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Jumping Into Your Gene Pool: Understanding Genetic Test Results

Dive into the world of genetic testing and learn how to interpret the results. This educational session covers topics such as chromosomes, genes, DNA structure, transcription and translation, inheritance patterns, and various types of genetic mutations.

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Jumping Into Your Gene Pool: Understanding Genetic Test Results

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  1. Jumping Into Your Gene Pool:Understanding Genetic Test Results Susan A. Berry, MD Professor and Director Division of Genetics and Metabolism Department of Pediatrics University of Minnesota

  2. Acknowledgment • American Society of Clinical Oncologists Curriculum - educational materials used for this session (plus a few of my own!) Look for ASCO • Understanding Gene Testing - National Cancer Institute, 1996

  3. Chromosomes, DNA, and Genes Gene Nucleus Cell Chromosomes Protein Adapted from Understanding Gene Testing, NIH, 1995 ASCO

  4. The DNA Double Helix Sugar phosphate backbone Base pair Bases Adenine (A) Thymine (T) Cytosine (C) Guanine (G) ASCO

  5. Genes are on chromosomes p Centromere q Chromosome 5 ASCO

  6. The Human Genome 23 pairs of chromosomes made of 700 million base pairs 20,000-25,000 genes = the exome • ExtragenicDNA • Repetitive sequences • Control regions • Spacer DNA between genes • Function mostly unknown 70% 30% ASCO

  7. The Cell Cycle G1 (cell growth) M (mitosis) G2 S (synthesis) G0 (resting) ASCO

  8. Mitosis and Meiosis 2N Mitosis 2N N N N Meiosis (germ cells only) N ASCO

  9. U A A G A A C U G Met Ala Genetic Code A codon is made of 3 base pairs 64 codons total 1 codon (AUG) encodes methionine and starts translation of all proteins 61 codons encode 20 amino acids (redundant code) 3 codons stop protein translation ASCO

  10. DNA Transcription and Translation Growing chain of amino acids mRNA Protein Ribosome Nuclear membrane Cell membrane DNA ASCO Adapted from Understanding Gene Testing, NIH, 1995

  11. Gene Structure RNA transcription start site Splice sites Stop site Promoter Exon 1 Intron Exon 2 Intron Exon 3 5' end 3' end Exon 1 Exon 2 Exon 3 mRNA ASCO

  12. RNA Processing Exon Intron Exon Intron Exon DNA Transcription Primary mRNA Processing Mature mRNA Translation Protein ASCO

  13. Alleles: What are they!? A a a a A a A a a a a a Alleles: variant forms of the same gene (A a) ASCO

  14. Autosomal Recessive Inheritance Noncarrier individual Non-affected carrier Affected individual • Two germline mutations (one from each parent) to express the condition • Equally transmitted by men and women ASCO

  15. Your Dr. wants to “phase” your family. Why? ? Child’s result or Is it this? This? ASCO

  16. Carrier Frequency Prevalence of an altered disease gene in a given population Carrier frequency = 20% ASCO

  17. Founder Effect Original population A high frequency of a specific gene mutation in a population founded by a small ancestral group Marked population decrease, migration, or isolation Generations later ASCO

  18. Environmental Factors Affecting Genes Modifier genes Carcinogens Response to DNA damage Hormonal/ reproductive factors Not every altered gene has the same effect on each person that inherits it ASCO

  19. Genotype/Phenotype Correlation • Different mutations in the same gene cause different effects • Where is the genetic change in the sequence? • What kind of change is it? ASCO

  20. Variations in DNA sequence: What kinds are there? A variant is a change in the normal base pair sequence Can cause a change that does NOT alter protein function OR We might not be able to tell if the change is harmful OR Can be a change that makes a protein not work ASCO

  21. Disease-Associated (Pathogenic) Variants Alter Protein Function Functional protein Nonfunctional or missing protein ASCO

  22. THE BIG RED DOG RAN OUT. THE BIG RAD DOG RAN OUT. THE BIG RED. THE BRE DDO GRA. THE BIG RED ZDO GRA. Normal Missense Nonsense Frameshift (deletion) Frameshift (insertion) Point Mutations Point mutation: a change in a single base pair ASCO

  23. G A G U U G U G A U C G C A A U A U Met Leu Gln Lys Phe Gly G A C A G U U G G U G A A U U G A A U C U Met Leu Gln Ala Lys Phe Gly Silent Sequence Variants mRNA Protein Normal G G A C Ala mRNA Protein Sequence variant Sequence variant: a base pair change that does not change the amino acid sequence ASCO Adapted from Campbell NA (ed). Biology, 2nd ed, 1990

  24. G A C A G U U G G U G A A U C G A A U C U Met Leu Gln Ala Lys Phe Gly A C A G U U U G A A U G A U U Met Leu Gln Lys Phe Missense Mutations mRNA Protein Normal mRNA Protein Missense G A G C A C Missense: changes to a codon for another amino acid (can be harmful or neutral) Ala Ser ASCO Adapted from Campbell NA (ed). Biology, 2nd ed, 1990

  25. G A C A G U U G G U G A A U C G A A U C U Met Leu Gln Ala Lys Phe Gly G A G U U G G U G U U C G A A U C U C A A Met Nonsense Mutations mRNA Protein Normal mRNA Protein Nonsense Nonsense: change from an amino acid codon to a stop codon, producing a shortened protein ASCO Adapted from Campbell NA (ed). Biology, 2nd ed, 1990

  26. G A C A G U U G G U G A A U C G A A U C U Met Leu Gln Ala Lys Phe Gly U G G U U G G A C G C A A A U C A U A U G Met Lys Leu Ala Frameshift Mutations mRNA Protein Normal mRNA Protein Frameshift Frameshift: insertion or deletion of base pairs, producing a stop codon downstream and (usually) shortened protein ASCO Adapted from Campbell NA (ed). Biology, 2nd ed, 1990

  27. Splice-Site Mutations Exon 1 Intron Exon 2 Intron Exon 3 Exon 2 Exon 3 Exon 1 Altered mRNA Splice-site mutation: a change that results in altered RNA sequence ASCO

  28. Other Types of Mutations • Mutations in regulatory regions of the gene • Large deletions or insertions • Chromosome translocations or inversions ASCO

  29. Deciphering Clinical Gene Tests MMMMM Good! E G G D ASCO C S P S C R P

  30. https://m1.healio.com/~/media/images/education-lab/learning-sites/learn-genomics-vs2/img/nextgensequencing.jpghttps://m1.healio.com/~/media/images/education-lab/learning-sites/learn-genomics-vs2/img/nextgensequencing.jpg

  31. Preparing DNA for Analysis DNA for analysis Centrifuge and extract DNA from white blood cells Blood sample ASCO

  32. Polymerase Chain Reaction (PCR) Isolate and denature DNA Anneal and extend primers Repeat as necessary Amplified segments Sequence to be amplified ASCO

  33. Principle of Microarray (Chip) Assay Prehybridization Posthybridization Synthetic DNA probes Probes with hybridized DNA ASCO

  34. By Suspencewl - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=13764860

  35. Pathogenic: associated with known disease state Likely pathogenic: strong evidence in favor of pathogenicity Uncertain (“VUS”): limited and/or conflicting evidence of association with disease Likely benign: strong evidence against pathogenicity Benign: very strong evidence against pathogenicity

  36. What kinds of evidence? • Published variant associated with condition • Segregation in a family or in others with the condition • Variant is very rare in an appropriate control population • Loss of gene function is proven • Prediction based on data tools • Variant highly likely to not yield protein

  37. Summary • FAOD conditions follow an autosomal recessive pattern of inheritance • Parental testing is needed to “phase” the child’s result • Results can be ambiguous (VUS) but often can be clarified by assessment of phenotype (how the child presented biochemically)

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