Fast Principal-Component Analysis Reveals Convergent Evolution of in Europe and East Asia
Searching for genetic variants with unusual differentiation between subpopulations is an established approach for identifying signals of natural selection. However, existing methods generally require discrete subpopulations. We introduce a method that infers selection using principal components (PCs) by identifying variants whose differentiation along top PCs is significantly greater than the null distribution of genetic drift. To enable the application of this method to large datasets, we developed the FastPCA software, which employs recent advances in random matrix theory to accurately approximate top PCs while reducing ...
Source: The American Journal of Human Genetics - February 25, 2016 Category: Genetics & Stem Cells Authors: Kevin J. Galinsky, Gaurav Bhatia, Po-Ru Loh, Stoyan Georgiev, Sayan Mukherjee, Nick J. Patterson, Alkes L. Price Tags: Article Source Type: research

Alleles Resulting in a −1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome
Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a −1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR...
Source: The American Journal of Human Genetics - February 25, 2016 Category: Genetics & Stem Cells Authors: Janson J. White, Juliana F. Mazzeu, Alexander Hoischen, Yavuz Bayram, Marjorie Withers, Alper Gezdirici, Virginia Kimonis, Marloes Steehouwer, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, Baylor-Hopkins Center for Mendelian Genomics, Bregj Tags: Report Source Type: research

Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures
We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 25, 2016 Category: Genetics & Stem Cells Authors: Ellen Knierim, Hiromi Hirata, Nicole I. Wolf, Susanne Morales-Gonzalez, Gudrun Schottmann, Yu Tanaka, Sabine Rudnik-Schöneborn, Mickael Orgeur, Klaus Zerres, Stefanie Vogt, Anne van Riesen, Esther Gill, Franziska Seifert, Angelika Zwirner, Janbernd Kir Tags: Article Source Type: research

Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases
Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between ...
Source: The American Journal of Human Genetics - February 25, 2016 Category: Genetics & Stem Cells Authors: Daniel Greene, NIHR BioResource, Sylvia Richardson, Ernest Turro Tags: Article Source Type: research

MEGSA: A Powerful and Flexible Framework for Analyzing Mutual Exclusivity of Tumor Mutations
The central challenges in tumor sequencing studies is to identify driver genes and pathways, investigate their functional relationships, and nominate drug targets. The efficiency of these analyses, particularly for infrequently mutated genes, is compromised when subjects carry different combinations of driver mutations. Mutual exclusivity analysis helps address these challenges. To identify mutually exclusive gene sets (MEGS), we developed a powerful and flexible analytic framework based on a likelihood ratio test and a model selection procedure. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 18, 2016 Category: Genetics & Stem Cells Authors: Xing Hua, Paula L. Hyland, Jing Huang, Lei Song, Bin Zhu, Neil E. Caporaso, Maria Teresa Landi, Nilanjan Chatterjee, Jianxin Shi Tags: Article Source Type: research

Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor
Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). (Source: The American Jo...
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Giuseppina Divisato, Daniela Formicola, Teresa Esposito, Daniela Merlotti, Laura Pazzaglia, Andrea Del Fattore, Ethel Siris, Philippe Orcel, Jacques P. Brown, Ranuccio Nuti, Pasquale Strazzullo, Maria Serena Benassi, M. Leonor Cancela, Laetitia Michou Tags: Article Source Type: research

Disease and Polygenic Architecture: Avoid Trio Design and Appropriately Account for Unscreened Control Subjects for Common Disease
Genome-wide association studies (GWASs) are an optimal design for discovery of disease risk loci for diseases whose underlying genetic architecture includes many common causal loci of small effect (a polygenic architecture). We consider two designs that deserve careful consideration if the true underlying genetic architecture of the trait is polygenic: parent-offspring trios and unscreened control subjects. We assess these designs in terms of quantification of the total contribution of genome-wide genetic markers to disease risk (SNP heritability) and power to detect an associated risk allele. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Wouter J. Peyrot, Dorret I. Boomsma, Brenda W.J.H. Penninx, Naomi R. Wray Tags: Report Source Type: research

The CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease
Huntington disease (HD) is caused by an expanded HTT CAG repeat that leads in a length-dependent, completely dominant manner to onset of a characteristic movement disorder. HD also displays early mortality, so we tested whether the expanded CAG repeat exerts a dominant influence on age at death and on the duration of clinical disease. We found that, as with clinical onset, HD age at death is determined by expanded CAG-repeat length and has no contribution from the normal CAG allele. Surprisingly, disease duration is independent of the mutation’s length. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Jae Whan Keum, Aram Shin, Tammy Gillis, Jayalakshmi Srinidhi Mysore, Kawther Abu Elneel, Diane Lucente, Tiffany Hadzi, Peter Holmans, Lesley Jones, Michael Orth, Seung Kwak, Marcy E. MacDonald, James F. Gusella, Jong-Min Lee Tags: Article Source Type: research

A Robust Example of Collider Bias in a Genetic Association Study
To the Editor: “Collider bias” (also referred to as the “reversal paradox”)1 describes the artificial association created between two exposures (A and B) when a shared outcome (X) is included in the model as a covariate (Figure 1). A recent paper by Aschard et al. described the potential for collider bias when adjusting for heritable covariates in genetic association studies.2 However, in their examples, the authors acknowledged that they could not exclude the possibility of a true biological explanation for the genetic association seen only in the adjusted model. (Source: The American Jou...
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Felix R. Day, Po-Ru Loh, Robert A. Scott, Ken K. Ong, John R.B. Perry Tags: Letters to the Editor Source Type: research

Response to Day et al.
To the Editor: Day et al. present a striking example of how adjusting for heritable covariates correlated with the outcome in a genetic association study can bias genetic effect estimates—possibly creating a strong association where genotype has no causal effect on outcome. This bias was the focus of our recent report.1 As Day et al. point out, this phenomenon is a special case of the broader concept of collider-stratification bias2,3. By choosing an outcome that is not associated with autosomal variation (gender), but strongly associated with the covariate (height), Day et al. (Source: The American Jo...
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Hugues Aschard, Bjarni J. Vilhjálmsson, Amit D. Joshi, Alkes L. Price, Peter Kraft Tags: Letters to the Editor Source Type: research

A Burden of Rare Variants Associated with Extremes of Gene Expression in Human Peripheral Blood
In order to evaluate whether rare regulatory variants in the vicinity of promoters are likely to impact gene expression, we conducted a novel burden test for enrichment of rare variants at the extremes of expression. After sequencing 2-kb promoter regions of 472 genes in 410 healthy adults, we performed a quadratic regression of rare variant count on bins of peripheral blood transcript abundance from microarrays, summing over ranks of all genes. After adjusting for common eQTLs and the major axes of gene expression covariance, a highly significant excess of variants with minor allele frequency less than 0.05 at both high a...
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Jing Zhao, Idowu Akinsanmi, Dalia Arafat, T.J. Cradick, Ciaran M. Lee, Samridhi Banskota, Urko M. Marigorta, Gang Bao, Greg Gibson Tags: Article Source Type: research

This Month in Genetics
Many of the genes considered to include actionable incidental findings, according to recommendations by the American College of Medical Genetics and Genomics, are cardiac genes implicated in arrhythmia and sudden cardiac death. Researchers classically seek variation in these genes to explain overt cardiac phenotypes in patients, but by definition, an incidental finding is one that does not explain the referring diagnosis. Because of this dichotomy, van Driest et al. used an unselected adult cohort to assess the presence of relevant cardiac phenotypes, as gleaned from electronic medical records, in individuals with var...
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors ’ Corner Source Type: research

This Month in
With the advent, and reduction in cost, of next-generation sequencing, large-scale studies of diverse cancer types have yielded unparalleled insights into the genetic causes of cancer. The hope is that these sequencing-based studies will inform the development and implementation of targeted therapeutics. Although many studies have focused on the identification of exonic single-nucleotide variants (SNVs), the presence of structural variation in cancer genomes is well documented and is also thought to contribute to both tumorigenesis and cancer progression. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors ’ Corner Source Type: research

Response to Hellenthal et al.:
To the editor: In our paper “The Kalash Genetic Isolate: Ancient Divergence, Drift, and Selection,” we reported that the Kalash people of present-day Pakistan experienced no detectable gene flow from their geographic neighbors in Pakistan, or from the other extant western Eurasian populations tested, since their split from a common ancestor.1 It is probably true that no human population is completely cut off from all others, but populations with limited gene flow to and from the outside, especially when combined with a small effective population size and increased genetic drift, endogamous practices, and a diff...
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Qasim Ayub, Massimo Mezzavilla, Luca Pagani, Marc Haber, Aisha Mohyuddin, Shagufta Khaliq, Syed Qasim Mehdi, Chris Tyler-Smith Tags: Letters to the Editor Source Type: research

The Kalash Genetic Isolate? The Evidence for Recent Admixture
To the editor: The recent paper “The Kalash Genetic Isolate: Ancient Divergence, Drift, and Selection,” by Ayub et al.1 suggests that the Kalash people of present-day Pakistan experienced “no detectable gene flow from their geographic neighbors in Pakistan or from other extant Eurasian populations” since their split from those populations over 8,000 years ago. They note that this finding of apparent genetic isolation contradicts the results of Hellenthal et al.,2 who inferred DNA introgression dated to 910–220 BCE in an overlapping sample of Kalash individuals. (Source: The Amer...
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Garrett Hellenthal, Daniel Falush, Simon Myers, David Reich, George B.J. Busby, Mark Lipson, Cristian Capelli, Nick Patterson Tags: Letters to the Editor Source Type: research

Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors
(The American Journal of Human Genetics 98, 22–33; January 7, 2016) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - February 4, 2016 Category: Genetics & Stem Cells Authors: Michael Dannemann, Aida M. Andrés, Janet Kelso Tags: Correction Source Type: research

CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation
Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 28, 2016 Category: Genetics & Stem Cells Authors: Jos C. Jansen, Sebahattin Cirak, Monique van Scherpenzeel, Sharita Timal, Janine Reunert, Stephan Rust, Belén Pérez, Dorothée Vicogne, Peter Krawitz, Yoshinao Wada, Angel Ashikov, Celia Pérez-Cerdá, Celia Medrano, Andrea Arnoldy, Alexander Hoischen Tags: Article Source Type: research

TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation
Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known a...
Source: The American Journal of Human Genetics - January 28, 2016 Category: Genetics & Stem Cells Authors: Jos C. Jansen, Sharita Timal, Monique van Scherpenzeel, Helen Michelakakis, Dorothée Vicogne, Angel Ashikov, Marina Moraitou, Alexander Hoischen, Karin Huijben, Gerry Steenbergen, Marjolein A.W. van den Boogert, Francesco Porta, Pier Luigi Calvo, M Tags: Report Source Type: research

Retrospective Binary-Trait Association Test Elucidates Genetic Architecture of Crohn Disease
In genetic association testing, failure to properly control for population structure can lead to severely inflated type 1 error and power loss. Meanwhile, adjustment for relevant covariates is often desirable and sometimes necessary to protect against spurious association and to improve power. Many recent methods to account for population structure and covariates are based on linear mixed models (LMMs), which are primarily designed for quantitative traits. For binary traits, however, LMM is a misspecified model and can lead to deteriorated performance. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 28, 2016 Category: Genetics & Stem Cells Authors: Duo Jiang, Sheng Zhong, Mary Sara McPeek Tags: Article Source Type: research

Whole-Genome Sequencing Reveals Diverse Models of Structural Variations in Esophageal Squamous Cell Carcinoma
Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and ...
Source: The American Journal of Human Genetics - January 28, 2016 Category: Genetics & Stem Cells Authors: Caixia Cheng, Yong Zhou, Hongyi Li, Teng Xiong, Shuaicheng Li, Yanghui Bi, Pengzhou Kong, Fang Wang, Heyang Cui, Yaoping Li, Xiaodong Fang, Ting Yan, Yike Li, Juan Wang, Bin Yang, Ling Zhang, Zhiwu Jia, Bin Song, Xiaoling Hu, Jie Yang, Haile Qiu, Gehong Z Tags: Article Source Type: research

Small 6q16.1 Deletions Encompassing Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability
Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin> melanocortin> SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 28, 2016 Category: Genetics & Stem Cells Authors: Paul R. Kasher, Katherine E. Schertz, Megan Thomas, Adam Jackson, Silvia Annunziata, María J. Ballesta-Martinez, Philippe M. Campeau, Peter E. Clayton, Jennifer L. Eaton, Tiziana Granata, Encarna Guillén-Navarro, Cristina Hernando, Caroline E. La Tags: Report Source Type: research

De Novo Loss-of-Function Mutations in Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations
Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polyd...
Source: The American Journal of Human Genetics - January 28, 2016 Category: Genetics & Stem Cells Authors: Margot R.F. Reijnders, Vasilios Zachariadis, Brooke Latour, Lachlan Jolly, Grazia M. Mancini, Rolph Pfundt, Ka Man Wu, Conny M.A. van Ravenswaaij-Arts, Hermine E. Veenstra-Knol, Britt-Marie M. Anderlid, Stephen A. Wood, Sau Wai Cheung, Angela Bar Tags: Report Source Type: research

Bi-allelic Truncating Mutations in Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy
Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different bi-allelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 21, 2016 Category: Genetics & Stem Cells Authors: Laura S. Kremer, Felix Distelmaier, Bader Alhaddad, Maja Hempel, Arcangela Iuso, Clemens Küpper, Chris Mühlhausen, Reka Kovacs-Nagy, Robin Satanovskij, Elisabeth Graf, Riccardo Berutti, Gertrud Eckstein, Richard Durbin, Sascha Sauer, Georg F. Hoffmann Tags: Report Source Type: research

Genome-wide Association Study of Platelet Count Identifies Ancestry-Specific Loci in Hispanic/Latino Americans
Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10−28) in ACTN1, a gene implicated in congenital macrothrombocytopenia. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 21, 2016 Category: Genetics & Stem Cells Authors: Ursula M. Schick, Deepti Jain, Chani J. Hodonsky, Jean V. Morrison, James P. Davis, Lisa Brown, Tamar Sofer, Matthew P. Conomos, Claudia Schurmann, Caitlin P. McHugh, Sarah C. Nelson, Swarooparani Vadlamudi, Adrienne Stilp, Anna Plantinga, Leslie B Tags: Article Source Type: research

Autosomal-Recessive Hearing Impairment due to Rare Missense Variants within
The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 21, 2016 Category: Genetics & Stem Cells Authors: Regie Lyn P. Santos-Cortez, Rabia Faridi, Atteeq U. Rehman, Kwanghyuk Lee, Muhammad Ansar, Xin Wang, Robert J. Morell, Rivka Isaacson, Inna A. Belyantseva, Hang Dai, Anushree Acharya, Tanveer A. Qaiser, Dost Muhammad, Rana Amjad Ali, Sulaiman Shams Tags: Report Source Type: research

Mitotic Intragenic Recombination: A Mechanism of Survival for Several Congenital Disorders of Glycosylation
Congenital disorders of glycosylation (CDGs) are disorders of abnormal protein glycosylation that affect multiple organ systems. Because most CDGs have been described in only a few individuals, our understanding of the associated phenotypes and the mechanisms of individual survival are limited. In the process of studying two siblings, aged 6 and 11 years, with MOGS-CDG and biallelic MOGS (mannosyl-oligosaccharide glucosidase) mutations (GenBank: NM_006302.2; c.[65C>A; 329G>A] p.[Ala22Glu; Arg110His]; c.[370C>T] p.[Gln124∗]), we noted that their survival was much longer than the previous report of MOGS-CDG, ...
Source: The American Journal of Human Genetics - January 21, 2016 Category: Genetics & Stem Cells Authors: Megan S. Kane, Mariska Davids, Christopher Adams, Lynne A. Wolfe, Helen W. Cheung, Andrea Gropman, Yan Huang, NISC Comparative Sequencing Program, Bobby G. Ng, Hudson H. Freeze, David R. Adams, William A. Gahl, Cornelius F. Boerkoel Tags: Report Source Type: research

Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia due to Bi-allelic Mutations
The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3&ndash...
Source: The American Journal of Human Genetics - January 21, 2016 Category: Genetics & Stem Cells Authors: Seema R. Lalani, Pengfei Liu, Jill A. Rosenfeld, Levi B. Watkin, Theodore Chiang, Magalie S. Leduc, Wenmiao Zhu, Yan Ding, Shujuan Pan, Francesco Vetrini, Christina Y. Miyake, Marwan Shinawi, Tomasz Gambin, Mohammad K. Eldomery, Zeynep Hande Coban Tags: Report Source Type: research

Biallelic Truncating Mutations in Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy
Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different biallelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 21, 2016 Category: Genetics & Stem Cells Authors: Laura S. Kremer, Felix Distelmaier, Bader Alhaddad, Maja Hempel, Arcangela Iuso, Clemens Küpper, Chris Mühlhausen, Reka Kovacs-Nagy, Robin Satanovskij, Elisabeth Graf, Riccardo Berutti, Gertrud Eckstein, Richard Durbin, Sascha Sauer, Georg F. Hoffmann Tags: Report Source Type: research

Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes
Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-th...
Source: The American Journal of Human Genetics - January 7, 2016 Category: Genetics & Stem Cells Authors: Matthieu Deschamps, Guillaume Laval, Maud Fagny, Yuval Itan, Laurent Abel, Jean-Laurent Casanova, Etienne Patin, Lluis Quintana-Murci Tags: Article Source Type: research

Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors
Pathogens and the diseases they cause have been among the most important selective forces experienced by humans during their evolutionary history. Although adaptive alleles generally arise by mutation, introgression can also be a valuable source of beneficial alleles. Archaic humans, who lived in Europe and Western Asia for more than 200,000 years, were probably well adapted to this environment and its local pathogens. It is therefore conceivable that modern humans entering Europe and Western Asia who admixed with them obtained a substantial immune advantage from the introgression of archaic alleles. (Source: The American ...
Source: The American Journal of Human Genetics - January 7, 2016 Category: Genetics & Stem Cells Authors: Michael Dannemann, Aida M. Andrés, Janet Kelso Tags: Article Source Type: research

Genotype Imputation with Millions of Reference Samples
We present a genotype imputation method that scales to millions of reference samples. The imputation method, based on the Li and Stephens model and implemented in Beagle v.4.1, is parallelized and memory efficient, making it well suited to multi-core computer processors. It achieves fast, accurate, and memory-efficient genotype imputation by restricting the probability model to markers that are genotyped in the target samples and by performing linear interpolation to impute ungenotyped variants. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 7, 2016 Category: Genetics & Stem Cells Authors: Brian L. Browning, Sharon R. Browning Tags: Article Source Type: research

Model-free Estimation of Recent Genetic Relatedness
Genealogical inference from genetic data is essential for a variety of applications in human genetics. In genome-wide and sequencing association studies, for example, accurate inference on both recent genetic relatedness, such as family structure, and more distant genetic relatedness, such as population structure, is necessary for protection against spurious associations. Distinguishing familial relatedness from population structure with genotype data, however, is difficult because both manifest as genetic similarity through the sharing of alleles. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 7, 2016 Category: Genetics & Stem Cells Authors: Matthew P. Conomos, Alexander P. Reiner, Bruce S. Weir, Timothy A. Thornton Tags: Article Source Type: research

Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules
Intellectual disability (ID) disorders are genetically and phenotypically extremely heterogeneous. Can this complexity be depicted in a comprehensive way as a means of facilitating the understanding of ID disorders and their underlying biology? We provide a curated database of 746 currently known genes, mutations in which cause ID (ID-associated genes [ID-AGs]), classified according to ID manifestation and associated clinical features. Using this integrated resource, we show that ID-AGs are substantially enriched with co-expression, protein-protein interactions, and specific biological functions. (Source: The American Jour...
Source: The American Journal of Human Genetics - January 7, 2016 Category: Genetics & Stem Cells Authors: Korinna Kochinke, Christiane Zweier, Bonnie Nijhof, Michaela Fenckova, Pavel Cizek, Frank Honti, Shivakumar Keerthikumar, Merel A.W. Oortveld, Tjitske Kleefstra, Jamie M. Kramer, Caleb Webber, Martijn A. Huynen, Annette Schenck Tags: Article Source Type: research

Genetic Diversity and Association Studies in US Hispanic/Latino Populations: Applications in the Hispanic Community Health Study/Study of Latinos
US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rica...
Source: The American Journal of Human Genetics - January 7, 2016 Category: Genetics & Stem Cells Authors: Matthew P. Conomos, Cecelia A. Laurie, Adrienne M. Stilp, Stephanie M. Gogarten, Caitlin P. McHugh, Sarah C. Nelson, Tamar Sofer, Lindsay Fernández-Rhodes, Anne E. Justice, Mariaelisa Graff, Kristin L. Young, Amanda A. Seyerle, Christy L. Avery Tags: Article Source Type: research

Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the Locus
Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 7, 2016 Category: Genetics & Stem Cells Authors: Emily M. Smith, Bryan R. Lajoie, Gaurav Jain, Job Dekker Tags: Article Source Type: research

This Month in Genetics
As the term polyQ disorder implies, Huntington disease (HD) is thought to be due almost exclusively to the toxicity of the expanded polyglutamine-containing tract in the open-reading frame of the gene. For some other trinucleotide repeat disorders caused by repeat expansions outside of the open-reading frame, repeat-associated non-ATG (RAN) translation has been implicated in disease pathogenesis, leading Laura Ranum and colleagues to explore whether this atypical form of protein translation has a role in HD. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 7, 2016 Category: Genetics & Stem Cells Authors: Kathryn B. Garber Tags: Editors ’ Corner Source Type: research

This Month in
Interactions with the environment have shaped the course of human history. Movement out of Africa and into Europe and Asia presented several challenges to early humans. In addition to fending off predators, early humans relied upon their immune systems to counter attacks from a variety of pathogens. Just how early immune systems adapted to such a rapidly changing environment has been a source of much speculation and conjecture. Now, using complementary approaches, Deschamps et al. and Dannemann et al. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - January 7, 2016 Category: Genetics & Stem Cells Authors: Sarah Ratzel, Sara B. Cullinan Tags: Editors ’ Corner Source Type: research

Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV
Recurrent deletions and duplications at chromosomal region 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses, including intellectual disability, coordination disorder, and language disorder. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent of origin of the 16p11.2 copy-number variant (CNV) and the presence of additional CNVs in 126 families for which detailed phenotype data were available. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 31, 2015 Category: Genetics & Stem Cells Authors: Michael H. Duyzend, Xander Nuttle, Bradley P. Coe, Carl Baker, Deborah A. Nickerson, Raphael Bernier, Evan E. Eichler Tags: Article Source Type: research

Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of
Congenital hereditary endothelial dystrophy 1 (CHED1) and posterior polymorphous corneal dystrophy 1 (PPCD1) are autosomal-dominant corneal endothelial dystrophies that have been genetically mapped to overlapping loci on the short arm of chromosome 20. We combined genetic and genomic approaches to identify the cause of disease in extensive pedigrees comprising over 100 affected individuals. After exclusion of pathogenic coding, splice-site, and copy-number variations, a parallel approach using targeted and whole-genome sequencing facilitated the identification of pathogenic variants in a conserved region of the OVOL2 proxi...
Source: The American Journal of Human Genetics - December 31, 2015 Category: Genetics & Stem Cells Authors: Alice E. Davidson, Petra Liskova, Cerys J. Evans, Lubica Dudakova, Lenka Nosková, Nikolas Pontikos, Hana Hartmannová, Kateřina Hodaňová, Viktor Stránecký, Zbyněk Kozmík, Hannah J. Levis, Nwamaka Idigo, Noriaki Sasai, Geoffrey J. Maher, James Tags: Article Source Type: research

Correlations between Synaptic Initiation and Meiotic Recombination: A Study of Humans and Mice
Meiotic recombination is initiated by programmed double strand breaks (DSBs), only a small subset of which are resolved into crossovers (COs). The mechanism determining the location of these COs is not well understood. Studies in plants, fungi, and insects indicate that the same genomic regions are involved in synaptic initiation and COs, suggesting that early homolog alignment is correlated with the eventual resolution of DSBs as COs. It is generally assumed that this relationship extends to mammals, but little effort has been made to test this idea. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 31, 2015 Category: Genetics & Stem Cells Authors: Jennifer R. Gruhn, Nasser Al-Asmar, Rachael Fasnacht, Heather Maylor-Hagen, Vanessa Peinado, Carmen Rubio, Karl W. Broman, Patricia A. Hunt, Terry Hassold Tags: Article Source Type: research

An Efficient Multiple-Testing Adjustment for eQTL Studies that Accounts for Linkage Disequilibrium between Variants
We present an alternative correction method called eigenMT, which runs over 500 times faster than permutations and has adjusted p values that closely approximate empirical ones. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 31, 2015 Category: Genetics & Stem Cells Authors: Joe R. Davis, Laure Fresard, David A. Knowles, Mauro Pala, Carlos D. Bustamante, Alexis Battle, Stephen B. Montgomery Tags: Report Source Type: research

Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA
We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 31, 2015 Category: Genetics & Stem Cells Authors: Tychele N. Turner, Fereydoun Hormozdiari, Michael H. Duyzend, Sarah A. McClymont, Paul W. Hook, Ivan Iossifov, Archana Raja, Carl Baker, Kendra Hoekzema, Holly A. Stessman, Michael C. Zody, Bradley J. Nelson, John Huddleston, Richard Sandstrom, Jos Tags: Article Source Type: research

Biallelic Mutations in Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability
Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent “leak” channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease. (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 17, 2015 Category: Genetics & Stem Cells Authors: Asbjørg Stray-Pedersen, Jan-Maarten Cobben, Trine E. Prescott, Sora Lee, Chunlei Cang, Kimberly Aranda, Sohnee Ahmed, Marielle Alders, Thorsten Gerstner, Kathinka Aslaksen, Martine Tétreault, Wen Qin, Taila Hartley, Shalini N. Jhangiani, Donna M. Muz Tags: Report Source Type: research

Mutations in , Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy
Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. (S...
Source: The American Journal of Human Genetics - December 17, 2015 Category: Genetics & Stem Cells Authors: Hanan E. Shamseldin, Eissa Faqeih, Ali Alasmari, Maha S. Zaki, Joseph G. Gleeson, Fowzan S. Alkuraya Tags: Report Source Type: research

Limited Clinical Utility of Non-invasive Prenatal Testing for Subchromosomal Abnormalities
The use of massively parallel sequencing of maternal cfDNA for non-invasive prenatal testing (NIPT) of aneuploidy is widely available. Recently, the scope of testing has increased to include selected subchromosomal abnormalities, but the number of samples reported has been small. We developed a calling pipeline based on a segmentation algorithm for the detection of these rearrangements in maternal plasma. The same read depth used in our standard pipeline for aneuploidy NIPT detected 15/18 (83%) samples with pathogenic rearrangements> 6 Mb but only 2/10 samples with rearrangements
Source: The American Journal of Human Genetics - December 17, 2015 Category: Genetics & Stem Cells Authors: Kitty K. Lo, Evangelia Karampetsou, Christopher Boustred, Fiona McKay, Sarah Mason, Melissa Hill, Vincent Plagnol, Lyn S. Chitty Tags: Article Source Type: research

Spell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders
Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals. We show that an adapted version of CRISPR/Cas9 increases the amount of utrophin, a known disease modifier in Duchenne muscular dystrophy (DMD). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 10, 2015 Category: Genetics & Stem Cells Authors: Daria Wojtal, Dwi U. Kemaladewi, Zeenat Malam, Sarah Abdullah, Tatianna W.Y. Wong, Elzbieta Hyatt, Zahra Baghestani, Sergio Pereira, James Stavropoulos, Vincent Mouly, Kamel Mamchaoui, Francesco Muntoni, Thomas Voit, Hernan D. Gonorazky, James J. Dowl Tags: Article Source Type: research

Mutations in Either or Cause Circumferential Skin Creases Kunze Type
Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing bra...
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Mala Isrie, Martin Breuss, Guoling Tian, Andi Harley Hansen, Francesca Cristofoli, Jasmin Morandell, Zachari A. Kupchinsky, Alejandro Sifrim, Celia Maria Rodriguez-Rodriguez, Elena Porta Dapena, Kurston Doonanco, Norma Leonard, Faten Tinsa, Stéphanie Tags: Article Source Type: research

Multiple Hepatic Regulatory Variants at the GWAS Locus Associated with High-Density Lipoprotein Cholesterol
We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r2> 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10−12). (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Tamara S. Roman, Amanda F. Marvelle, Marie P. Fogarty, Swarooparani Vadlamudi, Arlene J. Gonzalez, Martin L. Buchkovich, Jeroen R. Huyghe, Christian Fuchsberger, Anne U. Jackson, Ying Wu, Mete Civelek, Aldons J. Lusis, Kyle J. Gaulton, Praveen Se Tags: Article Source Type: research

Genome-wide Comparative Analysis of Atopic Dermatitis and Psoriasis Gives Insight into Opposing Genetic Mechanisms
(The American Journal of Human Genetics 96, 104–120; January 8, 2015) (Source: The American Journal of Human Genetics)
Source: The American Journal of Human Genetics - December 3, 2015 Category: Genetics & Stem Cells Authors: Hansjörg Baurecht, Melanie Hotze, Stephan Brand, Carsten Büning, Paul Cormican, Aiden Corvin, David Ellinghaus, Eva Ellinghaus, Jorge Esparza-Gordillo, Regina Fölster-Holst, Andre Franke, Christian Gieger, Norbert Hubner, Thomas Illig, Alan D. Irvine, Tags: Erratum Source Type: research