@article {595,
	title = {Insights into genetics, human biology and disease gleaned from family based genomic studies.},
	journal = {Genet Med},
	volume = {21},
	year = {2019},
	month = {2019 04},
	pages = {798-812},
	abstract = {<p>Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75\% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in~novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.</p>},
	keywords = {Databases, Genetic, Genetic Diseases, Inborn, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome, Human, Genomics, Humans, National Institutes of Health (U.S.), Pedigree, United States, Whole Exome Sequencing},
	issn = {1530-0366},
	doi = {10.1038/s41436-018-0408-7},
	author = {Posey, Jennifer E and O{\textquoteright}Donnell-Luria, Anne H and Chong, Jessica X and Harel, Tamar and Jhangiani, Shalini N and Coban Akdemir, Zeynep H and Buyske, Steven and Pehlivan, Davut and Carvalho, Claudia M B and Baxter, Samantha and Sobreira, Nara and Liu, Pengfei and Wu, Nan and Rosenfeld, Jill A and Kumar, Sushant and Avramopoulos, Dimitri and White, Janson J and Doheny, Kimberly F and Witmer, P Dane and Boehm, Corinne and Sutton, V Reid and Muzny, Donna M and Boerwinkle, Eric and G{\"u}nel, Murat and Nickerson, Deborah A and Mane, Shrikant and MacArthur, Daniel G and Gibbs, Richard A and Hamosh, Ada and Lifton, Richard P and Matise, Tara C and Rehm, Heidi L and Gerstein, Mark and Bamshad, Michael J and Valle, David and Lupski, James R}
}
@article {352,
	title = {Intensification: A Resource for Amplifying Population-Genetic Signals with Protein Repeats.},
	journal = {J Mol Biol},
	volume = {429},
	year = {2017},
	month = {2017 02 03},
	pages = {435-445},
	abstract = {<p>Large-scale genome sequencing holds great promise for the interpretation of protein structures through the discovery of many, rare functional variants in the human population. However, because protein-coding regions are under high selective constraints, these variants occur at low frequencies, such that there is often insufficient statistics for downstream calculations. To address this problem, we develop the Intensification approach, which uses the modular structure of repeat protein domains to amplify signals of selection from population genetics and traditional interspecies conservation. In particular, we are able to aggregate variants at the codon level to identify important positions in repeat domains that show strong conservation signals. This allows us to compare conservation over different evolutionary timescales. It also enables us to visualize population-genetic measures on protein structures. We make available the Intensification results as an online resource (http://intensification.gersteinlab.org) and illustrate the approach through a case study on the tetratricopeptide repeat.</p>},
	keywords = {Amino Acid Sequence, Chromosome Mapping, Codon, Computational Biology, Databases, Genetic, Evolution, Molecular, Genetics, Population, Humans, Internet, Molecular Structure, Protein Conformation, Proteins, Signal Processing, Computer-Assisted, X-Rays},
	issn = {1089-8638},
	doi = {10.1016/j.jmb.2016.12.003},
	author = {Chen, Jieming and Wang, Bo and Regan, Lynne and Gerstein, Mark}
}
