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Accounting for eXentricities: Analysis of the X Chromosome in GWAS Reveals X-Linked Genes Implicated in Autoimmune Diseases
Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.
Journal Article
Fine-Scale Resolution of Runs of Homozygosity Reveal Patterns of Inbreeding and Substantial Overlap with Recessive Disease Genotypes in Domestic Dogs
Inbreeding leaves distinct genomic traces, most notably long genomic tracts that are identical by descent and completely homozygous. These runs of homozygosity (ROH) can contribute to inbreeding depression if they contain deleterious variants that are fully or partially recessive. Several lines of evidence have been used to show that long (> 5 megabase) ROH are disproportionately likely to harbor deleterious variation, but the extent to which long vs. short tracts contribute to autozygosity at loci known to be deleterious and recessive has not been studied. In domestic dogs, nearly 200 mutations are known to cause recessive diseases, most of which can be efficiently assayed using SNP arrays. By examining genome-wide data from over 200,000 markers, including 150 recessive disease variants, we built high-resolution ROH density maps for nearly 2,500 dogs, recording ROH down to 500 kilobases. We observed over 678 homozygous deleterious recessive genotypes in the panel across 29 loci, 90% of which overlapped with ROH inferred by GERMLINE. Although most of these genotypes were contained in ROH over 5 Mb in length, 14% were contained in short (0.5 - 2.5 megabase) tracts, a significant enrichment compared to the genetic background, suggesting that even short tracts are useful for computing inbreeding metrics like the coefficient of inbreeding estimated from ROH (FROH). In our dataset, FROH differed significantly both within and among dog breeds. All breeds harbored some regions of reduced genetic diversity due to drift or selective sweeps, but the degree of inbreeding and the proportion of inbreeding caused by short vs. long tracts differed between breeds, reflecting their different population histories. Although only available for a few species, large genome-wide datasets including recessive disease variants hold particular promise not only for disentangling the genetic architecture of inbreeding depression, but also evaluating and improving upon current approaches for detecting ROH.
Journal Article
التعلم المقلوب : بوابة لمشاركة الطلاب : (الكتاب المرافق للصف المقلوب)
ينتقل كتاب \"التعلـم المقلوب : بوابة لمشاركة الطلاب\" إلى الخطوة المنطقية التالية في تطور مسار الصـف المقلوب-فالتعلـم المقلوب-متوجها نحو تعلـم أكثر إحكامـا واستراتيجيات تعليم تـحدث تحويلا في التعلـم بإشغال كل طالب وإحداث تعلـم أكثر عمقـا وتقدمـا. ويهدف الكتاب إلى إعانة المعلمين وإرشادهم إلى كيفية تحويل الصفوف إلى التعلم المقلوب، ليشبعوا حاجات كل طالب، من خلال مجموعة أنشطة يقدمها المؤلفان حول عمل معلمين وخبراء في التكنولوجيا ومتخصصين في التعليم المهني، تصف أثر التعلـم المقلوب على طلابهم وهم يتابعون مساره، وكيف وجهوا طلابهم نحو تعلـم أكثر تقدمـا وتكوين علاقات إيجابية بينهم. وجاء الكتاب في (14) فصلا تضم : نموذج التعلم المقلوب، مفاهيم مغلوطة في الصف المقلوب، محتوى وحب استطلاع وعلاقة، توجه إلى تعلـم أكثر عمقـا وأوسع أفقـا، واعمل على تكوين علاقات، تعلم أكثر عمقـا من خلال صف محوره الطالب، الانتقال إلى تعلـم محوره الطالب، الصف المقلوب في التربية البدنية، الانتقال بالصف المقلوب إلى تعلم أكثر عمقـا، رسخ ديموقراطية التعلـم من خلال الصف المقلوب، مساق اللغة الإنجليزية مهيأ للانقلاب، طريقي لأن أصبح مربيـا عصريـا، التعرف على طلابي, الصعود إلى الإبداع بالتطور المهني المقلوب، العصارة التربوية الحلوة.
BOOK
Flip Your Classroom, Revised Edition
This revised edition of the groundbreaking book shares innovators Jonathan Bergmann and Aaron Sams's insights on how to successfully flip a classroom and covers new advances in the field.
It started with a simple observation: Students need their teachers present to answer questions or to provide help if they get stuck on an assignment; they don't need their teachers present to listen to a lecture or review content. From there, Jon Bergmann and Aaron Sams began the flipped classroom. Students watched recorded lectures for homework and completed their assignments, labs and tests in class with their teacher available. What they found was that their students demonstrated a deeper understanding of the material than ever before. This is the authors' story, updated and expanded, to ensure it's as relevant to your classroom as ever.
The revised edition includes:
* New case studies illustrating flipped learning applied by an individual teacher and across a school district.
* A new appendix focused on best practices for creating videos for your classes.
* Educator examples that demonstrate the ISTE Standards in action.
* Updates to tools, terms and resources to reflect the current learning landscape.
In the revised edition of this landmark text, you'll discover the flipped mastery model that allows students to learn at their own pace, furthering opportunities for personalized education. This simple concept is easily replicable in any classroom, doesn't cost much to implement and helps foster self-directed learning.
Audience: Elementary and secondary classroom teachers
eBook
الصف المقلوب : الوصول كل يوم إلى كل طالب في كل صف
هذا الكتاب يطرح مفهوما وأسلوبا جديدا وطريقة تعليمية مبتكرة لمعالجة أهم الأسباب التي تدفع الشباب نحو العزوف عن التعلم بشكل عام .. ففي عصر التقدم والعولمة وانغماس الأجيال الحديثة في وسائل التقنية والتطور كالأجهزة المحمولة واللوحية، أصبحت الطرق التقليدية في التدريس غير مجدية، والمقصود بهذا العنوان هو أن يتم قلب العملية التعليمية بين الصف في المدرسة والمنزل وذلك عن طريق توظيف وسائل التكنولوجيا الحديثة لتحضير الدرس وعرضه. مثال : أن يطلع الطالب على المادة العلمية في المنزل ويتعرف عليها جيدا، فيقوم المعلم بإعداد ملف مرئي يشرح المفاهيم الجديدة باستخدام التقنيات السمعية والبصرية وبرامج المحاكاة والتقييم التفاعلي لتكون في متناول الطالب قبل الدرس، ومتاحة له على مدار الوقت.
Book
Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans
Background
The 2’-5’ oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking.
Results
Here we used a broad array of selection tests in concert with neutral coalescent simulations to demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of
OAS3
upon infection, as well as distinct isoforms of
OAS1
and
OAS2
.
Conclusions
We present evidence that a Neandertal haplotype at the OAS locus was subjected to positive selection in the human population. This haplotype is significantly associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely reintroduced an ancestral splice variant of
OAS1
encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.
Journal Article
Five genetic variants explain over 70% of hair coat pheomelanin intensity variation in purebred and mixed breed domestic dogs
In mammals, the pigment molecule pheomelanin confers red and yellow color to hair, and the intensity of this coloration is caused by variation in the amount of pheomelanin. Domestic dogs exhibit a wide range of pheomelanin intensity, ranging from the white coat of the Samoyed to the deep red coat of the Irish Setter. While several genetic variants have been associated with specific coat intensity phenotypes in certain dog breeds, they do not explain the majority of phenotypic variation across breeds. In order to gain further insight into the extent of multigenicity and epistatic interactions underlying coat pheomelanin intensity in dogs, we leveraged a large dataset obtained via a direct-to-consumer canine genetic testing service. This consisted of genome-wide single nucleotide polymorphism (SNP) genotype data and owner-provided photos for 3,057 pheomelanic mixed breed and purebred dogs from 63 breeds and varieties spanning the full range of canine coat pheomelanin intensity. We first performed a genome-wide association study (GWAS) on 2,149 of these dogs to search for additional genetic variants that underlie intensity variation. GWAS identified five loci significantly associated with intensity, of which two (CFA15 29.8 Mb and CFA20 55.8 Mb) replicate previous findings and three (CFA2 74.7 Mb, CFA18 12.9 Mb, CFA21 10.9 Mb) have not previously been reported. In order to assess the combined predictive power of these loci across dog breeds, we used our GWAS data set to fit a linear model, which explained over 70% of variation in coat pheomelanin intensity in an independent validation dataset of 908 dogs. These results introduce three novel pheomelanin intensity loci, and further demonstrate the multigenic nature of coat pheomelanin intensity determination in domestic dogs.
Journal Article
Direct-to-consumer DNA testing of 6,000 dogs reveals 98.6-kb duplication associated with blue eyes and heterochromia in Siberian Huskies
Consumer genomics enables genetic discovery on an unprecedented scale by linking very large databases of personal genomic data with phenotype information voluntarily submitted via web-based surveys. These databases are having a transformative effect on human genomics research, yielding insights on increasingly complex traits, behaviors, and disease by including many thousands of individuals in genome-wide association studies (GWAS). The promise of consumer genomic data is not limited to human research, however. Genomic tools for dogs are readily available, with hundreds of causal Mendelian variants already characterized, because selection and breeding have led to dramatic phenotypic diversity underlain by a simple genetic structure. Here, we report the results of the first consumer genomics study ever conducted in a non-human model: a GWAS of blue eyes based on more than 3,000 customer dogs with validation panels including nearly 3,000 more, the largest canine GWAS to date. We discovered a novel association with blue eyes on chromosome 18 (P = 1.3x10-68) and used both sequence coverage and microarray probe intensity data to identify the putative causal variant: a 98.6-kb duplication directly upstream of the Homeobox gene ALX4, which plays an important role in mammalian eye development. This duplication is largely restricted to Siberian Huskies, is strongly associated with the blue-eyed phenotype (chi-square P = 5.2x10-290), and is highly, but not completely, penetrant. These results underscore the power of consumer-data-driven discovery in non-human species, especially dogs, where there is intense owner interest in the personal genomic information of their pets, a high level of engagement with web-based surveys, and an underlying genetic architecture ideal for mapping studies.
Journal Article