A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease

Soft windowing application to improve analysis of high-throughput phenotyping data.

MOTIVATION: High-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors. RESULTS: Here we introduce \u27soft windowing\u27, a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources. AVAILABILITY AND IMPLEMENTATION: The method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

The mammalian gene function resource: the International Knockout Mouse Consortium.

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research

Nat Genet

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015

First carbon isotope chemostratigraphy of the Ouled Abdoun phosphate Basin, Morocco; implications for dating and evolution of earliest African placental mammals

The well-known Maastrichtian-Ypresian vertebrate-bearing phosphate series, in the Ouled Abdoun Basin, Morocco, is classically dated using regional selachian biostratigraphic zonation. These marine sediments yielded Paleocene and Eocene mammals comprising the earliest known placentals from Africa. This study provides the first insight into the organic carbon isotope chemostratigraphy (δ13Corg) of the Moroccan phosphate series and a refined dating of its vertebrate-bearing levels. Four Paleocene-Eocene sections in the NE Ouled Abdoun quarries show consistent δ13Corg long term evolutions, from the base to the top: 1) positive trend in phosphorite Bed IIa, beginning with the lower Bone Bed yielding mammals such as Eritherium, Ocepeia, Abdounodus, Lahimia, of early Thanetian and Selandian age; 2) transitional negative trend in the Intercalary phosphorite Beds II/I that includes the Otodus obliquus and Phosphatherium escuilliei Bone Bed of earliest Ypresian age; 3) negative trend to the lowermost δ13Corg values that are correlative to the early-middle Ypresian interval including ETM 2 and ETM 3 hyperthermal events in the global record; 4) positive trend in chert-enriched facies containing the middle Ypresian EECO global climatic event. Our chemostratigraphic study of the Ouled Abdoun phosphate series provides a new chronostratigraphic framework for calibrating the beginning of the evolution of placental mammals in Africa. The lower Bone Bed level from the Paleocene phosphorite Bed IIa yielding Eritherium is not younger than early Thanetian, and is most likely Selandian. The Phosphatherium Bone Bed in the Intercalary Beds II/I is earliest Ypresian. The phosphorite Bed 0, from which Daouitherium probably came, is early-middle Ypresian, just below the EECO. This suggests that the first large proboscideans evolved after the PETM, during mid-Ypresian warming events. The δ13Corg study does not support the presence of Lutetian in the NE Ouled Abdoun phosphate series and suggests that a noticeable part of the upper Thanetian is absent. © 2013 International Association for Gondwana Research