The Experts below are selected from a list of 153078 Experts worldwide ranked by ideXlab platform
Tzipora C Falikzaccai - One of the best experts on this subject based on the ideXlab platform.
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mammary digital nail mdn syndrome a novel phenotype maps to human chromosome 22q12 3 13 1
European Journal of Human Genetics, 2010Co-Authors: Dan Geiger, Leonid Kogan, Hector I Cohen, Tzipora C Falikzaccai, Mira Genzernir, Morad Khayat, Miriam HershkowitzAbstract:Mammary-digital-nail syndrome is a novel phenotypic association consisting of anonychia onychodystrophy with hypoplasia or absence of distal phalanges in males and females, accompanied by juvenile hypertrophy of the breast in affected females. This newly described Genetic Trait presents an autosomal dominant inheritance pattern, with either reduced penetrance or germ-line mosaicism. Analysis of the pedigree, linkage studies followed by a genome-wide screen and by haplotype analysis defined the locus for the phenotype within a 12 cM (4.3 Mb) interval on chromosome 22q12.3-13.1. This chromosomal region has not been implicated before in Genetic disorders of the mammary tissue or limbs. These data suggest a possibly novel signaling pathway affecting the organogenesis of limbs and mammary glands in humans.
D M Swallow - One of the best experts on this subject based on the ideXlab platform.
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World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection.
Human genetics, 2017Co-Authors: Anke Liebert, Nicolas Montalva, Saioa López, Bryony Leigh Jones, Pascale Gerbault, Winston Lau, Mark G Thomas, Neil Bradman, Nikolas Maniatis, D M SwallowAbstract:The Genetic Trait of lactase persistence (LP) is associated with at least five independent functional single nucleotide variants in a regulatory region about 14 kb upstream of the lactase gene [-13910*T (rs4988235), -13907*G (rs41525747), -13915*G (rs41380347), -14009*G (rs869051967) and -14010*C (rs145946881)]. These alleles have been inferred to have spread recently and present-day frequencies have been attributed to positive selection for the ability of adult humans to digest lactose without risk of symptoms of lactose intolerance. One of the inferential approaches used to estimate the level of past selection has been to determine the extent of haplotype homozygosity (EHH) of the sequence surrounding the SNP of interest. We report here new data on the frequencies of the known LP alleles in the 'Old World' and their haplotype lineages. We examine and confirm EHH of each of the LP alleles in relation to their distinct lineages, but also show marked EHH for one of the older haplotypes that does not carry any of the five LP alleles. The region of EHH of this (B) haplotype exactly coincides with a region of suppressed recombination that is detectable in families as well as in population data, and the results show how such suppression may have exaggerated haplotype-based measures of past selection.
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in vitro functional analyses of infrequent nucleotide variants in the lactase enhancer reveal different molecular routes to increased lactase promoter activity and lactase persistence
Annals of Human Genetics, 2016Co-Authors: Anke Liebert, D M Swallow, Bryony L Jones, Erik Thomas Danielsen, Anders Kruger Olsen, Jesper T TroelsenAbstract:The Genetic Trait that allows intestinal lactase to persist into adulthood in some 35% of humans worldwide operates at the level of transcription, the effect being caused by cis-acting nucleotide changes upstream of the lactase gene (LCT). A single nucleotide substitution, -13910 C>T, the first causal variant to be identified, accounts for lactase persistence over most of Europe. Located in a region shown to have enhancer function in vitro, it causes increased activity of the LCT promoter in Caco-2 cells, and altered transcription factor binding. Three other variants in close proximity, -13907 C>G, -13915 T>C and -14010 G>C, were later shown to behave in a similar manner. Here, we study four further candidate functional variants. Two, -14009 T>G and -14011 C>T, adjacent to the well-studied -14010 G>C variant, also have a clear effect on promoter activity upregulation as assessed by transfection assays, but notably are involved in different molecular interactions. The results for the two other variants (-14028 T>C, -13779 G>C) were suggestive of function, -14028*C showing a clear change in transcription factor binding, but no obvious effect in transfections, while -13779*G showed greater effect in transfections but less on transcription factor binding. Each of the four variants arose on independent haplotypic backgrounds with different geographic distribution.
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population Genetics of lactase persistence and lactose intolerance
eLS, 2012Co-Authors: Catherine J. E. Ingram, Anke Liebert, D M SwallowAbstract:Variation in the ability of adult humans to digest the lactose in milk is a Genetically determined Trait that has excited the interest of many for the past 50 years. The Trait seems to have risen to high frequencies by one of the strongest selection pressures ever described. This section describes the phenotypic polymorphism and the evidence that the Genetic Trait involves regulation of expression of the lactase gene and is caused by multiple independent mutations that have reached high frequencies in different populations, because of the benefits of drinking milk. The evolutionary history in Europe and Africa are rather different; there being a single high-frequency allele in Europe, in contrast to multiple alleles in Africa. Also the selective forces, which are likely to include both the nutritional and water content of milk, may have been different in these regions. Key Concepts: The enzyme, lactase, is restricted to the small intestine where it digests lactose in the milk of suckling mammals. Lactase persists into adult life in some, but not all, people. Lactase persistence is a Genetic Trait, which varies in frequency in different populations of the world. Mutations in an enhancer sequence, at a distance from the lactase gene, appear to be responsible for lactase persistence. These alleles arose in the last few thousand years and have been under strong positive selection. The selection may be attributable to one of the nutrients or water in fresh milk and/or its calorific value. Keywords: lactose; milk; lactase; selection; persistence; tolerance
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Genetics of lactase persistence and lactose intolerance
Annual Review of Genetics, 2003Co-Authors: D M SwallowAbstract:▪ Abstract The enzyme lactase that is located in the villus enterocytes of the small intestine is responsible for digestion of lactose in milk. Lactase activity is high and vital during infancy, but in most mammals, including most humans, lactase activity declines after the weaning phase. In other healthy humans, lactase activity persists at a high level throughout adult life, enabling them to digest lactose as adults. This dominantly inherited Genetic Trait is known as lactase persistence. The distribution of these different lactase phenotypes in human populations is highly variable and is controlled by a polymorphic element cis-acting to the lactase gene. A putative causal nucleotide change has been identified and occurs on the background of a very extended haplotype that is frequent in Northern Europeans, where lactase persistence is frequent. This single nucleotide polymorphism is located 14 kb upstream from the start of transcription of lactase in an intron of the adjacent gene MCM6. This change does...
Niels Van Den Berg - One of the best experts on this subject based on the ideXlab platform.
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longevity defined as top 10 survivors and beyond is transmitted as a quantitative Genetic Trait
Nature Communications, 2019Co-Authors: Niels Van Den Berg, Ingrid K. Van Dijk, R.j. Mourits, Kees Mandemakers, Marian Beekman, Mar Rodriguezgirondo, A A P O Janssens, Ken R. SmithAbstract:Survival to extreme ages clusters within families. However, identifying Genetic loci conferring longevity and low morbidity in such longevous families is challenging. There is debate concerning the survival percentile that best isolates the Genetic component in longevity. Here, we use three-generational mortality data from two large datasets, UPDB (US) and LINKS (Netherlands). We study 20,360 unselected families containing index persons, their parents, siblings, spouses, and children, comprising 314,819 individuals. Our analyses provide strong evidence that longevity is transmitted as a quantitative Genetic Trait among survivors up to the top 10% of their birth cohort. We subsequently show a survival advantage, mounting to 31%, for individuals with top 10% surviving first and second-degree relatives in both databases and across generations, even in the presence of non-longevous parents. To guide future Genetic studies, we suggest to base case selection on top 10% survivors of their birth cohort with equally long-lived family members.
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longevity defined as top 10 survivors is transmitted as a quantitative Genetic Trait results from large three generation datasets
bioRxiv, 2018Co-Authors: Niels Van Den Berg, Ingrid K. Van Dijk, R.j. Mourits, Kees Mandemakers, Marian Beekman, Ken R. Smith, Mar Rodriguezgirondo, A A P O Janssens, Eline P SlagboomAbstract:Survival to extreme ages clusters within families. However, identifying Genetic loci conferring longevity and low morbidity in such longevous families is challenging. There is debate concerning the survival percentile that best isolates the Genetic component in longevity. Here, we use three-generational mortality data from two large datasets, UPDB (US) and LINKS (Netherlands). We studied 21,046 unselected families containing index persons, their parents, siblings, spouses, and children, comprising 321,687 individuals. Our analyses provide strong evidence that longevity is transmitted as a quantitative Genetic Trait among survivors up to the top 10% of their birth cohort. We subsequently showed a survival advantage, mounting to 31%, for individuals with top 10% surviving first and second-degree relatives in both databases and across generations, even in the presence of non-longevous parents. To guide future Genetic studies, we suggest to base case selection on top 10% survivors of their birth cohort with equally long-lived family members.
Mira Genzernir - One of the best experts on this subject based on the ideXlab platform.
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mammary digital nail mdn syndrome a novel phenotype maps to human chromosome 22q12 3 13 1
European Journal of Human Genetics, 2010Co-Authors: Dan Geiger, Leonid Kogan, Hector I Cohen, Tzipora C Falikzaccai, Mira Genzernir, Morad Khayat, Miriam HershkowitzAbstract:Mammary-digital-nail syndrome is a novel phenotypic association consisting of anonychia onychodystrophy with hypoplasia or absence of distal phalanges in males and females, accompanied by juvenile hypertrophy of the breast in affected females. This newly described Genetic Trait presents an autosomal dominant inheritance pattern, with either reduced penetrance or germ-line mosaicism. Analysis of the pedigree, linkage studies followed by a genome-wide screen and by haplotype analysis defined the locus for the phenotype within a 12 cM (4.3 Mb) interval on chromosome 22q12.3-13.1. This chromosomal region has not been implicated before in Genetic disorders of the mammary tissue or limbs. These data suggest a possibly novel signaling pathway affecting the organogenesis of limbs and mammary glands in humans.
Lorin Crawford - One of the best experts on this subject based on the ideXlab platform.
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multi scale inference of Genetic Trait architecture using biologically annotated neural networks
PLOS Genetics, 2021Co-Authors: Pinar Demetci, Wei Cheng, Gregory Darnell, Xiang Zhou, Sohini Ramachandran, Lorin CrawfordAbstract:In this article, we present Biologically Annotated Neural Networks (BANNs), a nonlinear probabilistic framework for association mapping in genome-wide association (GWA) studies. BANNs are feedforward models with partially connected architectures that are based on biological annotations. This setup yields a fully interpretable neural network where the input layer encodes SNP-level effects, and the hidden layer models the aggregated effects among SNP-sets. We treat the weights and connections of the network as random variables with prior distributions that reflect how Genetic effects manifest at different genomic scales. The BANNs software uses variational inference to provide posterior summaries which allow researchers to simultaneously perform (i) mapping with SNPs and (ii) enrichment analyses with SNP-sets on complex Traits. Through simulations, we show that our method improves upon state-of-the-art association mapping and enrichment approaches across a wide range of Genetic architectures. We then further illustrate the benefits of BANNs by analyzing real GWA data assayed in approximately 2,000 heterogenous stock of mice from the Wellcome Trust Centre for Human Genetics and approximately 7,000 individuals from the Framingham Heart Study. Lastly, using a random subset of individuals of European ancestry from the UK Biobank, we show that BANNs is able to replicate known associations in high and low-density lipoprotein cholesterol content.
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multi scale inference of Genetic Trait architecture using biologically annotated neural networks
bioRxiv, 2020Co-Authors: Pinar Demetci, Wei Cheng, Gregory Darnell, Xiang Zhou, Sohini Ramachandran, Lorin CrawfordAbstract:Abstract Here, we present Biologically Annotated Neural Networks (BANNs), a novel probabilistic framework that makes machine learning fully amenable for GWA applications. BANNs are feedforward models with partially connected architectures that are based on biological annotations. This setup yields a fully interpretable neural network where the input layer encodes SNP-level effects, and the hidden layer models the aggregated effects among SNP-sets. Part of our key innovation is to treat the weights and connections of the network as random variables with prior distributions that reflect how Genetic effects manifest at different genomic scales. The BANNs software uses scalable variational inference to provide fully interpretable posterior summaries which allow researchers to simultaneously perform (i) fine-mapping with SNPs and (ii) enrichment analyses with SNP-sets on complex Traits. Through simulations, we show that our method improves upon state-of-the-art fine mapping and enrichment approaches across a wide range of Genetic architectures. We then further illustrate the benefits of BANNs by analyzing real GWA data assayed in approximately 2,000 heterogenous stock of mice from Wellcome Trust Centre for Human Genetics and approximately 7,000 individuals from the Framingham Heart Study. Lastly, using a subset of individuals of European ancestry from the UK Biobank, we show that BANNs is able to replicate known associations that required functional validation using statistics alone.