Mirror, mirror? An evaluation of identical twin mirroring in tooth crown morphology.

It has been estimated that 25% of monozygotic ("identical") twin pairs exhibit reverse asymmetry (RA) or "mirroring" of minor anatomical features as a result of delayed zygote division. Here, we examine whether identical twin mirroring accounts for patterns of dental asymmetry in a sample of monozygotic and dizygotic ("fraternal") twins. We focus on crown morphology to approach the following question: is there an association between dental RA frequency and twin type suggestive of the presence of mirror image twins in our sample? Data were collected from 208 deciduous and 196 permanent dentitions of participants of the University of Adelaide Twin Study using Arizona State University Dental Anthropology System standards. RA frequencies were compared across morphological complexes (deciduous, permanent), twin types (monozygotic, dizygotic), and traits. Fisher's exact tests were performed to formally evaluate the association between twin type and dental RA. Across the entire dataset, RA rates failed to exceed 8% for any twin type. In monozygotic twins, deciduous mirroring totaled 5.3% of observed cases, while permanent mirroring totaled 7.8% of observed cases. We found no statistically significant association between RA and twin type for any morphological character (p-value range: 0.07-1.00). Our results suggest the timing of monozygotic twin division does not explain the structure of asymmetry for our morphology dataset and that published estimates of identical twin mirroring rates may be inflated or contingent upon phenotype. Instead, rates reported for this sample more closely align with the proposed etiology of this condition.

Protospacer modification improves base editing of a canonical splice site variant and recovery of CFTR function in human airway epithelial cells.

Canonical splice site variants affecting the 5' GT and 3' AG nucleotides of introns result in severe missplicing and account for about 10% of disease-causing genomic alterations. Treatment of such variants has proven challenging due to the unstable mRNA or protein isoforms that typically result from disruption of these sites. Here, we investigate CRISPR-Cas9-mediated adenine base editing for such variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We validate a CFTR expression minigene (EMG) system for testing base editing designs for two different targets. We then use the EMG system to test non-standard single-guide RNAs with either shortened or lengthened protospacers to correct the most common cystic fibrosis-causing variant in individuals of African descent (c.2988+1G>A). Varying the spacer region length allowed placement of the editing window in a more efficient context and enabled use of alternate protospacer adjacent motifs. Using these modifications, we restored clinically significant levels of CFTR function to human airway epithelial cells from two donors bearing the c.2988+1G>A variant.

Relationships between Dental Topography, Gross Wear, and Bang and Ramm/Liversidge and Molleson Age Estimates for a Sample of Human Premolar Teeth.

Objectives: Molar crown wear is often used in bioarchaeological research as a proxy for age at death. However, a small number of researchers have used premolars or compared the application of different methods of relative age estimation. Material and methods: Using a sample of 197 previously extracted maxillary first premolars from US dental patients, we considered three protocols for estimating age: the Bang and Ramm/Liversidge and Molleson (BRLM) age estimate method, occlusal topographic analysis, and the Smith system of macrowear scoring. A previous study utilizing the Bang and Ramm method yielded an age estimate range of 9.4 to 10.8 years for the sample. Results: Our analyses showed no associations between occlusal topography parameters (occlusal slope, relief, or faceting) and BRLM age estimates, but some concordance was found between Smith scoring and BRLM ages estimates and between Smith scoring and occlusal topography parameters. Conclusion: The results of the present study suggest that relationships between gross tooth wear, tooth shape, and dental age estimates are complex, and available methods should be considered together to gain a more comprehensive understanding of how teeth change their shape with wear throughout the lifecourse.

Identifying barriers to shared decision-making about bariatric surgery in two large health systems.

OBJECTIVE: Prior research suggests shared decision-making (SDM) could improve patient and health care provider communication about bariatric surgery. The aim of this work was to identify and prioritize barriers to SDM around bariatric surgery to help guide implementation of SDM. METHODS: Two large US health care systems formed multidisciplinary teams to facilitate the implementation of SDM around bariatric surgery. The teams used a nominal group process approach involving (1) generation of multilevel barriers, (2) round-robin recording of barriers, (3) facilitated discussion, and (4) selection and ranking of barriers according to importance and feasibility to address. RESULTS: One health system identified 13 barriers and prioritized 5 as the most important and feasible to address. The second health system identified 14 barriers and prioritized 6. Both health systems commonly prioritized six barriers: lack of insurance coverage; lack of understanding of insurance coverage; lack of organizational prioritization of SDM; lack of knowledge about bariatric surgery; lack of interdepartmental clarity between primary and specialty care; and limited training on SDM conversations and tools. CONCLUSIONS: Health systems face numerous barriers to SDM around bariatric surgery, and these can be easily identified and prioritized by multistakeholder teams. Future research should seek to identify effective strategies to address these common barriers.

Genetic Correlation, Pleiotropy, and Molar Morphology in a Longitudinal Sample of Australian Twins and Families.

This study aims to expand our understanding of the genetic architecture of crown morphology in the human diphyodont dentition. Here, we present bivariate genetic correlation estimates for deciduous and permanent molar traits and evaluate the patterns of pleiotropy within (e.g., m1-m2) and between (e.g., m2-M1) dentitions. Morphology was observed and scored from dental models representing participants of an Australian twin and family study (deciduous n = 290, permanent n = 339). Data collection followed Arizona State University Dental Anthropology System standards. Genetic correlation estimates were generated using maximum likelihood variance components analysis in SOLAR v.8.1.1. Approximately 23% of deciduous variance components models and 30% of permanent variance components models yielded significant genetic correlation estimates. By comparison, over half (56%) of deciduous-permanent homologues (e.g., m2 hypocone-M1 hypocone) were significantly genetically correlated. It is generally assumed that the deciduous and permanent molars represent members of a meristic molar field emerging from the primary dental lamina. However, stronger genetic integration among m2-M1/M2 homologues than among paired deciduous traits suggests the m2 represents the anterior-most member of a "true" molar field. The results indicate genetic factors act at distinct points throughout development to generate homologous molar form, starting with the m2, which is later replaced by a permanent premolariform crown.

CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor.

The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl-]; 87-105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl-] (75-123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o-) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.

The genetic architecture of anterior tooth morphology in a longitudinal sample of Australian twins and families.

OBJECTIVE: This study presents a quantitative genetic analysis of human anterior dental morphology in a longitudinal sample of known genealogy. The primary aim of this work is to generate a suite of genetic correlations within and between deciduous and permanent characters to access patterns of integration across the diphyodont dental complex. DESIGN: Data were recorded from casted tooth crowns representing participants of a long-term Australian twin and family study (deciduous n = 290, permanent n = 339). Morphological trait expression was observed and scored following Arizona State University Dental Anthropology System standards. Bivariate genetic correlations were estimated using maximum likelihood variance decomposition models in SOLAR v.8.1.1. RESULTS: Genetic correlation estimates indicate high levels of integration between antimeres but low to moderate levels among traits within a tooth row. Only 9% of deciduous model comparisons were significant, while pleiotropy was indicated for one third of permanent trait pairs. Canine characters stood out as strongly integrated, especially in the deciduous dentition. For homologous characters across dentitions (e.g., deciduous i1 shoveling and permanent I1 shoveling), ∼70% of model comparisons yielded significant genetic correlations. CONCLUSIONS: Patterns of genetic correlation suggest a morphological canine module that spans the primary and secondary dentition. Results also point to the existence of a genetic mechanism conserving morphology across the diphyodont dental complex, such that paired deciduous and permanent traits are more strongly integrated than characters within individual tooth rows/teeth.

Heterogeneous frailty and the expression of linear enamel hypoplasia in a genealogical population.

OBJECTIVES: Linear enamel hypoplasia (LEH) is a common skeletal marker of physiological stress (e.g., malnutrition or illness) that is studied within and across populations, without reference to familial risk. We examine LEH prevalence in a population with known genealogical relationships to determine the potential influence of genetic heritability and shared environment. METHODS: LEH data of 239 individuals from a single population were recorded from the Ohio State University Menegaz-Bock collection dental casts. All individuals were of known age, sex, and genealogy. Narrow-sense heritability estimates were obtained for LEH presence and count data from all unworn, fully erupted teeth (excluding third molars) using SOLAR (v.8.1.1). Age, sex, and age-sex interaction were included as covariates. Models were re-run with a household effect variable. RESULTS: LEH persists across generations in this study population with moderate, significant heritability estimates for presence in four teeth, and count in four teeth (three teeth were significant for both). When a household effect variable was added, no residual heritability remained for LEH count on any tooth. There was no significant household effect for three of the four teeth that had significant heritability estimates for LEH presence. Age was a significant covariate. Further analyses with birth year data revealed a secular trend toward less LEH. CONCLUSIONS: This study provides evidence for familial risk of LEH (genetic and environmental) that has consequences for the broad use of this skeletal marker of stress. These results have repercussions for archaeological assemblages, or population health studies, where genetic relatives and household groups might be heavily represented.

Measuring Greater Patient-Provider Continuity in a Clinic-First Family Medicine Residency Curriculum.

INTRODUCTION: Continuity is valued by patients, clinicians, and health systems for its association with higher-value care and satisfaction. Continuity is a commonly cited reason for entering primary care; however, it is difficult to achieve in residency settings. We sought to determine the effect of transitioning from a traditional "block" (13 4-week rotations per year) to a "clinic-first" (priority on outpatient continuity) curriculum on measures of continuity in our family medicine residency. METHODS: For the 3 years prior to and the 4 years following the transition from block to clinic-first curriculum (July 2011-June 2018, n = 51 block resident-years and n = 72 clinic-first resident-years), we measured resident panel size, clinic time, office visits, and both resident- and patient-sided continuity measures. We also defined a new longitudinal continuity measure, "familiar faces," which is the number of patients that a resident saw at least 3 times during residency. RESULTS: The transition from block to clinic-first curriculum increased panel size, clinic time for first- and second-year residents, overall total visits, and total number of clinic visits with paneled patients. Continuity measures demonstrated an increased resident-sided continuity at all training levels, an increase (first-year residents) or unchanged (second- and third-year residents) continuity from the patient perspective, and a near doubling of longitudinal continuity. CONCLUSION: Redesigning our family medicine residency curriculum from a traditional block schedule to a clinic-first curriculum improved our residents' continuity experience.

Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies.

Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design of therapeutic options. Treatment of cystic fibrosis (CF) is an exemplar of this paradigm as the development of CFTR modulator therapies has allowed for targeted and effective treatment of individuals harboring specific genetic variants. However, the mechanism of these drugs limits effectiveness to particular classes of variants that allow production of CFTR protein. Thus, assessment of the molecular mechanism of individual variants is imperative for proper assignment of these precision therapies. This is particularly important when considering variants that affect pre-mRNA splicing, thus limiting success of the existing protein-targeted therapies. Variants affecting splicing can occur throughout exons and introns and the complexity of the process of splicing lends itself to a variety of outcomes, both at the RNA and protein levels, further complicating assessment of disease liability and modulator response. To investigate the scope of this challenge, we evaluated splicing and downstream effects of 52 naturally occurring CFTR variants (exonic = 15, intronic = 37). Expression of constructs containing select CFTR intronic sequences and complete CFTR exonic sequences in cell line models allowed for assessment of RNA and protein-level effects on an allele by allele basis. Characterization of primary nasal epithelial cells obtained from individuals harboring splice variants corroborated in vitro data. Notably, we identified exonic variants that result in complete missplicing and thus a lack of modulator response (e.g. c.2908G>A, c.523A>G), as well as intronic variants that respond to modulators due to the presence of residual normally spliced transcript (e.g. c.4242+2T>C, c.3717+40A>G). Overall, our data reveals diverse molecular outcomes amongst both exonic and intronic variants emphasizing the need to delineate RNA, protein, and functional effects of each variant in order to accurately assign precision therapies.

Patterns of heritability across the human diphyodont dental complex: Crown morphology of Australian twins and families.

OBJECTIVES: This study generates a series of narrow-sense heritability estimates for crown morphology of the deciduous and permanent dentition with two overarching aims. The first is to test the hypothesis that deciduous teeth provide a more faithful reflection of genetic information than their permanent successors. The second is to use quantitative genetic methods to evaluate assumptions underlying common data collection and analysis practices in biodistance research. MATERIALS AND METHODS: Dental morphology data were collected from longitudinal dental casts representing Australian twins and families using Arizona State Dental Anthropology System standards. Polygenic models and estimates of narrow-sense heritability were generated using SOLAR v.8.1.1. Each model considered age, sex, and age/sex interaction as covariates. RESULTS: Heritability estimates significantly differed from zero for the majority of morphological crown characters. Most estimates fell within the 0.4-0.8 range typically observed for crown morphology. Mean heritability was stable across the dental complex, but for paired homologues, permanent traits often yielded higher estimates than their deciduous counterparts. Results indicate directional asymmetry in environmental influence for crown morphology and inform biodistance "best practices" related to data collection and treatment. CONCLUSIONS: Overall, results for this sample support the use of crown morphology as a proxy for genetic variation in evolutionary research. This includes the deciduous dentition, which justifies the expansion of efforts to incorporate subadults into reconstructions of past microevolutionary processes. Results do not indicate that deciduous phenotypes more closely approximate underlying genotype, at least for deciduous/permanent homologues.

Impact of a Telehealth-Based Antimicrobial Stewardship Program in a Community Hospital Health System.

BACKGROUND: Data on antimicrobial stewardship programs (ASPs) facilitated via telehealth in the community hospital setting are limited. METHODS: A telehealth-based ASP was implemented in 2 community hospitals (285 and 176 beds). Local pharmacists without residency or prior antimicrobial stewardship training were trained to conduct prospective audit and feedback. For approximately 60 minutes 3 times weekly at the 285-bed hospital and 2 times weekly at the 176-bed hospital, infectious diseases (ID) physicians remotely reviewed patients on broad-spectrum antibiotics and those admitted with lower respiratory tract infections and skin and soft tissue infections with local pharmacists. Recommendations for ASP interventions made by ID physicians were relayed to primary teams and tracked by local pharmacists. Antimicrobial utilization was collected in days of therapy (DOT) per 1000 patient-days (PD) for a 12-month baseline and 6-month intervention period, and analyzed with segmented linear regression analysis. Local ID consultations were tracked and antimicrobial cost savings were estimated. RESULTS: During the 6-month intervention period, 1419 recommendations were made, of which 1262 (88.9%) were accepted. Compared to the baseline period, broad-spectrum antibiotic utilization decreased by 24.4% (342.1 vs 258.7 DOT/1000 PD; P < .001) during the intervention period. ID consultations increased by 40.2% (15.4 consultations per 1000 PD vs 21.5 consultations per 1000 PD; P = .001). Estimated annualized savings on antimicrobial expenditures were $142 629.83. CONCLUSIONS: An intense ASP model, facilitated in the community hospital setting via telehealth, led to reduced broad-spectrum antimicrobial utilization, increased ID consultations, and reduced antimicrobial expenditures.

Quantitative genetic analyses of postcanine morphological crown variation.

OBJECTIVES: This article presents estimates of narrow-sense heritability and bivariate genetic correlation for 14 tooth crown morphological variants scored on permanent premolars, first molars, and second molars. The objective is to inform data collection and analytical practices in dental biodistance and to provide insights on the development of molar crowns as integrated structures. MATERIALS AND METHODS: African American dental casts from the Menegaz-Bock collection were recorded for the Arizona State University Dental Anthropology System. Estimates of narrow-sense heritability and genetic correlation were generated using SOLAR v.8.1.1, which included assessment of age, sex, and birth year as covariates. Both continuous scale and dichotomized estimates are provided. RESULTS: Heritability estimates were nonsignificant for the majority of variables; however, for variables yielding significant estimates, values were moderate to high in magnitude and comparable to previous studies. Comparing left and right-side heritability estimates suggests directional asymmetry in the expression of environmental variance, something not seen in anterior tooth traits. Genetic correlations were moderate among antimeres and metameres and low for different traits scored on the same tooth crown. Although several negative correlations were noted, few reached statistical significance. Results affirm some of the current data cleaning and analytical practices in dental biodistance, but others are called into question. These include the pooling of males and females and combining left and right-side data into a single dataset. CONCLUSIONS: In comparison to anterior tooth crown traits, postcanine heritabilities were more often non-significant; however, those traits with significant heritability also tended to produce higher estimates. Genetic correlations were unremarkable, in part, because they were underpowered. However, M1 results may provide insight into the complex relationship between genes, environment, and development in determining ultimate crown form.

Heritability and genetic integration of anterior tooth crown variants in the South Carolina Gullah.

OBJECTIVES: This article presents estimates of narrow-sense heritability and bivariate genetic correlation for a series of morphological crown variants of the anterior dentition. These results provide insight into the value of dental phenotypes as evolutionary proxies, as well as the development of tooth crowns as integrated or modular structures. MATERIALS AND METHODS: African American dental casts from the Menegaz-Bock collection were scored for a standard set of dental morphological variables using the Arizona State Dental Anthropology System. Estimates of narrow-sense heritability and genetic correlations were generated using SOLAR v. 8.1.1, controlling for the covariates of age, sex, and birth year. Analyses were run using ordinal/continuous scale variables that were then dichotomized at various breakpoints, consistent with standard practices in dental anthropology. RESULTS: Heritability estimates were low to moderate for most traits, and lower in magnitude than those reported for odontometric data from the same study sample. Only winging, canine shoveling, and canine double shoveling returned narrow-sense heritabilities that did not differ significantly from zero. Genetic correlations were high among antimeres and metameres and low for different traits scored on the same tooth crown. These results affirm standard data cleaning practices in dental biodistance. Double shoveling was atypical in returning strong negative correlations with other traits, shoveling in particular. CONCLUSIONS: Additive genetic variation contributes to dental morphological variation, although the estimates are uniformly lower than those observed for odontometrics. Patterns of genetic correlation affirm most standard practices in dental biodistance. Patterns of negative pleiotropy involving lingual and labial crown features suggest a genetic architecture and developmental complex that differentially constrain morphological variation of distinct surfaces of the same tooth crown. These patterns warrant greater consideration and cross-population validation.

Heritability and genetic integration of tooth size in the South Carolina Gullah.

OBJECTIVES: This article provides estimates of narrow-sense heritability and genetic pleiotropy for mesiodistal tooth dimensions for a sample of 20th century African American individuals. Results inform biological distance analysis and offer insights into patterns of integration in the human dentition. MATERIALS AND METHODS: Maximum mesiodistal crown dimensions were measured using Hillson-FitzGerald calipers on 469 stone dental casts from the Menegaz-Bock Collection. Narrow-sense heritability estimates and genetic and phenotypic correlations were estimated using SOLAR 8.1.1 with covariate screening for age, sex, age*sex interaction, and birth year. RESULTS: Heritability estimates were moderate (∼0.10 - 0.90; h2 mean = 0.51) for most measured variables with sex as the only significant covariate. Patterns of genetic correlation indicate strong integration across tooth classes, except molars. Comparison of these results to previously published work suggests lower overall heritability relative to other human populations and much stronger genetic integration across tooth classes than obtained from nonhuman primate genetic pleiotropy estimates. CONCLUSIONS: These results suggest that the high heritabilities previously published may reflect overestimates inherent in previous study designs; as such the standard estimate of 0.55 used in biodistance analyses may not be appropriate. For the Gullah, isolation and endogamy coupled with elevated levels of physiological and economic stress may suppress narrow-sense heritability estimates. Pleiotropy analyses suggest a more highly integrated dentition in humans than in other mammals.

Comparative performance of deciduous and permanent dental morphology in detecting biological relatives.

OBJECTIVES: Dental morphology plays a key role in reconstructing population history and evolutionary relationships at global, regional, and intracemetery scales. At the inter-individual level, it is assumed that close biological kin exhibit greater phenotypic similarity than non-relatives. Heritability estimates provide one measure of phenotypic resemblance but are not easily incorporated into analyses of archaeological samples. In this study we evaluate the assumption that relatives are more similar phenotypically than non-relatives. We compare results for permanent dental morphology to those obtained using deciduous dental morphology in a matched dataset (Paul & Stojanowski, ). MATERIALS AND METHODS: Permanent trait expression was scored from dental casts representing 69 sibling pairs, curated as part of the longitudinal Burlington Growth Study. Simulating a biodistance approach, 22 morphological traits of permanent tooth crowns were used to generate 69 inter-relative and 2,076 non-relative Euclidean distances. Following distance ordination, family-specific dispersion values were calculated from multidimensional scaling coordinates. Output was compared to that of a previous study that focused on deciduous crown variation in the same set of individuals (Paul & Stojanowski, ). Mantel tests were used to evaluate the correlation of a proxy genetic distance matrix to both the permanent and deciduous dental distance matrices. RESULTS: On average, inter-relative distances generated from morphological traits of permanent tooth crowns were smaller than expected by chance based on resampling (p < 0.001). While family-specific dispersion varied greatly for both permanent and deciduous datasets, over 75% of the families exhibited greater dispersion with permanent traits. This suggests that morphological traits of the permanent dentition provide a less faithful reflection of biological relatedness than morphological traits of the deciduous dentition. Mantel tests indicate that both the deciduous and permanent distance matrices are significantly correlated with a matrix of genetic relatedness coefficients; however, the magnitude of the correlations was low. DISCUSSION: Overall, morphological traits of permanent tooth crowns perform moderately well in distinguishing relatives from non-relatives, but deciduous crown variations may provide a more direct reflection of the underlying genetic structure of intra-site or intra-cemetery samples. These findings have implications for bioarchaeological research and biodistance practices. In particular, morphological traits of the deciduous dentition should be incorporated into standard data collection protocols because of their stronger signal of relatedness.

The Patterning Cascade Model and Carabelli's trait expression in metameres of the mixed human dentition: exploring a morphogenetic model.

OBJECTIVES: The Patterning Cascade Model (PCM) provides an evolutionary developmental framework for exploring diversity in tooth crown form. According to the model, proximity of secondary enamel knots and tooth germ size track underlying developmental processes that dictate ultimate crown morphology (i.e., cusp number, accessory cusp presence/size). Previous research has shown the model to successfully predict variation in Carabelli's trait expression between antimeric and metameric pairs of human permanent molars. In this study, we quantify Carabelli's trait expression for metameres of the mixed dentition (dm2 and M1) and assess the PCM's potential for explaining differences in expression between the two elements. MATERIALS AND METHODS: Crown dimensions, intercusp distances, and Carabelli's trait expression were collected from 49 subadults possessing observable dm2/M1 pairs. Wilcoxon signed-rank tests and paired t-tests were performed to assess whether metameres differ significantly in morphometric variables. We explored the relationships between relative intercusp distances (RICDs) and Carabelli's trait expression using proportional odds logistic regression. RESULTS: Intra-individual dm2/M1 pairs differed significantly in Carabelli's trait expression (p = 0.01), with dm2 exhibiting higher grades of expression more commonly despite its smaller crown size. Paired molars differed in only one statistically significant RICD: metacone-hypocone (p < 0.01). Most RICDs shared the predicted negative relationship with Carabelli's trait expression, but this relationship was only statistically significant for three RICDs in the dm2 (mean, protocone-paracone, metacone-hypocone). CONCLUSIONS: We found mixed support for the PCM's ability to explain differences in Carabelli's trait expression between metameres of the mixed molar row. Results suggest that protocone-paracone enamel knot spacing has the greatest influence on Carabelli's trait expression. Lack of statistical significance for many of the relationships explored may reflect limitations related to sample composition and sample size.

A simple rule governs the evolution and development of hominin tooth size.

The variation in molar tooth size in humans and our closest relatives (hominins) has strongly influenced our view of human evolution. The reduction in overall size and disproportionate decrease in third molar size have been noted for over a century, and have been attributed to reduced selection for large dentitions owing to changes in diet or the acquisition of cooking. The systematic pattern of size variation along the tooth row has been described as a 'morphogenetic gradient' in mammal, and more specifically hominin, teeth since Butler and Dahlberg. However, the underlying controls of tooth size have not been well understood, with hypotheses ranging from morphogenetic fields to the clone theory. In this study we address the following question: are there rules that govern how hominin tooth size evolves? Here we propose that the inhibitory cascade, an activator-inhibitor mechanism that affects relative tooth size in mammals, produces the default pattern of tooth sizes for all lower primary postcanine teeth (deciduous premolars and permanent molars) in hominins. This configuration is also equivalent to a morphogenetic gradient, finally pointing to a mechanism that can generate this gradient. The pattern of tooth size remains constant with absolute size in australopiths (including Ardipithecus, Australopithecus and Paranthropus). However, in species of Homo, including modern humans, there is a tight link between tooth proportions and absolute size such that a single developmental parameter can explain both the relative and absolute sizes of primary postcanine teeth. On the basis of the relationship of inhibitory cascade patterning with size, we can use the size at one tooth position to predict the sizes of the remaining four primary postcanine teeth in the row for hominins. Our study provides a development-based expectation to examine the evolution of the unique proportions of human teeth.