How the Environmental influences on Child Health Outcome (ECHO) Cohort can spur discoveries in environmental epidemiology.

NIH's Environmental influences on Child Health Outcome (ECHO) program is an innovative, large, collaborative research initiative whose mission is to enhance the health of children for generations to come. The goal of the ECHO Cohort is to examine effects of a broad array of early environmental exposures on child health and development. It includes longitudinal data and biospecimens from over 100,000 children and family members from diverse settings across the U.S. ECHO investigators have published collaborative analyses showing associations of environmental exposures--primarily in the developmentally sensitive pre-, peri-, and post-natal periods--with preterm birth and childhood asthma, obesity, neurodevelopment, and positive health. Investigators have addressed health disparities, joint effects of environmental and social determinants, and effects of mixtures of chemicals. The ECHO Cohort is now entering its second 7-year cycle (2023-2030), which will add the preconception period to its current focus on prenatal through adolescence. Through a controlled access public use database, ECHO makes its deidentified data available to the general scientific community. ECHO Cohort data provide opportunities to fill major knowledge gaps in in environmental epidemiology, and to inform policies, practices, and programs to enhance child health.

Consent Codes: Upholding Standard Data Use Conditions.

A systematic way of recording data use conditions that are based on consent permissions as found in the datasets of the main public genome archives (NCBI dbGaP and EMBL-EBI/CRG EGA).

The pleiotropic mouse phenotype extra-toes spotting is caused by translation initiation factor Eif3c mutations and is associated with disrupted sonic hedgehog signaling.

Polydactyly is a common malformation and can be an isolated anomaly or part of a pleiotropic syndrome. The elucidation of the mutated genes that cause polydactyly provides insight into limb development pathways. The extra-toes spotting (Xs) mouse phenotype manifests anterior polydactyly, predominantly in the forelimbs, with ventral hypopigmenation. The mapping of Xs(J) to chromosome 7 was confirmed, and the interval was narrowed to 322 kb using intersubspecific crosses. Two mutations were identified in eukaryotic translation initiation factor 3 subunit C (Eif3c). An Eif3c c.907C>T mutation (p.Arg303X) was identified in Xs(J), and a c.1702_1758del mutation (p.Leu568_Leu586del) was identified in extra-toes spotting-like (Xsl), an allele of Xs(J). The effect of the Xs(J) mutation on the SHH/GLI3 pathway was analyzed by in situ hybridization analysis, and we show that Xs mouse embryos have ectopic Shh and Ptch1 expression in the anterior limb. In addition, anterior limb buds show aberrant Gli3 processing, consistent with perturbed SHH/GLI3 signaling. Based on the occurrence of Eif3c mutations in 2 Xs lines and haploinsufficiency of the Xs(J) allele, we conclude that the Xs phenotype is caused by a mutation in Eif3c, a component of the translation initiation complex, and that the phenotype is associated with aberrant SHH/GLI3 signaling.

Multiple Asian pig origins revealed through genomic analyses.

Previous mitochondrial DNA (mtDNA) studies have suggested that European and Asian pig populations were derived through multiple domestication events. We investigated whether domestic pig populations were derived from distinct ancestors within their respective regions, using eight domestic breeds (five European and three Asian), and also European and Asian wild boar populations. Genomic analyses utilized 21 microsatellite markers (MS) selected for their distribution across the pig genome in addition to the mtDNA D-loop region. The number of alleles per MS loci ranged from 8 (Sw2008) to 16 (S0097 and S0218). Few significant departures from Hardy-Weinberg equilibrium were detected, suggesting the absence of heterozygote deficiencies. Analyses within populations revealed observed mean heterozygosity from 0.48 (Erhualian) to 0.68 (Dutch WB) and an expected mean heterozygosity from 0.53 (Hampshire) to 0.80 (Japanese WB) with effective alleles ranging from 2.28 (Hampshire) to 3.74 (French WB). Wild boar populations demonstrated a higher level of heterozygosity than domestic breeds. Genetic differentiation estimated by fixation indices (F(ST)) ranged from 0.021 (Yorkshire and Duroc) to 0.410 (Meishan and Hampshire) and was consistent with previous mtDNA analysis. Both phylogenetic and principal component analyses revealed a distinct separation of European and Asian derived populations with tight clustering of the European domestic breeds. Conversely, the use of both MS and mtDNA clarified that the Asian populations were comprised of three groups, one represented by Erhualian and Meishan breed, the second represented by Lanyu pigs and the third represented by the Asian wild boars. The current findings support the hypothesis that Asian domestic populations were derived from multiple Asian ancestral origins whereas the European domestic populations represent a single ancestral European lineage.

Diversification of porcine MHC class II genes: evidence for selective advantage.

The major histocompatibility complex (MHC) is an immunological gene-dense region of high diversity in mammalian species. Sus scrofa was domesticated by at least six independent events over Eurasia during the Holocene period. It has been hypothesized that the level and distribution of MHC variation in pig populations reflect genetic selection and environmental influences. In an effort to define the complexity of MHC polymorphisms and the role of selection in the generation of class II gene diversity (DQB, DRB1, and pseudogene PsiDRB3), DNA from globally distributed unrelated domestic pigs of European and Asian origins and a Suidae out-group was analyzed. The number of pseudogene alleles identified (PsiDRB3 33) was greater than those found in the expressed genes (DQB 20 and DRB1 23) but the level of observed heterozygosity (PsiDRB3 0.452, DQB 0.732, and DRB1 0.767) and sequence diversity (PsiDRB3 0.029, DQB 0.062, and DRB1 0.074) were significantly lower in the pseudogene, respectively. The substitution ratios reflected an excess of d (N) (DQB 1.476, DRB1 1.724, and PsiDRB3 0.508) and the persistence of expressed gene alleles suggesting the influence of balancing selection, while the pseudogene was undergoing purifying selection. The lack of a clear MHC phylogeographic tree, coupled with close genetic distances observed between the European and Asian populations (DQB 0.047 and DRB1 0.063) suggested that unlike observations using mtDNA, the MHC diversity lacks phylogeographic structure and appears to be globally uniform. Taken together, these results suggest that, despite regional differences in selective breeding and environments, no skewing of MHC diversity has occurred.

Functional characterization of the chicken peptide transporter 1 (pept1, slc15a1) gene.

Dietary amino acids can be transported into intestinal epithelial cells as di- and tripeptides by the action of the peptide transporter, PepT1 (SLC15A1). Expression of the chicken PepT1 (cPepT1) gene changes in response to dietary crude protein level; however, the molecular mechanism governing this regulation is unknown. This study analyzed the promoter region of the cPepT1 gene. Using deletion analysis, positive-acting (-314 to -261, -169 to -155, and -120 to -60) and negative-acting (-419 to -386 and -214 to -169) regions were mapped in transfected chick embryo fibroblasts (CEF). The addition of neither amino acids Phe, Arg, or Val, nor the dipeptides Gly-Sar (glycyl-sarcosine), Gly-Pro, Gly-Phe, Met-Pro, Met-Lys or Lys-Lys, had an effect on cPepT1 promoter activity in transfected CEF. The cPepT1 promoter was more active in CEF and primary chicken intestinal cells than in chicken liver cells. This study represents a functional characterization of the molecular regulation of the chicken PepT1 gene.