The genes controlling high-level production of Shiga-like toxin (SLT) in Escherichia coli were cloned from the SLT converting phage 933J. This phage was isolated from a strain of E. coli that caused a foodborne outbreak of hemorrhagic colitis. The genes that convert normal E. coli to organisms producing high levels of toxin were cloned into the plasmid pBR328 and expressed in E. coli HB101. DNA restriction mapping, subcloning, examination of the cloned gene products by minicell analysis, neutralization, and immunoprecipitation with antibodies to SLT were used to localize the toxin converting genes and identify them as structural genes for SLT. Southern hybridization studies established that the DNA fragment carrying the cloned toxin structural genes had homology with the DNA of Shigella.

This study evaluated associations between craniofacial candidate genes and skeletal variation in patients with malocclusion. Lateral cephalometric radiographs of 269 untreated adults with skeletal classes I, II, and III malocclusion were digitized with 14 landmarks. Twodimensional coordinates were analyzed using Procrustes fit and principal component (PC) analysis to generate continuous malocclusion phenotypes. Skeletal class classifications (I, II, or III) were used as a categorical phenotype. Individuals were genotyped for 198 singlenucleotide polymorphisms (SNPs) in 71 craniofacial genes and loci. Phenotype-genotype associations were tested via multivariate linear regression for continuous phenotypes and multinomial logistic regression for skeletal malocclusion class. PC analysis resulted in 4 principal components (PCs) explaining 69% of the total skeletal facial variation. PC1 explained 32.7% of the variation and depicted vertical discrepancies ranging from skeletal deep to open bites. PC1 was associated with a SNP near PAX5 (P = 0.01). PC2 explained 21.7% and captured horizontal maxillomandibular discrepancies. PC2 was associated with SNPs upstream of SNAI3 (P = 0.0002) and MYO1H (P = 0.006). PC3 explained 8.2% and captured variation in ramus height, body length, and anterior cranial base orientation. PC3 was associated with TWIST1 (P = 0.000076). Finally, PC4 explained 6.6% and detected variation in condylar inclination as well as symphysis projection. PC4 was associated with PAX7 (P = 0.007). Furthermore, skeletal class II risk increased relative to class I with the minor alleles of SNPs in FGFR2 (odds ratio [OR] = 2.1, P = 0.004) and declined with SNPs in EDN1 (OR = 0.5, P = 0.007). Conversely, skeletal class III risk increased versus class I with SNPs in FGFR2 (OR 2.2, P = 0.005) and COL1A1 (OR = 2.1, P = 0.008) and declined with SNPs in TBX5 (OR = 0.5, P = 0.014). PAX5, SNAI3, MYO1H, TWIST1, and PAX7 are associated with craniofacial skeletal variation among patients with malocclusion, while FGFR2, EDN1, TBX5, and COL1A1 are associated with type of skeletal malocclusion.

Malocclusions affect individuals worldwide, resulting in compromised function and esthetics. Understanding the etiological factors contributing to the variation in dentofacial morphology associated with malocclusions is the key to develop novel treatment approaches. Advances in dentofacial phenotyping, which is the comprehensive characterization of hard and soft tissue variation in the craniofacial complex, together with the acquisition of large-scale genomic data have started to unravel genetic mechanisms underlying facial variation. Knowledge on the genetics of human malocclusion is limited even though results attained thus far are encouraging, with promising opportunities for future research. This review summarizes the most common dentofacial variations associated with malocclusions and reviews the current knowledge of the roles of genes in the development of malocclusions. Lastly, this review will describe ways to advance malocclusion research, following examples from the expanding fields of phenomics and genomic medicine, which aim to better patient outcomes.

During ontogeny, the nasal septum exerts a morphogenetic influence on the surrounding facial skeleton. While the influence of the septum is well established in long snouted animal models, its role in human facial growth is less clear. If the septum is a facial growth center in humans, we would predict that deviated septal growth would be associated with facial skeletal asymmetries. Using computed tomographic (CT) scans of n 5 55 adult subjects, the purpose of this study was to test whether there is a correlation between septal deviation and facial asymmetries using three-dimensional (3D) geometric morphometric techniques. We calculated deviation as a percentage of septal volume relative to the volume of a modeled non-deviated septum. We then recorded skeletal landmarks representing the nasal, palatal, and lateral facial regions. Landmark data were superimposed using Procrustes analysis. First, we examined the correlation between nasal septal deviation and the overall magnitude of asymmetry. Next, we assessed whether there was a relationship between nasal septal deviation and more localized aspects of asymmetry using multivariate regression analysis. Our results indicate that while there was no correlation between septal deviation and the overall magnitude of asymmetry, septal deviation was associated with asymmetry primarily in the nasal floor and the palatal region. Septal deviation was unassociated with asymmetries in the lateral facial skeleton. Though we did not test the causal relationship between nasal septal deviation and facial asymmetry, our results suggest that the nasal septum may have an influence on patterns of adult facial form. Anat Rec, 299:295-306, 2016. V C 2015 Wiley Periodicals, Inc. Key words: ontogeny; geometric morphometrics; facial skeletonCraniofacial and occlusal asymmetries are commonly observed in populations and can result from a number of causative factors. These include the early loss of primary teeth, loss of permanent teeth, genetic or congenital malformations (e.g., hemifacial microsomia, unilateral clefts, etc.), environmental factors (e.g., habits and trauma), and functional deviations (Bishara et al., 1994;Burstone, 1998

Family relatives of children with nonsyndromic cleft lip with or without cleft palate (NSCL/P) who presumably carry a genetic risk yet do not manifest overt oral clefts, often present with distinct facial morphology of unknown genetic etiology. This study investigates distinct facial morphology among unaffected relatives and examines whether candidate genes previously associated with overt NSCL/P and left–right body patterning are correlated with such facial morphology. Cases were unaffected relatives of individuals with NSCL/P (n = 188) and controls (n = 194) were individuals without family history of NSCL/P. Cases and controls were genotyped for 20 SNPs across 13 candidate genes for NSCL/P (PAX7, ABCA4-ARHGAP29, IRF6, MSX1, PITX2, 8q24, FOXE1, TGFB3 and MAFB) and left–right body patterning (LEFTY1, LEFTY2, ISL1 and SNAI1). Facial shape and asymmetry phenotypes were obtained via principal component analyses and Procrustes analysis of variance from 32 coordinate landmarks, digitized on 3D facial images. Case–control comparisons of phenotypes obtained were performed via multivariate regression adjusting for age and gender. Phenotypes that differed significantly (P < 0.05) between cases and controls were regressed on the SNPs one at a time. Cases had significantly (P < 0.05) more profile concavity with upper face retrusion, upturned noses with obtuse nasolabial angles, more protrusive chins, increased lower facial heights, thinner and more retrusive lips and more protrusive foreheads. Furthermore, cases showed significantly more directional asymmetry compared to controls. Several of these phenotypes were significantly associated with genetic variants (P < 0.05). Facial height and width were associated with SNAI1. Midface antero-posterior (AP) projection was associated with LEFTY1. The AP position of the chin was related to SNAI1, IRF6, MSX1 and MAFB. The AP position of the forehead and the width of the mouth were associated with ABCA4–ARHGAP29 and MAFB. Lastly, facial asymmetry was related to LEFTY1, LEFTY2 and SNAI1. This study demonstrates that, genes underlying lip and palate formation and left–right patterning also contribute to facial features characteristic of the NSCL/P spectrum.