetic
(2) Epigenetics marks in cancer	14.7%	Methylation, DNA, histone, epigenetic, cancer, gene, process, nature, various, role, biomarker, modification, discovery, translational, hdac, progression, consider, acetylation, hdac inhibitor, initiation, code, normal, involve, comprehensive, approve, repair, occur, enzyme, certain, cellular
(3) General health/effects of early exposure to stress	12.3%	Health, disease, body, chronic, system, evidence, also, sex, disorder, life, risk, exposure, prostate, death, source, increased, age, cellular, activation, rights reserve, challenge, early, stress, high, organ, change, defective, excessive, dysfunction, effect
(4) Undefined	11.3%	Pd, checkpoint, individual, patient, identify, treatment, base, mutation, genetic, often, blockade, diagnosis, time, sample, genomic mutant, analysis, biopsy, characterize, RNA, gene, somatic, use, people, evolution, animal, mutate, screen, datum, sequence
(5) Apoptotic signaling pathway	10.1%	Signal, cell, pathway, anti, apoptosis, canonical, bcl, infection, notch, shift, receptor, antibody, activate, overall, program, correlate, efficacy, overcome, exhaustion, resistance, efflux, respond, regulate, unique, regulator, functional, control, beta, molecule, finding
(6) Immune system and regulation of gene expression	9.8%	Cell, myc, innate, expression, deficient, cd, cytokine, brain, adaptive, subset, transcription factor, differentiation, foxp, culture, allergy, nfatc, dependent, growth, drive, transcription, promote, element, treg, proliferation, response, regulation, selective, helper, lineage, differentiate
(7) Epithelial to mesenchymal transition in cancer	6.4%	Emt, pancreatic, histone lysine, mesenchymal, report, stromal, aacr, isoform, line, metastasis, specificity, epithelial, reflect, plasticity, lysine, exhibit, integral, orchestrate, start, acquisition, set, see, first, carcinoma, ras, oscc, amino, established, bias, neoplastic
(8) Undefined	3%	Subtype, idh, metastatic, article, elucidate, combine, depend, copy, bcl, structurally, demethylase, embryogenesis, exemplify, derangement, transducer, defect, future, apply, domain, tet, protein, action, interference, hypothesis, share, identify, clinical, reversible, yy, cohort
(9) Impact of diabetes	2.6%	Country, ontogeny, complication, transporter, vascular, endothelial, propose, mitochondrial, iugr, diabetes, proportion, inducible, determinant, xenobiotic, persist, remodeling, hba, hyperglycemia, pdx, antioxidant, increase, follow, primarily, spike, diabetic, keap, function, reduce, nf kappa, cause
(10) Obesity epidemic	2.1%	Obesity, food, diet, public, physical, epidemic, account, composition, pool, able, address, weight, accept, policy, barrier, cycle, relevant, especially, utero, counter, abdominal, burden, build, assess, half, mass, cdks, fat, effort, even
(11) Maternal effects/intrauterine exposure	1.9%	Metabolic, maternal, behavior, ascorbate, undernutrition, pharmacological, electron, adversity, significant, offspring, offspre, theme, transport, difficult, gut, analogue, broad, induction, decitabine, shape, need, rationale, predict, clinical, deregulate, neoantigen, hpa, foetal, prodrug, donor
(12) Cancer, regulation, and methodology	1.7%	Divergent, crc, alternative, overlap, place, characterized, tgf beta, reversion, integrity, knockout, state, motility, tumor, extent, clonal, intra, feature, btg, dac, strongly, morphological, restore, silence, existence, observe, drive, suppressor, induction, substantial, driver
(13) Immunology, research, and cancer	1.7%	Macrophage, tissue, month, condition, test, mgmt promoter, pregnancy, compelling, hypertension, chain, exogenous, favorable, radiotherapy, interval, confidence, percent, monocyte, mortality, concept, diversity, methylate, temozolomide, rank, log, define, physiological, activation, derive, fat, hazard
(14) Epigenetics, cancer, and telomeres	1.6%	Uncover, advanced, less, glioblastoma, viral, secondary, telomere, acetyl, capability, hat, diffuse, oppose, transferase, definitive, prominent, absent, histologically, lifetime, harbor, precursor, person, telomerase, bone, differ, primary, people, directly, similar, largely, instability
(15) Longitudinal cancer research	1.2%	Decade, outline, option, subgroup, recurrent, origin, dismal, past, discussion, possibly, view, lastly, formation, marker, manner, progress, gbm, rise, direction, major, kill, prognosis, central, third, inherent, derive, research, mutation, drug, brain
(16) Leukemia and its treatment	1.2%	Mll, experience, deplete, leukemia, mgmt, haematopoietic, ongoing, regimen, alkylating agent, translocation, fusion, schedule, mixed, leukaemogenic, hox, lose, positively, poor, pseudosubstrate, chemoresistance, standard, nontoxic, dense, inevitably, note, mgmt promoter, useful, stem, glioma, unclear
(17) Dysregulation of hormones in cancer	0.7%	Aberrantly, dysregulate, androgen, ar, small molecule, neoantigen, antitumor, promising, repressive, et, durable, regression, erg, tmprss, management, prostate, recruitment, rapid, follow, disrupt, potentiating, fuse, rearrangement, massively, regulated, sequencing, iv, immunology, remission, widen

E: Proximal biology 1990–2004

Topic #, label	% corpus	Word list at $\lambda$ 0.5 (pyLDAvis)
(1) The epigenetic regulation of gene expression and genomic structure	31.1%	Chromatin, histone, methylation, gene, epigenetic, modification, bind, domain, site, state, protein, structure, complex, mechanism. DNA, heterochromatin, centromere, regulation, role, lys, activity, mecp, lysine, understand, specific, enzyme, nucleosome, provide, chromosome, transcriptional
(2) The influence of epigenetics on disease	17.6%	Cancer, tumor, loss, cell, gene, methylation, colorectal, associate, tumor suppressor, progression, aberrant, tumorigenesis, cellular, lung, cpg island, DNA, promoter, tumour, hypermethylate, beta, art, technology, repair, inactivation, inactivate, alteration, lesion, event, high, mgmt
(3) The epigenetic reprogramming of cells in the germline/development	12.6%	Cell, demethylation, reprogramme, germ, cd, imprint, stage, development, zygote, fertilization, insight, germline, occur, genomic, thymocyte, genome, first, stem, process, epigenetic, produce, mouse, pgcs, gene, normally, differentiate, runx, hepatocellular, hepatocyte, number
(4) The use of epigenetics in treating disease	10.3%	Suv, small RNA, sir, therapy, identifiy, target, protein, RNA, component, key, family, molecule, serve, specification, multiple, sequence, local, motif, promote, correspond, modifier, fate, predict, peptide, transient, significance, currently, possible, dependent, factor
(5) The heritability of epigenetic marks/parental effects/genomic analysis	9.7%	Igf, imprint, hypomethylation, sequence, fetal, express, paternal, ddm, transcript, maternal, tissue, environment, mutant, parental, methylation, allele, paternally, deletion, DNA, analyze, parent, region, observe, short, ref, repeat, self, progeny, snrpn, chromosome
(6) The relationship between epigenetic regulation and development	5.7%	Polycomb, history, respectively, group, embryo, synthesis, deposition, insulator, reporter, main, hold, exposure, great, procedure, homeotic, possibly, retinoblastoma, egg, extinction, maintenance, neural, design, endometrial, mlh, pcg, fifth, interesting, accelerate, occasionally, constitutive
(7) Inheritance of disorders	4.6%	Schizophrenia, twin, breast, prb, disorder, brca, specimen, effect, rtt, etiology, tnpa, hmr, contribution, heritability, selectively, benign, basic, autonomous, estimate, wild type, transgene, spm, chimera, regression, maternal, age, dz, discordant, probandwise, noninherite
(8) Cancer research using lab animals/mechanisms of blood clotting	3.3%	Cadmium, injection, human, testicular, rat, pai, dose, rate, rodent, prostate, occupational, metal, right, poorly, sa, cenp, plasma, factor viii, retroviral, induce, animal, carcinogenesis, secrete, reserve, mepai, hml, trx, satellite, effectively
(9) Epigenetics and cancer/bacteria	3%	Sirtuin, sirt, class, understanding, research, oncogene, area, oncogenesis, see, bacteria, protozoan, decitabine, phylogenetic, array, press, academic, prokaryotic, bacterial, prevention, extra, weak, sequential, comprehensive, year, effective, eukaryote, influence, elsevi, wide, epithelial
(10) Maternal effects and the agouti mouse	1.3%	Yellow, agouti, supplementation, nutrition, dietary, viable, donor, especially, in, deleterious, labile, ala, choline, beneficial, betaine, metastability, dam, lability, folic, metastable, presume, harbor, unintended, vitamin, offspring, cluster, mash, range, sibling, pseudoagouti
(11) Morphology	0.4%	Skull, individualized, ontogeny, decomposition, spline, facial, cranial, integration, cotton, complicate, familiar, heterotopy, heterochrony, spatiotemporal, integrated, weaning, geometric, sigmodon, adequately, precocial, thin, count, warp, priori, fulviventer, arbitrary, chew, whole, demanding, growth
(12) Plant Genetics	0.3%	Chs, sense, transgenote, cosuppression, antisense, synthase, readthrough, repetitiveness, chalcone, score, flower, phenotypically. pigmentation, construct, produce. transgene, cotton, complicate, familiar, heterotopy, heterochrony, spatiotemporal, integrated, weaning, geometric, sigmodon, adequately, precocial, thin, count

F: Proximal biology 2005–2019

Topic label	% corpus	Word list
(1) Prospects/promise for biomedical research (1)	22.3%	Epigenetic, cellular, process, histone, role, cancer, mechanism, review, include, recent, drug, discover, biomarker, modification, biological, response, protein, many, therapy, involve, study, disease, year, influence, field, acetylation, target, discovery, question, regulation, health, future
(2) Epigenetic regulation of gene expression	16.1%	Methylation, DNA, sequence, promoter, gene, level, inflammatory, genome, use, region, previously, context, critical, sex, cpgs, differentially, methylate, cpg, observe, activation, element, silence, loop, rapidly, probe, array, expression, interfere, potentially, resolution
(3) Epigenetics and cancer	12.7%	Cancer, cell, inhibitor, tumor, reprogramme, early, progression, selective, low, epigenetic, reveal, enhancer, progenitor, gene, mouse, part, abnormal, find, tissue, establish, stem, regulator, demethylation, bet, identification, germline, suggest, however, plasticity, development
(4) Clinical methods	11.8%	Molecular, clinical, pathway, prostate, demonstrate, tet, hematopoietic, method, alpha, include, decade, specific, activity, well, vivo, edit, study, develop, available, analysis, intervention, general, production, possible, apply, ability, investigation, give, induce, discuss
(5) Examination of maternal effects	6.9%	Maternal, treat, site, domain, newborn, mark, methylation, pattern, examine, cohort, status, methyl, division, success, specifically, past, bivalent, functionally, assess, discuss, specific, dinucleotide, mood, statistical, wide, presence, region, late, association, highly
(6) Immune system, ageing, and mortality	4.9%	Age, immune, chronological, factor, blood, individual, cd, estimate, life, rate, measure, foxp, death, lifespan, observation, enhance, treg, risk, concentration, naïve, hat, compelling, build, lead, cell, acceleration, response, contribute, suppression, predict
(7) Effect of ncRNAs on hematopoietic cells and genomic structure	3.9%	LncRNA, hsc, type, editing, independent, open, access, deep, nuclease, composition, lineage, correlate, location, memory, accessible, monocyte, hold, code, package, noncoding RNA, enable, local, readily, remodel, accomplish, distinguish, least, regulatory, generate, mitosis
(8) Noncoding RNA and effects on cancer and genome structure	3.8%	RNA, tumour, small, compartment, structure, dysregulation, uncover transcriptome, mRNA, subgroup, present, long, demethylase, organization, encode, scaffold, complexe, relevance, newly, defence, mode, disrupt, systematic, lesion, lncRNA, resource, polymerase, gbm, extensive, event
(9) Methodological reflection	2.6%	Application, tool, nature, set, researcher, query, subtype, mutate, datum, scna, link, interface, clinician, biomedical, dmrs, meeting, proteomic, potency, summary, short, guide, recurrent, explore, move, comparative, region, program, provide, interest, practical
(10) Reprogramming of somatic cells to induced pluripotent stem cells	2.5%	Stem, pluripotent, cell, es, differentiate, fibroblast, sox, rely, somatic, klf, adult, embryonic, disorder, ip, human, capable, ipsc, ips, state, surface, germline, origin, myc, generate, self, fold, transmission, induce, perpetual, lock
(11) Noncding RNAs and their function	2.5%	Diverse, accessibility, family, modulate, orchestrate, hox, recruit, strong, incRNA, guiding, allosteric, rapid, almost, interaction, substrate, diversity, regulatory, simultaneously, modifying, directly, landscape dpendent, analyse, ncRNA, conserve, hoxd, hotair, kilobase, remove, preimplantation
(12) Technologies	2.1%	Laboratory, next generation, testing, perform, variant, emphasis, consideration, example, sequence, chip, computational, describe, genetic, technology, technical, seq, experience, cardiovascular, pharmaceutical, canonical, mitochondrial, species, hallmark, datum, challenge, condition, comprise, pot, increase, therefore
(13) Noncoding RNAs and their role in disease and regulation	1.7%	MiRNA, dysregulate, oncogene, deletion, suppressor, ink, amplification, control, arf, biogenesis, degradation, interact, precursor, clear, turn, small, cnr, act, microRNA, become, fruit, epimutation, ripen, colorless, processing, cleavage, siRNA, damage, gene, guide
(14) Epigenetics and cancer	1.7%	Emt, transition, modifier, course, epithelial, mesenchymal, brd, diagnostic, representative, point, widespread, purine, modality, phenotypic, modulator, batch, link, peptide, address, recognize, inflammation, design, state, inactive, often, maintenance, plasticity, shift, inactivation, induction
(15) Cancer	1.1%	Heterogeneity, substantial, divergent, clonal, tumor, diagnosis, attribute, primary, source, receptor, metastatic, intra, morphological, right, reserve, elsevi, yet, experimental, clinical, extent, angiogenic, rare, startling, outgrowth, exception, furthermore, feature, time, clone, originate
(16) Epigenetic regulation in plants	0.9%	Plant, contact, dicer, lay, argonaute, biogenesis, territory, domain, small, chromosomal, silence, overlap, imprint, clustering, linearly, modeling, remote, realization, detailed, confine, drosophila, partition, systematically, conformation, hierarchically, extensively, unanticipated, draw, deepen, rdr
(17) Specification of germ layers	0.8%	Specification, robust, epiblast, pgc, competent, fungi, surround, easy, locate, appropriate, pgclcs, epilcs, esc, transmission, entity, pregastrulating, meticulously, episc, spermatogenic, ssea, reconstitution, gamete, properly, isolation, pgclc, multisteppe, surprise, irreversibly, integral, appropriately
(18) Ageing	0.5%	Annotation, prediction, biologically, accurately, predictor, healthy, number, data, set, clock, fourth, passage, freely, informative, meaningful, chimpanzee, cumulative, inversely, ontogenetically, applicable, surrogate, attributable, variance, core, multi, fact, greatly, predominant, third, year, site

G: Evolutionary biology 1990–2004

Topic label	% corpus	Word list
(1) Epigenetic mechanisms in evolution/Waddington	14.1%	Gene, level, sex, imprint, duplicate, chromosome, evolutionary, age, constraint, differential, extinction, flower, sexuality, developmental, silence, specific, mapping, duplication, conserve, polycomb, reduction, canalize, bnflc, removal, newly, study, canalization, mammal, methylation, expression
(2) Epigenetic inheritance as a complementary evolutionary system	12.3%	Cell, redundancy, memory, epigenetic, inheritance, DNA, system, state, clone, regulatory, particular, concept, heredity, architecture, gap, plasticity, genetic assimilation, mechanism, discuss, evolution, redundant, function, role, paper, transmit, gene, mutation, propose, fidelity, cytosine
(3) Variation and stability of morphological structures	12.2%	Lateral, epigenetic, insertion, femoral, stability, mal, meniscus, expect, joint, genetic, hominid, pattern, determine, maleness, carrier, phase, epiphysis, select, variation, covariance, interaction, expression, mutation, developmental, mitotic, offspring, development, tibial, lip, distal
(4) Effects of methylation on gene expression in plants	10.5%	Genome, gene, fot, arabidopsis, code, sequence, allopolyploid, polyploid, wheat, non, methylation, site, alteration, change, amplifiy, associate, novel, esterase, element, microarray, turn, duplication, pair, brassica, section, translocation, insecticide, resistant, chromosome, specie
(5) Traits that exhibit adaptive plasticity	9%	Tortoise, primitive, digit, phalangeal, hominin, afarensis, horn, head, forage, reconstruct, plastic, hypothesis, anatomy, behavior, character, size, trait, usually, adaptation, selection, datum, discrete, behaviour, ask, interested, null, individual, fish, specie, phenotypically
(6) Development of cranial morphology/Waddington	8.5%	Effect, shift, skull, integration, genotypic, maternal, approach, environmental, growth, observe, evolve, cranial, facial, individualized, developmental, factor, integrate, craniofacial, base, landscape, age, population, information, system, epigenetic, modern, dynamic, diverse, face, ontogeny
(7) Biological anthropology and sexual dimorphism	7.3%	Sexual dimorphism, sample, uterine, skeletal, canine, zygomatic, adenohypophysis, prehistoric, biodistance, australian, tayassuid, nhp, hypothalmic, population, size, process, relationship, heritable, extend, transfer, large, pattern, late, correlation, adult, significant, sex, mortuary, coastal, ad
(8) Evolvability of phenotypes/Waddington	5.6%	Aphid, asexual, parthenogenesis, trigger, morphological, evolvability, particulate, body, trade, lineage, paradigm, adaptive, postcranial, upper, evolution, overall, appearance, prion, read, translation, eventually, temporally, cycle, ecological, list, threshold, dependency, inform, confirmatory, archaic
(9) Retroviruses in plants	4.3%	Codon, eprvs, cpg, plant, cpt, cpa, epiallele, dinucleotide, contain, tabacum, substitution, confound, mammal, term, bat, epiallelic, tomentosiformis, nicotiana, sylvestris, eprv, affect, family, elevate, natural, rate, virus, fitness, impact, differ, represent
(10) Fluctuating asymmetry	4.1%	Neandertal, predator, marginal, fluctuating asymmetry, stress, symmetric, degree, development, bilaterally, good, side, trait, large, symbiose, ossification, exaggerated, prefer, otherwise, unable, cue, mate, area, concern, secondary, cranial, embryo, cranium, interaction, character, argument
(11) Parental effects	3.5%	Eg cell, copulation, line, germ, pef, latency, duration, allele, cell, somatic, resemble, chimera, ds, performance, fa, statistically, bristle, heritability, pfa, significant, embryonic, female, similar, hence, parental, igf, methylation, male, spartina, burst
(12) Sexual display	3.1%	Ornament, cortical, paternal, map, global, male, mite, sexual, ascribe, extravagant, secondary, elimination, demonstrate, preference, choice, flat, female, absolute, structure, relationship, size, cope, ocular, net, cortex, macaque, concentrate, approximate, anisotropic, uniform
(13) Transposons	1.8%	Selfish, repetitive, rie, narrative, functionality, DNA, component, remain, integrally, connection, couple, suppose, criticism, critique, untestable, overview, enigmatic, brief, specificity, elucidating, prokaryotic, monomer, story, selfishness, scheme, purpose, nearly, macro, substantial, replicator
(15) Parasites	1.1%	Parasitoid, virulence, host, resistance, defence, melanogaster, insect, parasitize, coevolutionary, dear, appraise, trail, coevolution, community, parasitism, elsewhere, hymenopterous, southern, survive, immunological, internal, mount, positively, critically, evidence, unlikely, explanation, central, attack, low

H: Evolutionary biology 2005–2019

Topic#, label	% corpus	Word list
(1) Gene expression and evolution	17.5%	Evolutionary, evolution, molecular, gene, provide, insect, question, methylate, include, process, genomic, new, te, novel, present, genome, future, require, facilitate, consider, gene expression, study, lack, together, diversity, major, toad, biology, rapid, advance
(2) Phenotypic plasticity/epigenetic switch	12.2%	Cue, plasticity, divergence, developmental, temperature, natural, integration, underline, whole, phenotype, development, challenge, source, scale, specie, match, adult, shape, respond, long, study, highlight, increase, different, great, trait, salt, divergent, phenotypic, differ
(3) Environmental influences on methylation/phenotypic responses	12%	Methylation, DNA, climate, variation, epigenetic, age, significant, plant, response, find, occur, profile, site, estimate, population, animal, role, association, cytosine, negative, strong, local, heritability, method, low, exhibit, treatment, level, datum, obtain
(4) Adaptive phenotypic plasticity	12%	Effect, environment, mutation, phenotypic, global, change, genetic, epigenetic, promoter, environmental, vertebrate, invertebrate, adaptation, life, plasticity, phenotype, result, population, selection, natural selection, model, generation, fitness, transmission, variation, influence, value, variant, contrast, condition
(5) Epigenetic effects on primate sociality	8.8%	Social, degree, generation, course, expression, relate, baboon, skeletal, control, mismatch, involve, differential, early, theory, human, outcome, other, measure, imprint, consistency, induce, day, link, behavioral, pattern, presence, inherit, line, growth, specify
(6) Relative advantages of sexual vs asexual modes of reproduction	6.1%	Habitat, asexual, reproductive, differentiation, apomictic, aflp, epigenetic, variation, reset, gradients, beneficial, length, directly, stage, genetically, lineage, interpret, genetic, slow, population, cycle, shift, correlation, end, variance, sexual, advantage, qualitatively, involvement, complete
(7) Parental effects	3.8%	Care, maternal, offspring, pass, hpa, trade, off, glucocorticoid, distribute, mother, paternal, follow, step, receptor, survival, last, offspre, modification, female, pituitary, hypothalamic, deprivation, biosynthesis, immune, isolate, elevate, transfer, information, modulate, short
(8) Chromosome features/Waddingtonian development	3.7%	Chromosome, environmentally, telomere, constraint, revolve, undergo, sex, locus, genome, especially, foster, newly, diverse, neocortex, host, assume, convergent, status, favor, stability, nonetheless, determine, region, canalization, additional, sessile, operate, parasitic, progress, compatible
(9) Chromosome features	3.5%	Centromere, satellite, within, predict, integrate, acession, non, recently, exploratory, order, select, DNA, humpback, centromeric, percentage, form, transcript, repeat, correlation, fit, site, cento, ant, part, chromatin, unit, muscle, bee, ccgg, inner
(10) Methylation, plants, and transposons	3.3%	Flower, amount, plant, demethylation, reduce, genotype, inheritance, quality, ecologically, inbreede, marker, dispersal, powerful, unknown, redundancy, nucleotide, arabidopsis, ltr, depression, idea, difference, experimental, rt, nectar, relatedness, noise, generality, heterogeneous, manipulate, drift
(11) Biological anthropology and diet	3.1%	Exposure, sensitivity, experimental, epigenome, laboratory, health, span, temporal, microwear, application, circumstance, pr afarensis, increasingly, scenario, food, concern, investigation, permanent, detailed, carry, explanatory, toxicant, consume, item, paleoecological, appear, robust, sufficient, susceptibility, limited