Genes, Genomes and Human Disease, Part 1 3/18/13. Katherine M. Hyland, PhD

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1 Updated 03/18/13 Genes, Genomes and Human Disease, Part 1 3/18/13 Katherine M. Hyland, PhD BIOGRAPHY: Katherine M. Hyland, PhD is a Professor in the Department of Biochemistry and Biophysics, and an affiliate member of the Institute for Human Genetics at UCSF School of Medicine. She received her B.S. in Biochemistry from Virginia Tech, an M.S. in Molecular Cytogenetics from Rutgers University, and a Ph.D. in Molecular and Human Genetics from the Johns Hopkins University. Her PhD thesis focused on chromosome structure and function in budding yeast. She was a postdoctoral fellow at the Centre for Molecular Medicine and Therapeutics at the University of British Columbia in , and a postdoctoral fellow at the UCSF Comprehensive Cancer Center from In 2002, she joined the faculty at UCSF. Her primary roles at UCSF are in professional school education and faculty development. She is Course Director of the Mechanisms, Methods and Malignancies Block, an interdisciplinary second year medical school course that focuses on the basic and clinical science of cancer, and directs the Medical Genetics component of the integrated medical school curriculum. She is also a co director of the Postdoctoral Teaching Fellowship Program. In 2008, Dr. Hyland was inducted into the Haile T. Debas Academy of Medical Educators, and she currently serves as co Chair of the Faculty Development Working Group. She has participated in numerous educational workshops, and has completed the UCSF Teaching Scholars Program and the Harvard Macy Program for Educators in the Health Professions. She has led faculty development workshops at UCSF as well as at national meetings and other medical schools, including the University of Kragujevac, Serbia, and St. George s University, Grenada. She has developed an online peer feedback training program for educators that will be shared with other medical schools, and is involved in several innovative educational projects. She is Chair of the Genetics Course Directors group in the Association of Professors of Human and Medical Genetics (APHMG), and is also an active a member of the International Association of Medical Science Educators (IAMSE), the American Society of Human Genetics (ASHG), the Association of Biochemistry Course Directors (ABCD) and the Western Group on Educational Affairs (WGEA).

2 Genes, Genomes and Human Disease UCSF Mini Medical School Katherine Hyland, PhD Department of Biochemistry & Biophysics, Institute of Human Genetics Common Variable Immune Deficiency (CVID) late onset humoral immune deficiency Significant % = genetic cause Heterogeneous: defect in single or multiple genes 75-80% = unknown cause, genetics likely plays a role Elizabeth Genetics of CVID Outline: Genetics Part % have known genetic cause Inherited in either Autosomal Dominant or Autosomal Recessive manner 5 known genes Different types of mutations in different families/geographic populations 1. Intro: Genetics of CVID Genetic Contribution to Dis-ease 2. The Basics DNA, Genes, chromosomes, genomes 3. Genetic Variation Mutations and polymorphisms Outline: Genetics Part 2 Learning Goals 1. Inheritance of genetic disease Inheritance patterns and pedigrees 2. Genetic Testing Methods of analyzing single genes, chromosomes and whole genomes Direct to Consumer Testing (TCT) 1. Describe how genetics contributes to human disease 2. Understand basic genetic terminology 3. Describe the organization of the human genome 4. Describe the types of variation seen in the human genome, and potential phenotypic consequences 1

3 Genetic Dis-ease is due to combination of Genetics and Environment Environmental Diet, lifestyle, etc. Medicine through a Genetic Lens Why this person? Why this disease? Rare, diseasecausing mutation Examples: Cystic fibrosis, Down syndrome CVID Common/Rare, susceptibility variants Diabetes, stroke, Measles, lung hypertension, Alzheimer dz cancer CVID Why now? What can we do to restore this person to her/his own unique steady state? Outline: Genetics Part 1? 1. Intro: Genetics of CVID Genetic Contribution to Dis-ease 2. The Basics DNA, Genes, chromosomes, genomes 3. Genetic Variation Mutations and polymorphisms The ABC s of Genes and Genomes DNA = letters Genes = words Genome = Entire book ~ A manual for creating a living being!! Chromosomes = chapters What do we have in common with every other living thing on earth?? DNA!! Composed of 4 basic elements : A = Adenine T = Thymine C = Cytosine G = Guanine *The 4 letters of the DNA alphabet! 2

4 DNA Structure Human DNA is packaged into 24 chromosomes 22 autosomes and 2 sex chromosomes, X &Y Each somatic cell has 46 chromosomes: F 2 copies of each autosome and 2 sex chromosomes, XX (female) or XY (male) Molecular Biology of the Cell, 5 th Edition. By Alberts, Johnson, Lewis, Raff, Roberts and Walter. Garland Science Publishing, 2008 Packaging DNA into Chromosomes Human DNA is packaged into 24 chromosomes Molecular Biology of the Cell, 5 th Edition. By Alberts, Johnson, Lewis, Raff, Roberts and Walter. Garland Science Publishing, 2008 Chromosomes range in size from 50 million to 250 million base pairs of DNA Each gene has a specific location on one of the 24 chromosomes (e.g. street address ) Prophase Prometaphase (nuclear envelope breakdown) Metaphase spread of human chromosomes Metaphase Anaphase Cytokinesis 3

5 Human Karyotype: 46,XY Human Karyotype 46,XY G-banded karyotype Spectral karyotype Venter, PLoS Biology 5(10), Oct What is a GENE? Homologous chromosomes Alleles Wildtype Mutation 1 Mutation 2 en.wikipedia.org A sequence of DNA that carries the information to make a specific protein (or functional RNA) Humans are diploid = 2 copies of every gene Each gene has a specific location on one of the 24 chromosomes (e.g. street address ) Alleles Locus Homozygous wildtype Heterozygous Homozygous mutant Compound Heterozygous Genotype Phenotype = Alleles present in an individual at a specific locus = Physical expression of genotype; result of interaction of genotype with the environment What is a GENOME? An organism s complete DNA sequence - a blueprint to make a human being! Both genes and non-coding regions Nuclear + Mitochondrial DNA Every cell in your body contains a complete copy of your genome Not all genes are turned on in every cell - only a subset that are needed to carry out the functions of that cell type 4

6 How big is the Human Genome? 3 billion base pairs of DNA (A/T, C/G) <20,000 genes = many fewer than anticipated! ACGTC TCAGT CGCGT CATGC CATGC ACGTC TCAGT CGCGT Length of complete DNA sequence equivalent to 200 volumes of a Manhattan telephone book (1000 pgs each)! How big is the Human Genome? ~ 2 meters! (> 6 feet) DNA from all 100 trillion cells of our bodies = over 113 billion miles! From earth to sun and back 610 times!!! Alberts et al, Molecular Biology of the Cell, 5 th Ed. Fig 4-16, Garland Publishing The function and organization of the human genome Coding Regions = gene rich Non-coding Regions = Dark Matter 20,000 ~1-2% of genome Actively transcribed Decondensed during interphase Euchromatin ~98-99% of genome Not transcribed - but functional! e.g. maintain chromosome structure Condensed throughout cell cycle Heterochromatin 1990 Began ~ planned 15 year project Human Genome Project 2000/2001 Working draft published 2003 High quality finished sequence completed Advances in Whole Genome/Exome Sequencing, Genetic Variation Final ENCODE sequence papers published Nature ENCODE Explorer Sept Encyclopedia of DNA Elements (ENCODE) project Goal: characterize all the functional elements in the human genome Results: HG is much more active than anticipated! Non-coding DNA contains genetic switches >80% has biological function Chromatin structure Transcription regulators Epigenetic regulation Huge significance for understanding human disease! 5

7 Outline: Genetics Part 1 1. Intro: Genetics of CVID Genetic Contribution to Dis-ease 2. The Basics DNA, Genes, chromosomes, genomes 3. Genetic Variation Mutations and polymorphisms Human Genetic Variation We are all alike, but not the same!!! Human Genome = 3 billion bp DNA = average sequence 6 billion human genomes! Any two humans are % genetically identical ~3.5 million nucleotide differences ~100 structural differences Rare vs. common variants Each individual heterozygous at ~20% of all loci Human Genetic Variation Where does genetic variation come from? Mutation = Any change in DNA sequence 1. Errors introduced during DNA replication ~1 error per 10 8 base pairs per cell division 100 s of new mutations genome-wide! 2. Errors in homologous recombination when producing egg and sperm 3. Mutagens in environment, e.g. radiation, chemicals, cigarette smoke 4. Failure to repair DNA damage Consequences of Genetic Variation Vary Location of Genetic Variants Genetic Disease (e.g. cystic fibrosis, Down syndrome Rare, high impact on health Mutations Common Multifactorial Disease (e.g. diabetes, stroke, hypertension) Benign phenotypic differences (e.g. hair/skin color, asparagus smell) 1% Frequency of variant in population Polymorphisms Neutral Variants Common, low impact on health In or near gene (coding or regulatory region) Usually Rare, high impact* In non-coding regions (intergenic regions or introns) Usually Common, low impact* intergenic Gene 2 6

8 Sequence Variants: single nucleotide Single Nucleotide Polymorphisms (SNPs) 80% BEER BEER BEAR I d like to drink a beer. I d like to drink a bear. 20% Word Misspelled word Interpret sentence Synonymous SNP (silent) Non-synonymous SNP SNPs: How different are we? Deletions and Duplications NORMAL: I LIKE TO SWIM IN THE OCEAN BUT I DO NOT LIKE TO SWIM IN THE POOL. Occur every ~ bps Account for majority (~90%) of genetic variation On average, 3-10 million single nucleotide variations between 2 people DELETION: I LIKE TO SWIM IN THE POOL. DUPLICATION: I LIKE TO SWIM IN THE OCEAN BUT I DO NOT LIKE TO SWIM IN THE OCEAN BUT I DO NOT LIKE TO SWIM IN THE POOL. Copy Number Variants (CNVs) Structural Variation Large chunks of DNA- repeated or deleted Consequences vary Many are neutral or benign Those that alter gene dosage or expression or disrupt genes may contribute to disease risk CNVs and Cake Mix: - Add one egg - Add one egg, egg, egg 7

9 Key words DNA Gene Allele Chromosome Genome Genotype Phenotype Mutation Polymorphism Learning Goals QUESTIONS? 1. Describe how genetics contributes to human disease 2. Understand basic genetic terminology 3. Describe the organization of the human genome 4. Describe the types of variation seen in the human genome, and potential phenotypic consequences 8