@article {89, title = {A positively selected FBN1 missense variant reduces height in Peruvian individuals.}, journal = {Nature}, volume = {582}, year = {2020}, month = {2020 06}, pages = {234-239}, abstract = {

On average, Peruvian individuals are among the shortest in the world. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7\%) reduces height by 2.2~cm (4.4~cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin~1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.

}, keywords = {Body Height, Female, Fibrillin-1, Gene Frequency, Genome-Wide Association Study, Heredity, Humans, Indians, South American, Male, Microfibrils, Mutation, Missense, Peru, Selection, Genetic}, issn = {1476-4687}, doi = {10.1038/s41586-020-2302-0}, author = {Asgari, Samira and Luo, Yang and Akbari, Ali and Belbin, Gillian M and Li, Xinyi and Harris, Daniel N and Selig, Martin and Bartell, Eric and Calderon, Roger and Slowikowski, Kamil and Contreras, Carmen and Yataco, Rosa and Galea, Jerome T and Jimenez, Judith and Coit, Julia M and Farro{\~n}ay, Chandel and Nazarian, Rosalynn M and O{\textquoteright}Connor, Timothy D and Dietz, Harry C and Hirschhorn, Joel N and Guio, Heinner and Lecca, Leonid and Kenny, Eimear E and Freeman, Esther E and Murray, Megan B and Raychaudhuri, Soumya} } @article {31, title = {Functional genomics of stromal cells in chronic inflammatory diseases.}, journal = {Curr Opin Rheumatol}, volume = {30}, year = {2018}, month = {2018 Jan}, pages = {65-71}, abstract = {

PURPOSE OF REVIEW: Stroma is a broad term referring to the connective tissue matrix in which other cells reside. It is composed of diverse cell types with functions such as extracellular matrix maintenance, blood and lymph vessel development, and effector cell recruitment. The tissue microenvironment is determined by the molecular characteristics and relative abundances of different stromal cells such as fibroblasts, endothelial cells, pericytes, and mesenchymal precursor cells. Stromal cell heterogeneity is explained by embryonic developmental lineage, stages of differentiation to other cell types, and activation states. Interaction between immune and stromal cell types is critical to wound healing, cancer, and a wide range of inflammatory diseases. Here, we review recent studies of inflammatory diseases that use functional genomics and single-cell technologies to identify and characterize stromal cell types associated with pathogenesis.

RECENT FINDINGS: High dimensional strategies using mRNA sequencing, mass cytometry, and fluorescence activated cell-sorting with fresh primary tissue samples are producing detailed views of what is happening in diseased tissue in rheumatoid arthritis, inflammatory bowel disease, and cancer. Fibroblasts positive for CD90 (Thy-1) are enriched in the synovium of rheumatoid arthritis patients. Single-cell RNA-seq studies will lead to more discoveries about the stroma in the near future.

SUMMARY: Stromal cells form the microenvironment of inflamed and diseased tissues. Functional genomics is producing an increasingly detailed view of subsets of stromal cells with pathogenic functions in rheumatic diseases and cancer. Future genomics studies will discover disease mechanisms by perturbing molecular pathways with chemokines and therapies known to affect patient outcomes. Functional genomics studies with large sample sizes of patient tissues will identify patient subsets with different disease phenotypes or treatment responses.

}, keywords = {Arthritis, Rheumatoid, Cell Differentiation, Chemokines, Endothelial Cells, Fibroblasts, Flow Cytometry, Genomics, Humans, Inflammatory Bowel Diseases, Mesenchymal Stem Cells, Pericytes, Rheumatic Diseases, RNA, Messenger, Sequence Analysis, RNA, Single-Cell Analysis, Stromal Cells, Synovial Membrane, Thy-1 Antigens}, issn = {1531-6963}, doi = {10.1097/BOR.0000000000000455}, author = {Slowikowski, Kamil and Wei, Kevin and Brenner, Michael B and Raychaudhuri, Soumya} }