Molecular Development - Genetics
|Embryology - 15 Dec 2018 Expand to Translate|
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- 1 Introduction
- 2 Some Recent Findings
- 3 Diploid Chromosome Number
- 4 Chromatin Structure
- 5 Chromosome Banding
- 6 Human Genome
- 7 Chromosome Regions
- 8 Chromosome Abnormalities
- 9 Some Human Disease Gene Locations
- 10 Inheritance Genetics
- 11 DNA Sequencing
- 12 Using Genetic Databases
- 13 Genetic Editing
- 14 References
- 15 Genetic Terms
- 16 External Links
- 17 Glossary Links
Genetics (Greek, genetikos = “origin”) and embryology have merged to such an extent that the two cannot now be separated from each other. The strong evolutionary conservation of developmental mechanisms has been astounding. Currently, much of modern medicine is a search for a disease gene and having found it, embryology is usually employed in understanding its mechanism. Embryological development begins with meiosis and is after all the opportunity for a specific genome to be expressed, regulated and utilized as it will never be again in the adult animal.
Humans have genetic information stored within the nucleus and within mitochondria. The nuclear chromosomes consist of 22 autosome pairs and 2 gonadosomes (sex chromosomes; X, Y). The mitochondrial genome consists of multiple copies of circular DNA 16,569 base pairs in length.
In combination with our statistical understanding of congenital abnormalities there now exist a large number of clinical tests for inherited abnormalities. This particular section of the notes is a link to bind our understanding of genetics with its relevance to development. There are several pages on DNA and links from the computer activities below to relevant sections. You can jump right in and look through the DNA database for a gene of interest using a keyword, or browse through the human genome by chromosome or by genetic diseases that have been identified. Or you can work through an exercise in using genetic databases for diseases.
See also the list of mouse gene knockouts which has made the geneticists not only use embryological tools, but also go back and learn some embryology. Recent research has also focussed on the new science of Epigenetics, the inheritance mechanisms that lie outside the actual DNA sequence of our genes.
|Molecular Links: molecular | genetics | epigenetics | mitosis | meiosis | X Inactivation | Signaling | Factors | Mouse Knockout | microRNA | Mechanisms | Developmental Enhancers | Protein | Genetic Abnormal | Category:Molecular|
|Human Chromosomes: 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | X | Y|
Some Recent Findings
|More recent papers|
This table shows an automated computer PubMed search using the listed sub-heading term.
References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.
Aneta Ścieżyńska, Aleksandra Nogowska, Maria Sikorska, Justyna Konys, Anita Karpińska, Michał Komorowski, Monika Ołdak, Jacek Malejczyk Isolation and culture of human primary keratinocytes - a methods review. Exp. Dermatol.: 2018; PubMed 30548893
Lubos Danisovic, Martina Culenova, Maria Csobonyeiova Induced Pluripotent Stem Cells for Duchenne Muscular Dystrophy Modeling and Therapy. Cells: 2018, 7(12); PubMed 30544588
Jun-Feng Zhang, Jian-Shui Zhang, Zhao-Hua Zhao, Peng-Bo Yang, Sheng-Feng Ji, Nan Li, Qin-Dong Shi, Jing Tan, Xi Xu, Cang-Bao Xu, Ling-Yu Zhao MicroRNA-770 affects proliferation and cell cycle transition by directly targeting CDK8 in glioma. Cancer Cell Int.: 2018, 18;195 PubMed 30524203
Azra Metovic, Jasmin Musanovic, Selma Alicelebic, Esad Pepic, Senad Sljuka, Maida Mulic Predictive Analysis of Palmar Dermatoglyphics in Patients with Breast Cancer for Small Bosnian-Herzegovinian Population. Med Arch: 2018, 72(5);357-361 PubMed 30524169
Ying Chen, Lu Zhu, Lei Ji, Ying Yang, Lu Lu, Xiaodong Wang, Guomim Zhou Silencing the ACAT1 Gene in Human SH-SY5Y Neuroblastoma Cells Inhibits the Expression of Cyclo-Oxygenase 2 (COX2) and Reduces β-Amyloid-Induced Toxicity Due to Activation of Protein Kinase C (PKC) and ERK. Med. Sci. Monit.: 2018, 24;9007-9018 PubMed 30541014
Diploid Chromosome Number
|Human (Homo sapiens)||46|
|Mouse (Mus musculus)||40|
|Fruit fly (Drosophila melanogaster)||8|
|Worm (Caenorhabditis elegans)||12|
|Frog (Xenopus laevis)||36|
|Dog (Canis familiaris)||78|
|Chicken (Gallus gallus)||78|
|Echidna (Tachyglossus)||63 male 64 female|
|Cow (Bos primigenius)||60|
|Species Chromosome Number|
|Cells not undergoing cell division have their DNA dispersed throughout the nucleus in what are know as "chromosomal domains". There is also a peripheral nuclear rim area that does not contain gene-rich regions of DNA, which tend to be located in the core of the nucleus.||
Adult G0 fibroblast DNA and gene localization.
| Cells undergoing division have their DNA compacted into chromosomes with a short arm (p), a long arm (q), and a mid-section (centromere). The duplicated chromosomes are also joined together as pairs at the centromere. These chromosomal arms are only seen when the chromosome is folded for cell division.
These letters prefixed by the chromosome number and followed by the chromosome band number, indicate gene location.
Chromosome pair structure
The term refers to the light and dark pattern, seen after staining with a dye, of individual chromosomes identified in metaphase. It is only in meiosis and mitosis during metaphase that chromosomes can be easily identified, during the normal cell life (interphase) the chromosomes are unravelled and distributed within the nucleus in chromosome territories. A band is that part of a chromosome which is clearly distinguishable from nearby regions by appearing darker or brighter with one or more banding techniques.
Depending on the type of stain used a number of different banding patterns can be seen:
- G-banding - banding pattern seen by treating with trypsin and then staining with the dye giemsa.
- R-banding - banding pattern seen as a of reverse giemsa chromosome banding, producing bands complementary to G-bands often used to determine whether there are deletions. Can be fluorescent using the dye acridine orange.
- Q-banding - banding pattern seen by treating with a fluorochrome or the fluorescent dye quinacrin.
- C-banding - banding pattern seen for centromeric or constitutive heterochromatin, the centromere appears as a stained band compared to other regions.
Metaphase is a cell division term referring to the third mitotic stage, mitotic spindle kinetochore microtubules align chromosomes in one midpoint plane. Metaphase ends when sister kinetochores separate. Originally based on light microscopy of living cells and electron microscopy of fixed and stained cells. A light microscope analysis called a "metaphase spread" was originally used to detect chromosomal abnormalities in cells.
- Links: Histology Stains
Human Genome Length 3,101,788,170 bp. Mitochondrial Genome 16,568 bp.
|Human Chromosomes: 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | X | Y|
- Links: Human Genome Project (HGP) | NCBI Human Genome Resources | History of the Human Genome Project | Project Timeline
- In humans this genome is maternally inherited.
- Exists as multiple copies within the matrix of each mitochondrion within the cytoplasm of cells.
- In 1981 the human mitochondrial genome was sequenced.
- The genome is a small circular DNA molecule 16,568 bp in length containing 37 genes.
- 24 genes specify RNA molecules involved in protein synthesis (22 transfer RNAs (tRNA) and 2 ribosomal RNAs (rRNA))
- 13 genes encode proteins required for the biochemical reactions that make up respiration.
Ploidy refers to the chromosomal genetic content of cells. Euploidy (euploid) is the genetic term used to describe the normal cell genome chromosomal set (n, 2n, 3n) or complement for a species, in humans this is diploid (2n).
The terms used to describe the classes of numerical chromosomal abnormalities include:
- Aneuploidy are chromosome mutations in which chromosome number is abnormal (increased or reduced), nondisjunction in meiosis or mitosis (anaphase of meiosis I, sister chromatids fail to disjoin at either meiosis II or at mitosis) is the cause of most aneuploids.
- Polyploidy includes triploidy, usually due to two sperm fertilizing a single egg.
- Mixoploidy includes mosaicism, where there are two or more genetically different cell lines in an individual.
Some Human Disease Gene Locations
- Inheritance Pattern images: Genetic Abnormalities | Autosomal dominant inheritance | Autosomal recessive inheritance | X-Linked dominant (affected father) | X-Linked dominant (affected mother) | X-Linked recessive (affected father) | X-Linked recessive (carrier mother) | Mitochondrial genome inheritance | Codominant inheritance | Genogram symbols | Genetics
A clinical diagram constructed to show an individual's family relationships and medical history, more detailed than a pedigree chart including non-genetic factors such as family emotional and social relationships. Additional colour coded symbols and connectors are used to show these relationships and interactions.
Changes in genes can occur by a number of different methods including mutations, deletions and epigenetic modifications. Specific changes in DNA sequences can also be detected by a range of techniques, including direct sequencing of the DNA.
Recent technological developments have improved how DNA sequencing occurs and we are said to now be up to the "third generation" of sequencing techniques.
|First and second generation sequencing||Third generation sequencing|
Using Genetic Databases
This exercise is an exploration of the available WWW and other database resources that relate to Human genetic diseases. The exercise is to explore the Human genome and its relationship to examples of know human genetic diseases that affect development and impact on health.
To start with, think of a specific Human disease and see what you can find out about:
- Known gene?
- What are the major effects of the disorder?
- Does it have an effect/role in development?
- Known mutations?
- Likely hood of mortality?
- History of the disease?
- Who discovered the cause of the disease?
- Most recent published data relationg to the disease?
- What therapies are being explored?
- Where to next?
Originally a more general approach was used to study the fly model of development, where random genome mutation (random mutagenesis) was carried out to identify a specific fly phenotype and then researchers would go back and find the gene that had been altered.
More recently in vertebrate models of development, mainly in mice, genetic editing was carried to to "knock out" (KO mice) a specific gene and then to look for a specific phenotype. Generally targeting known genetic disorder genes, but later a range of genes involved in signalling, proliferation, migration, cell cytoskeleton. This technology has developed to the stage where we can now not only "knock out" but also "knock in" as well as "transiently knock out" (at a specific stage) a specific gene of interest. This KO technology was complex and required long term projects to generate these knock out animal models.
More recently a new technology called CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) has allowed more accurate and faster genetic editing. There has been concern in the scientific community that this technique may be applied to the human genome, and lead to "germ line" changes in the human genome. See also review.
|Like any great discovery, some contention as to who writes the history...|
- Links: Nature News 12 March 2015
Other Gene Editing Mechanisms
DNA Targeting Platforms for Genome Editing
|Zinc finger nucleases||Meganucleases|
|Zinc finger (ZF) proteins are the most abundant class of transcription factors and the Cys2-His2 zinc finger domain is one of the most common DNA-binding domains encoded in the human genome. The crystal structure of Zif268 has served as the basis for understanding DNA recognition by zinc fingers. In the presence of a zinc atom, the zinc finger domain forms a compact ββα structure with the α-helical portion of each finger making contact with 3 or 4 bp in the major groove of the DNA. Tandem fingers in a zinc finger array wrap around the DNA to bind extended target sequences such that a three-finger protein binds a 9 bp target site.||Meganuclease technology involves re-engineering the DNA-binding specificity of naturally occurring homing endonucleases. The largest class of homing endonucleases is the LAGLIDADG family, which includes the well-characterized and commonly used I-CreI and I-SceI enzymes.140 Through a combination of rational design and selection, these homing endonucleases can be re-engineered to target novel sequences.|
|The discovery of a simple one-to-one code dictating the DNA-binding specificity of TALE proteins from the plant pathogen Xanthomonas again raised the exciting possibility for modular design of novel DNA-binding proteins.114,115 Highly conserved 33–35 amino acid TALE repeats each bind a single base pair of DNA with specificity dictated by two hypervariable residues. Crystal structures of TALEs bound to DNA revealed that each repeat forms a two-helix structure connected by a loop which presents the hypervariable residue into the major groove as the protein wraps around the DNA in a superhelical structure. These modular TALE repeats can be linked together to build long arrays with custom DNA-binding specificities.||CRISPR-Cas RNA-guided nucleases are derived from an adaptive immune system that evolved in bacteria to defend against invading plasmids and viruses. Decades of work investigating CRISPR systems in various microbial species has elucidated a mechanism by which short sequences of invading nucleic acids are incorporated into CRISPR loci. They are then transcribed and processed into CRISPR RNAs (crRNAs) which, together with a trans-activating crRNAs (tracrRNAs), complex with CRISPR-associated (Cas) proteins to dictate specificity of DNA cleavage by Cas nucleases through Watson-Crick base pairing between nucleic acids. Building off of two studies showing that the three components required for the type II CRISPR nuclease system are the Cas9 protein, the mature crRNA and the tracrRNA, Doudna, Charpentier and colleagues showed through in vitro DNA cleavage experiments that this system could be reduced to two components by fusion of the crRNA and tracrRNA into a single guide RNA (gRNA). Furthermore, they showed that re-targeting of the Cas9/gRNA complex to new sites could be accomplished by altering the sequence of a short portion of the gRNA. Thereafter, a series of publications demonstrated that the CRISPR/Cas9 system could be engineered for efficient genetic modification in mammalian cells. Collectively these studies have propelled the CRISPR/Cas9 technology into the spotlight of the genome-editing field.|
(text extract above from original article
- Tang L, Zeng Y, Du H, Gong M, Peng J, Zhang B, Lei M, Zhao F, Wang W, Li X & Liu J. (2017). CRISPR/Cas9-mediated gene editing in human zygotes using Cas9 protein. Mol. Genet. Genomics , 292, 525-533. PMID: 28251317 DOI.
- Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, Lv J, Xie X, Chen Y, Li Y, Sun Y, Bai Y, Songyang Z, Ma W, Zhou C & Huang J. (2015). CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell , 6, 363-372. PMID: 25894090 DOI.
- Bolzer A, Kreth G, Solovei I, Koehler D, Saracoglu K, Fauth C, Müller S, Eils R, Cremer C, Speicher MR & Cremer T. (2005). Three-dimensional maps of all chromosomes in human male fibroblast nuclei and prometaphase rosettes. PLoS Biol. , 3, e157. PMID: 15839726 DOI.
- Shoubridge EA. (2009). Developmental biology: Asexual healing. Nature , 461, 354-5. PMID: 19759608 DOI.
- Schadt EE, Turner S & Kasarskis A. (2010). A window into third-generation sequencing. Hum. Mol. Genet. , 19, R227-40. PMID: 20858600 DOI.
- Sandve GK, Gundersen S, Johansen M, Glad IK, Gunathasan K, Holden L, Holden M, Liestøl K, Nygård S, Nygaard V, Paulsen J, Rydbeck H, Trengereid K, Clancy T, Drabløs F, Ferkingstad E, Kalas M, Lien T, Rye MB, Frigessi A & Hovig E. (2013). The Genomic HyperBrowser: an analysis web server for genome-scale data. Nucleic Acids Res. , 41, W133-41. PMID: 23632163 DOI.
- Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA & Charpentier E. (2012). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science , 337, 816-21. PMID: 22745249 DOI.
- Lander ES. (2016). The Heroes of CRISPR. Cell , 164, 18-28. PMID: 26771483 DOI.
- Maeder ML & Gersbach CA. (2016). Genome-editing Technologies for Gene and Cell Therapy. Mol. Ther. , 24, 430-46. PMID: 26755333 DOI.
- Genomes (2nd edition) Brown, T.A. New York and London: Garland Science ; c2002 PMID20821850
- Introduction to Genetic Analysis Griffiths, Anthony J.F.; Miller, Jeffrey H.; Suzuki, David T.; Lewontin, Richard C.; Gelbart, William M. New York: W. H. Freeman & Co.; c1999
- Modern Genetic Analysis Griffiths, Anthony J.F.; Gelbart, William M.; Miller, Jeffrey H.; Lewontin, Richard C. New York: W. H. Freeman & Co.; c1999
- Human Molecular Genetics 2 Strachan, Tom and Read, Andrew P. New York and London: Garland Science; c1999
- Genetics for Surgeons Morrison, Patrick J.; Spence, Roy A.J., authors Hatchwell, Eli, series editor London: Remedica; c2000
- Sequence - Evolution - Function: Computational Approaches in Comparative Genomics Koonin, Eugene V; Galperin, Michael Y. Norwell (MA): Kluwer Academic Publishers ; c2003
- The Genetic Landscape of Diabetes [Internet] Dean, Laura; McEntyre, J.R. Bethesda (MD): National Library of Medicine (US), NCBI; 2004 Jun
- Madame Curie Bioscience Database Chapters taken from the Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database) Eurekah.com and Landes Bioscience and Springer Science+Business Media; c2009
Tang L, Zeng Y, Du H, Gong M, Peng J, Zhang B, Lei M, Zhao F, Wang W, Li X & Liu J. (2017). CRISPR/Cas9-mediated gene editing in human zygotes using Cas9 protein. Mol. Genet. Genomics , 292, 525-533. PMID: 28251317 DOI.
Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, Lv J, Xie X, Chen Y, Li Y, Sun Y, Bai Y, Songyang Z, Ma W, Zhou C & Huang J. (2015). CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell , 6, 363-372. PMID: 25894090 DOI.
Not easy to generate a good search term for this topic.
Search "Genetic Development" All (151839) Review (31389) Free Full Text (54818)
- antisense - a sequence of DNA that is complementary usually to coding sequence of DNA or mRNA. Has been used experimentally to perturb or block gene expression. Also a mechanism that has been found to occur naturally as a regulatory mechanism.
- autosomal inheritance - some hereditary diseases are described as autosomal which means that the disease is due to a DNA error in one of the 22 pairs that are not sex chromosomes. Both boys and girls can then inherit this error. If the error is in a sex chromosome, the inheritance is said to be sex-linked.
- base - another term for nucleotide (usually a t c g).
- base pair - Double stranded DNA has nucleotides A-T, C-G, paired by hydrogen bonds (2 for AT, 3 for GC). Note this means that GC is harder to separate that AT.
- cis-acting elements - DNA sequences that through transcription factors or other trans-acting elements or factors, regulate the expression of genes on the same chromosome.
- cohesin - a multi-protein subunit complex required to keep the sister chromatids together until their separation at anaphase (both in mitosis and meiosis), can also form rings that connect two DNA segments.
- DNMT - DNA methyltransferase.
- DNA - DeoxyriboNucleic Acid. The genetic material found in mammalian chromosomes and mitochondria. Consisting of 4 nucleic acids (ATCG) that combine in a triptych (3 nucleotide codon) code for protein amino acids (3nt=1aa).
- DNA duplex - double stranded base-paired DNA forming a helix.
- dominant inheritance - With autosomal dominant inheritance, there is an error in one of the 22 chromosome pairs. But the damaged gene dominates over the normal gene received from the other parent. If one of the parents has a disease caused by an autosomal dominant gene, all the children will have a 50 per cent risk of inheriting the dominant gene and a 50 per cent chance of not inheriting it. The children who do not inherit the damaged dominant gene will not themselves suffer from the disease, nor will they be able to pass the gene on to future children. This type of inheritance is present for example in Huntington's disease.
- enhancer - A cis-regulatory sequence that can regulate levels of transcription from an adjacent promoter. Many tissue-specific enhancers can determine spatial patterns of gene expression in higher eukaryotes. Enhancers can act on promoters over many tens of kilobases of DNA and can be 5' or 3' to the promoter they regulate.
- exon - a block of protein encoding sequence of DNA in a gene. Many proteins are made of several exons "stitched" or spliced together by editing out non-coding (intron) sequences.
- fasta - a format for listing DNA sequence, where the first line has descritive information followed on the next line by the sequence without numbering.
- GC repeat - a string of GC sequence repeated several times. Also associated with GC expansion, a mutational process that may lead eventually to serious gene expression effects.
- gene - a sequence of DNA that encodes an individual protein.
- genetic code - the 3 nucleotide sequence that forms a codon for a single amino acid or stop. See the gene code.
- genome - the complete genetic information in the form of DNA available to a specific species.
- hairpin loop - a folding of RNA generated by base pairing making a "===()" structure, the end loop and or stem of this structure can then interact with proteins or other RNA.
- HyperD - hypermethylated domain
- HypoD - hypomethylated domain
- igDMR - imprinted germline differentially methylated regions
- intron - a block of DNA within a gene not encoding a protein. Edited, spliced, out during transcription into mRNA. Originally thought not to contain any information, but more and more this appears not to be the case. Some intron sequences have been shown to regulate gene expression during development (eg c elegans, Lin 14)
- karyotype - [Greek, karyon = kernel or nucleus + typos= stamp] The chromosomal makeup of a cell.
- mRNA - messenger, transcribed from DNA in the nucleus and in mitochondria. Is translated by the ribosome in the cytoplasm (or mitochondrial matrix). Intermediate step in gene expression. (DNA-> mRNA-> protein).
- mutation - any process which results in the alteration of the DNA sequence. Some conservative mutations may have no effect on the final amino acid encoded.
- ncRNA - non-coding RNA.
- ploidy - refers to the chromosomal genetic content of cells.
- promoter - A regulatory region a short distance upstream from the 5' end of a transcription start site that acts as the binding site for RNA polymerase II. A region of DNA to which RNA polymerase IIbinds in order to initiate transcription.
- point mutation - a change in a single nucleotide.
- recessive inheritance - With autosomal recessive inheritance, the diseased individual has inherited the same gene damage from both father and mother. The damage is found on both chromosomes in the pair. But as this is not ´dominant gene damageª, neither father nor mother show any sign of disease, they are healthy carriers of the gene. We are all carriers of about five recessive genes of this type, but as spouses are seldom carriers of exactly the same damaged gene(s), all will probably go well in the next generation.
- regulatory sequence - (regulatory region, regulatory area) is a segment of DNA where regulatory proteins such as transcription factors bind preferentially.
- ribosome - complex of rRNA and ribosomal proteins, bind mRNA and translate it into protein.
- RNA - RiboNucleic Acid. The intermediate nucleic acid involved in gene expression. It comes in 3 forms: tRNA, mRNA, rRNA.
- rRNA - ribosomal, translates mRNA into protein. rRNA provides the "scaffolding" on which many ribosomal proteins are assembled as 2 subunits that themselves assemble to form a ribosome. rRNA genes are localized to the nucleolus in the nucleus, a sometimes visible region of DNA usually constantly being transcribed.
- telomere - regions at the end of chromosomes. Shortening of the telomeres is thought to be associated with cellular aging. The enzyme that maintains the telomere is called telomerase. Introducing this gene into a cell can extend the cells lifespan.
- transcription factor - a protein which binds to DNA activating (usually) gene expression. There are many different ways and forms that this activation can take place, but most transcription factors fall into specific classes (eg zinc fingers, helix loop helix).
- tRNA - transfer, binds single amino acids acts as a "donor' for protein synthesis.
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- Human Genome Project (HGP) | History of the Human Genome Project | Project Timeline
- NCBI Human Genome Resources
- Online Mendelian Inheritance in Man
- NHGRI Catalog of Published Genome-Wide Association Studies | PDF
- Genome-Wide Associations (GWA) Karyogram
- Idiogram Album David Adler
- Genetic Education Resources for Teachers
- MITOMAP A human mitochondrial genome database.
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Cite this page: Hill, M.A. (2018, December 15) Embryology Molecular Development - Genetics. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Molecular_Development_-_Genetics
- © Dr Mark Hill 2018, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G