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 1998‐99, and a postdoctoral fellow at the UCSF Comprehensive  Cancer Center from 1999‐2002. 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).          

3/18/2013

Genes, Genomes and Human Disease

UCSF Mini Medical School Katherine Hyland, PhD

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

Department of Biochemistry & Biophysics, Institute of Human Genetics

Genetics of CVID  10-20% 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

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

Outline: Genetics Part 2

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)

Learning Goals 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

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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?

Genetic Common/Rare, susceptibility variants

Rare, diseasecausing mutation Examples: • Cystic fibrosis, Down syndrome • CVID

• Diabetes, stroke, • Measles, lung hypertension, Alzheimer dz cancer

Why now? What can we do to restore this person to her/his own unique steady state?

• CVID

Outline: Genetics Part 1

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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

What do we have in common with every other living thing on earth??

DNA!!

DNA = “letters” Chromosomes = “chapters” Genes = “words”

Composed of 4 basic elements :  A = Adenine  T = Thymine  C = Cytosine

Genome = Entire book ~ A manual for creating a living being!!

 G = Guanine *The 4 letters of the DNA alphabet!

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Human DNA is packaged into 24 chromosomes

DNA Structure

 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, 5th Edition. By Alberts, Johnson, Lewis, Raff, Roberts and Walter. Garland Science Publishing, 2008

Packaging DNA into Chromosomes

Human DNA is packaged into 24 chromosomes  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’)

Molecular Biology of the Cell, 5th Edition. By Alberts, Johnson, Lewis, Raff, Roberts and Walter. Garland Science Publishing, 2008

Prophase

Metaphase

Prometaphase (nuclear envelope breakdown)

Anaphase

Metaphase spread of human chromosomes

Cytokinesis

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Human Karyotype: 46,XY

Human Karyotype 46,XY

G-banded karyotype

Spectral karyotype Venter, PLoS Biology 5(10), Oct 2007.

What is a GENE?

Homologous chromosomes

Alleles

Wildtype Mutation 1 Mutation 2

 A sequence of DNA that carries the information to make a specific protein (or functional RNA)  Humans are diploid = 2 copies of every gene

en.wikipedia.org

 Each gene has a specific location on one of the 24 chromosomes (e.g. ‘street address’)

Alleles

Locus

Homozygous wildtype

Genotype

= Alleles present in an individual at a specific locus

Heterozygous Homozygous Compound mutant Heterozygous

What is a GENOME?  An organism’s complete DNA sequence - a blueprint to make a human being!  Both genes and non-coding regions

Phenotype

= Physical expression of genotype; result of interaction of genotype with the environment

 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

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How big is the Human Genome?

How big is the Human Genome?

 3 billion base pairs of DNA (A/T, C/G)

 ~ 2 meters! (> 6 feet)

80% has biological function

2012

• Chromatin structure

“Working High quality Final ENCODE draft” “finished sequence published sequence” papers completed published…

• Transcription regulators • Epigenetic regulation

Nature ENCODE Explorer Sept. 2012 http://www.nature.com/encode/

• Huge significance for understanding human disease!

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Human Genetic Variation

Outline: Genetics Part 1

We are all alike, but not the same!!!  Human Genome = 3 billion bp DNA = “average sequence”

1. Intro:

 6 billion human genomes!

 Genetics of CVID

 Any two humans are 99-99.9% genetically identical

 Genetic Contribution to Dis-ease

2. The Basics

 ~3.5 million nucleotide differences

 DNA, Genes, chromosomes, genomes

 ~100 structural differences

3. Genetic Variation

 Rare vs. common variants

 Mutations and polymorphisms

 Each individual heterozygous at ~20% of all loci

Where does genetic variation come from?

Human Genetic Variation

Mutation = Any change in DNA sequence 1. Errors introduced during DNA replication •

~1 error per 108 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 Genetic Disease (e.g. cystic fibrosis, Down syndrome

Common “Multifactorial” Disease

(e.g. diabetes, stroke, hypertension)

Benign phenotypic differences (e.g. hair/skin color, asparagus smell)

1% Rare, high Frequency of variant in population impact on health

“Mutations”

“Polymorphisms”

Location of Genetic Variants In or near gene (coding Neutral Variants

or regulatory region)  Usually Rare, high impact*

In non-coding regions Common, low impact on health

intergenic

Gene 2

(intergenic regions or introns)  Usually Common, low impact*

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Sequence Variants: single nucleotide

Single Nucleotide Polymorphisms (SNPs) 80%

BEER

I’d like to drink a beer.

BEER

Word

BEAR

I’d like to drink a bear.

Misspelled word

Interpret sentence

SNPs: How different are we?

20%  Synonymous SNP (silent)  Non-synonymous SNP

Deletions and Duplications NORMAL: “I LIKE TO SWIM IN THE OCEAN BUT I DO NOT LIKE TO SWIM IN THE POOL.” DELETION: “I LIKE TO SWIM IN THE POOL.”

 Occur every ~300-1000 bps  Account for majority (~90%) of genetic variation  On average, 3-10 million single nucleotide variations between 2 people

Copy Number Variants (CNVs)

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.”

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

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Key words     

Learning Goals

DNA Gene Allele Chromosome Genome

   

Genotype Phenotype Mutation Polymorphism

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

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