Genes, Mutations and Genetic Testing
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Genes, Mutations and Genetic Testing
Wen Jie Zhang, MD, PhD
School of Medicine, Health Sciences and EngineeringSusquehanna Township High School
Lecture Series Week 6, September 2013
Clinical Relevance of This Week’s Topic
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CarcinogenesisEnvironmental Factors Genetic Factors
Physical
Chemical
Biological
(Mutations)
Substitutions
Deletions
Insertions
Lifestyle
Cancer(Carcinogens)
Translocations
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ASCO
The Human Genome
23 pairs of chromosomes made of 3 billion base pairs
30%70%
~35,000 genesExtragenic
DNARepetitive
sequencesControl regionsSpacer DNA
between genesFunction mostly
unknown
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The chemical structure of a four-base fragment of A DNA double helix.
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Genes
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Chromosome and Gene
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Gene StructureTranscription and Translation
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Polymorphism
DNA sequence changes that may or may not alter protein function (common definition)
Functional protein Functional protein
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ASCO
Disease-Associated Mutations Alter Protein Function
Functional protein Nonfunctional or missing protein
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Common MutationsSubstitutions (point mutation)
In a DNA sequence, a single nucleotide is exchanged for another (A G, C T), leading to missense or nonsense mutation.
Insertions (insertion mutation)The addition of one or more nucleotide base pairs into a DNA sequence.
Deletions (deletion mutation)Part of a chromosome or a sequence (base pairs) of DNA is missing from a DNA sequence.
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Missense MutationMissense Mutation (non-synonymous)
is a point mutation in which a single nucleotide change (substitution) results in a codon that codes for a different amino acid
Example Genetic Disease Sickle-cell disease (SCD) or sickle-cell anemia (SCA) – a hereditary blood disorder, characterized by red blood cells that assume an abnormal, rigid, sickle shape.
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A Missense Mutation
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Mutations
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Missense Mutation (cont’d)Missense Mutation (non-synonymous)
is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid
Example Genetic Disease Sickle-cell disease (SCD) or sickle-cell anemia (SCA) – a hereditary blood disorder, characterized by red blood cells that assume an abnormal, rigid, sickle shape.
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Nonsense MutationsNonsense mutation
is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product.
Example Genetic Diseaseβ-Thalassemia – are forms of inherited autosomal recessive blood disorders that originated in the Mediterranean region. In thalassemia, the disease is caused by the weakening and destruction of red blood cells.
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Simple Nonsense Mutation
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Large Insertion Mutation
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Large Deletion Mutation
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Chromosomal Translocation
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Genetic Testing• Genetic testing is “the analysis of, chromosomes
(DNA), proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes.”
• There were more than 1,200 clinically applicable genetic tests available.
• Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue such as semen.
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Types of Genetic Testing
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Prenatal Diagnostic Testing
• Prenatal testing is used to detect changes in a fetus's genes or chromosomes before birth, offered to couples with an increased risk of having a baby with a genetic or chromosomal disorder.
• Sex determination (discernment)
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Cleft Lip/Palate
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Newborn Screening Test
• Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. The routine testing of infants for certain disorders is the most widespread use of genetic testing
• Millions of babies are tested each year in the United States.
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Carrier Testing
• Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder.
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Pre-implantation Genetic Diagnosis
• Genetic testing procedures are performed on human embryos prior to the implantation as part of an in vitro fertilization procedure.
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Predictive and Presymptomatic Testing
• Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no symptoms of the disorder themselves at the time of testing (BRCA1/2).
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ASCO
BRCA1-Linked Hereditary Breast and Ovarian Cancer
Noncarrier
BRCA1-mutation carrierAffected with cancer
Breast,dx 45, d. 89
92 86
73 68 Ovary, dx 59d. 62
Breast, dx 59
71
Breast, dx 36
36
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ASCO
First menstrual period: 15 yPrior biopsy: 0Atypical hyperplasia: UnknownFirst live birth: No birth
Risk Assessment Models
Beth(27)
Cindy, 39
Diana(32)
ModelGailClausNormal person
Breast cancer at 69 yRisk (%)
19397
Predicted possibility of BRCA1 mutation=8.5% (Couch Model)
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BRCA1
ASCO
Tumor suppressor gene on chromosome 17 Autosomal dominant transmission Protein has role in genomic stability >1,200 different mutations reported
Breast Cancer Information Core
Nonsense Missense Splice-site
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ASCO
BRCA2
Breast Cancer Information Core
Tumor suppressor gene on chromosome 13 Autosomal dominant transmission Protein has role in genomic stability >1,200 different mutations reported
Nonsense Missense Splice-site
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Forensic/Identity Testing
• Forensic/identity testing uses DNA sequences to identify an individual for legal purposes.
• Can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).
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Testing for Phamacogenomics
• A type of genetic testing that determines the influence of genetic variation on drug response.
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ChromosomeNomenclature &Banding Patterns
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Tumor Suppressor GenesGene Human Disease Function
APC Colon cancer Interacts with cateninsDCC Colon cancer CAM domainsE-cadherin Breast cancer Intracellularly interacts(CDH1) with cateninsDPC4 Pancreatic cancer TGF--related signalingBRCA1 Mammary cancer/ DNA damage repair,
Ovarian cancer checkpoint control, apoptosisBRCA2 Mammary cancer DNA damage repair, genomic
stabilityATM Ataxia-telangiectasia DNA damage response
mutated gene upstream in p53 pathwayP53 Mutated in >50% Transcription factor,
tumors checkpoint control, apoptosis
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Coda