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Genetic Aspects of Dental Anomalies

 

 

 

The Human Genome Project

 

An international research effort to sequence and map all the genes together known as the genome was completed in April, 2003.

·         Complete genetic blueprint

Genomes of various organisms commonly used in biomedical model organisms

·         Mice, fruit flies, and roundworms

·         Involved NIH, NHGRI, DOE , universities and research facilities in US, UK, France, Germany, Japan, & China

 

DNA Structure

HGP researchers deciphered the human genome

·         Determining the sequence

·         Making maps that show the locations of genes for major sections of all chromosomes

·         Produced linkage maps which inherited traits (genetic disease) can be tracked over generations

·         30,000-40,000 genes

 

Genetics 101

DNA from all organisms is made up of the same chemical and physical components. The DNA sequence is the particular side-by-side arrangement of bases along the DNA strand (e.g., ATTCCGGA). This order spells out the exact instructions required to create a particular organism with its own unique traits.

The genome is an organism’s complete set of DNA including its gene. Human and mouse genomes both have 3 billion. Except for mature red blood cells, all human cells contain a complete genome.

 

Genes are specific sequences of bases that encode instructions on how to make proteins.

·         Genes comprise only about 2% of the human genome

·         Remainder consists of noncoding regions

·         Functions include providing chromosomal structural integrity and regulating where, when, and in what quantity proteins are made.

·         Human genome is estimated to contain 30,000 to 40,000 genes

 

Genomes are expressed by the set of direction embedded in the DNA sequence.

Protein is responsible for:

·         Cellular structure

·         Digest nutrients

·         Metabolic function

·         Mediate information within the cells

 

Cells divide into two daughter cell and the full genome is duplicated in the nucleus.

RNA is produced by transcription.

·         Substitutes the sugar ribose for deoxyribose and the base uracil for thymine

·         Single stranded

·         MRNA conveys the DNA information for protein synthesis to the cell cytoplasm

 

What we’ve learned so far

The human genome contains 3164.7 million chemical nucleotide bases (Adenine, Cytosine, Thymine, and Guanine).

The average gene consists of 3000 bases, but varies in size

Almost all (99.9%) nucleotide bases are exactly the same in all people.

The functions are unknown for over 50% of discovered genes.

Less than 2% of the genome codes for proteins.

Repeated sequences that do not code for proteins ("junk DNA") make up at least 50% of the human genome.

Repetitive sequences are thought to have no direct functions, but they shed light on chromosome structure and dynamics. Over time, these repeats reshape the genome by rearranging it, creating entirely new genes, and modifying and reshuffling existing genes.

During the past 50 million years, a dramatic decrease seems to have occurred in the rate of accumulation of repeats in the human  genome.

 

Humans compared to other organisms

Humans have on average three times as many kinds of proteins as the fly or worm because of mRNA transcripts  and chemical  modifications to the proteins.

Humans share most of the same protein families with worms, flies and plants, but the number of gene family members has expanded in humans.

The human genome has a much greater portion (50%) of repeat sequences than the mustard weed (11%), the worm (7%), and the fly  (3%).

Although humans appear to have stopped accumulating repeated DNA over 50 million years ago, there seems to be no such decline in rodents. This may account for some of the fundamental differences between hominids and rodents, although gene estimates are similar in these species.

 

Variations and Mutations

Scientists have identified about 1.4 million locations where single-base DNA differences (SNPs) occur in humans. This information changes the processes of finding chromosomal locations for a disease.

 

Gene Test

Gene tests (also called DNA-based tests), used to test for genetic disorders, involve direct examination of the DNA molecule itself.

Genetic tests are used for several reasons, including:

·         carrier screening

·         newborn screening

·         preimplantation genetic diagnosis

·         presymptomatic testing for predicting adult-onset disorders

·         presymptomatic testing for estimating the risk of developing adult-onset cancers and Alzheimer's disease

·         confirmational diagnosis of a symptomatic individual

·         forensic/identity testing

·         prenatal diagnostic testing

 

How Does it Work

·         Scan a patient's DNA sample for a mutated sequences

·         DNA sample can be obtained from any tissue

·         Design short pieces of DNA called probes

·         sequences are complementary to the mutated sequences.

·         Probes will seek their complement among the three billion base pairs of an individual's genome.

·         Mutated sequence is present in the patient's genome, the probe will bind to it and flag the mutation.

 

Genetic Mapping

Isolation of single gene

·         Confirm that a disease is transmitted from parent to child

·         Tells which chromosome contains the gene and where it is in the chromosome

·         Cystic fibrosis  and muscular dystrophy

 

Gene Therapy

Correcting defective genes responsible for disease development

An abnormal gene could be swapped for a normal gene through homologous recombination.

The abnormal gene could be repaired through selective reverse mutation, which returns the gene to normal.

A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene.

 

Gene Therapy Vectors

Retroviruses

Double stranded DNA copies RNA genomes.

·         Integrated into the chromosomes of host cell

Adenoviruses

·         Double stranded DNA genomes that cause respiratory, intestinal, and eye infections in humans

Adeno-associated viruses

·         Single stranded DNA viruses that can insert their genetic material at a specific site on chromosome 19

Herpes Simplex viruses

·         Double stranded DNA viruses that infect a particular cell type (neurons)

 

Non Viral Options for Gene Therapy

·         Direct introduction of therapeutic DNA into target cell

·         Creation of an artificial lipid sphere with an aqueous core

·         Chemically linking the DNA to a molecule that will bind to special receptors

·         Factors that have kept gene therapy from becoming effective

·         Short lived nature of gene therapy

·         Immune response

·         Problem with viral vectors

·         Multigene disorder

 

Potential Benefits of Human Genome Project

·         Molecular medicine

·         Risk Assessment

·         Microbial Genomics

·         Anthropology, Evolution, and Human Migration

·         DNA Forensics

·         Agriculture, Livestock Breeding, and Bioprocessing

·         Revolutionary ways to diagnose, treat, and prevent thousands of disorders

 

Ethical Consideration

·         Fairness in the use of genetic information by insurers, employers, courts, schools, adoption agencies, and the military, among others.

·         Who should have access to personal genetic information, and how will it be used?

·         Privacy and confidentiality of genetic information.

·         Who owns and controls genetic information?

·         Reproductive issues including adequate informed consent for complex and potentially controversial procedures, use of genetic information in reproductive decision making, and reproductive rights.

·         Do healthcare personnel properly counsel parents about the risks and limitations of   genetic technology?

·         How reliable and useful is fetal genetic testing?

·         Psychological impact and stigmatization due to an individual's genetic differences.

·         How does personal genetic information affect an individual and society's perceptions of that individual?

·         How does genomic information affect members of minority communities?

·         Commercialization of products including property rights (patents, copyrights, and trade secrets) and accessibility of data and materials.

·         Who owns genes and other pieces of DNA?

·         Will patenting DNA sequences limit their accessibility and development into useful   products?

 

Where is this going?

·         Study an individual’s genotype

·         Risk for complex condition

·         Hereditary

·         Environmental

·         Ex.  Dental Caries, Cleft lip/ cleft palate, oral cancer

 

Molecular basis of a disease

An accurate molecular based diagnosis helps clinicians to delineate conditions with a similar phenotype.

·         Congenitally missing teeth

·         Premature loss of teeth

·         Amelogenesis Imperfecta

·         Dentinogenesis Imperfecta

·         Determining the molecular basis is helpful in confirming the diagnosis

·         Provide counseling for recurrence risk

 

Congenitally Missing Teeth

·         Most common hereditary dental condition

·         Simple dental trait

·         MSX1 homeobox gene

·         PAX9 transcription

·         Can be part of a syndrome

·         Ectodermal Dyslplasia

·         Down’s Syndrome

·         Incontinentia Pigmenti

 

Premature Loss of Teeth

·         Hypophosphatasia

·         Papillon-LeFevere Syndrome

·         Cyclic Neutropenia

·         Chediak Higashi Syndrome

·         Histiocytosis X

·         Prepubertal Periodontitis

 

Dentin Defects

Dentinogenesis Imperfecta

      Dentinogenesis  Type I

·         Occurs with osteogenesis imperfecta

·         Primary teeth more severe

·         Permanent teeth central incisors and 1st molars

·         Rapid attrition

·         Pulpal obliteration

·         Scalloped DEJ, normal mantle dentin

·         Bulbous crowns and short roots

·         Amber translucence

 

Dentinogenesis Imperfecta II

·         Hereditary Opalescent dentin

·         Primary and permanent equally affected

·         Irregular or tubular pattern

·         Periapical radiolucencies, alveolar abscess

·         Similar to DI-I

 

Dentinogenesis Imperfecta III

·         Brandywine Isolate

·         Bell shaped crowns, opalescent hue

·         Shell teeth with short roots and enlarged pulp chambers; only mantle dentin formed

·         Outer layer of primary dentin, less mineralized

·         Multiple pulpal exposure

·         Enamel pitting

·         Different expression for the same DI-II gene

 

Enamel Defects

Systemic

Phenotypic overlap

Ex. Amelogenesis Imperfecta

·         Genetic studies allow for accurate diagnosis

·         X linked AI forms are caused by mutation in the amelogenin gene (12 mutation)

·         Smooth hypoplastic AI – mutation in the enamelin gene

 

Hypoplastic (Type I)

Hypomaturation (Type II)

Hypocalcified (Type III)

Hypomaturation, Hypoplasia, Taurodontism(Type IV)

 

Amelogenesis Imperfecta

Problem with the enamel could arise from:

·         Elaboration of the organic matrix

·         Mineralization of the matrix

·         Maturation of the enamel

14 different hereditary subtypes

·         Numerous patterns of inheritance

·         Wide variety of clinical manifestation

 

Deciduous and permanent

Treatment varies depending on the severity

 

Periodontal Disease

Environmental

·         Smoking

Hereditary

·         Gene IL6

 

What to look forward to as the Human Genome Project advances

Improved diagnostics

Better prediction of disease risk

Early preventive therapies or interventions

Advances in tissue engineering and  tissue regeneration

New and effective biopharmaceuticals

 

The Next Step

Structural genomics

·         To generate a 3-D structures of one or more proteins from each protein family, which will offer clues to function and biological targets for drug design.

Proteomics

·         Reveals what happens in the cell than gene expression studies.  Will help with drug design.

Transcriptomics

·         Analysis of messenger RNAs transcribed from active genes to follow when, where and what conditions are expressed.

 

Bioinformatics

·         Integration of molecular biology and computer science to help analyze and interpret the information derived from the genome and related projects.

Comparative genomics

·         Analyzing DNA sequencing pattern of humans and well studied model organisms side by side.

Knockout Studies

·         Experimental method for understanding functions DNA sequencing. 

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