@article {1021, title = {Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 04 16}, pages = {2282}, abstract = {

Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer-promoter interactions.

}, keywords = {Animals, Binding Sites, CCCTC-Binding Factor, Chromatin Immunoprecipitation Sequencing, Disease Models, Animal, Embryo, Mammalian, Enhancer Elements, Genetic, Exons, Extremities, Female, Foot Deformities, Congenital, Gene Expression Regulation, Developmental, Genetic Loci, Genetic Testing, Hand Deformities, Congenital, Hedgehog Proteins, Humans, Introns, Male, Membrane Proteins, Mice, Mice, Knockout, Promoter Regions, Genetic, Sequence Deletion, Species Specificity, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-021-22470-z}, author = {Ushiki, Aki and Zhang, Yichi and Xiong, Chenling and Zhao, Jingjing and Georgakopoulos-Soares, Ilias and Kane, Lauren and Jamieson, Kirsty and Bamshad, Michael J and Nickerson, Deborah A and Shen, Yin and Lettice, Laura A and Silveira-Lucas, Elizabeth Lemos and Petit, Florence and Ahituv, Nadav} } @article {881, title = {Copy number variants~and fixed duplications among 198 rhesus macaques (Macaca mulatta).}, journal = {PLoS Genet}, volume = {16}, year = {2020}, month = {2020 05}, pages = {e1008742}, abstract = {

The rhesus macaque is an abundant species of Old World monkeys and a valuable model organism for biomedical research due to its close phylogenetic relationship to humans. Copy number variation is one of the main sources of genomic diversity within and between species and a widely recognized cause of inter-individual differences in disease risk. However, copy number differences among rhesus macaques and between the human and macaque genomes, as well as the relevance of this diversity to research involving this nonhuman primate, remain understudied. Here we present a high-resolution map of sequence copy number for the rhesus macaque genome constructed from a dataset of 198 individuals. Our results show that about one-eighth of the rhesus macaque reference genome is composed of recently duplicated regions, either copy number variable regions or fixed duplications. Comparison with human genomic copy number maps based on previously published data shows that, despite overall similarities in the genome-wide distribution of these regions, there are specific differences at the chromosome level. Some of these create differences in the copy number profile between human disease genes and their rhesus macaque orthologs. Our results highlight the importance of addressing the number of copies of target genes in the design of experiments and cautions against human-centered assumptions in research conducted with model organisms. Overall, we present a genome-wide copy number map from a large sample of rhesus macaque individuals representing an important novel contribution concerning the evolution of copy number in primate genomes.

}, keywords = {Animals, Chromosome Mapping, DNA Copy Number Variations, Female, Gene Duplication, Genetics, Population, Genome, High-Throughput Nucleotide Sequencing, Humans, Macaca mulatta, Male, Open Reading Frames, Phylogeny, Sequence Analysis, DNA, Species Specificity}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1008742}, author = {Bras{\'o}-Vives, Marina and Povolotskaya, Inna S and Hartas{\'a}nchez, Diego A and Farr{\'e}, Xavier and Fernandez-Callejo, Marcos and Raveendran, Muthuswamy and Harris, R Alan and Rosene, Douglas L and Lorente-Galdos, Belen and Navarro, Arcadi and Marques-Bonet, Tomas and Rogers, Jeffrey and Juan, David} } @article {260, title = {Mutations in TJP2 cause progressive cholestatic liver disease.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Apr}, pages = {326-8}, abstract = {

Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.

}, keywords = {Animals, Base Sequence, Cholestasis, Intrahepatic, High-Throughput Nucleotide Sequencing, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Models, Biological, Molecular Sequence Data, Mutation, Pedigree, Real-Time Polymerase Chain Reaction, Sequence Alignment, Species Specificity, Tight Junctions, Zonula Occludens-2 Protein}, issn = {1546-1718}, doi = {10.1038/ng.2918}, author = {Sambrotta, Melissa and Strautnieks, Sandra and Papouli, Efterpi and Rushton, Peter and Clark, Barnaby E and Parry, David A and Logan, Clare V and Newbury, Lucy J and Kamath, Binita M and Ling, Simon and Grammatikopoulos, Tassos and Wagner, Bart E and Magee, John C and Sokol, Ronald J and Mieli-Vergani, Giorgina and Smith, Joshua D and Johnson, Colin A and McClean, Patricia and Simpson, Michael A and Knisely, A S and Bull, Laura N and Thompson, Richard J} }