Physiological Genomics Condensed notes from class, including extras from slides and mentioned in class!
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1. Genetic Control of Cell Physiology
Cellular Physiology: Trying to understand how cells function
Mammals have hundreds of different cell types, each with unique biological roles and specialized properties. These
differences (shape, size, function) have to be taken into account when studying cell function.
Most of the neurons in the brain no longer proliferate.
Two main processes required for a mature, healthy organism
Cell multiplication =
Cell specialization =
For each cell doubling this information must be duplicated in the
process of DNA-replication
- Replication coupled to cell division through cell cycle
- Replication occurs in S phase (synthesis)
- Cell division, including equal distribution of DNA into
the two daughter cells, occurs in the M Phase (mitosis)
- M and S phases separated by two Gap phases, G1 (cell
decides what to do next; proliferate/differentiate, die, or not do anything) and G2 (prepares for mitosis)
- Nothing much goes on in G phases…G2 shorter than G1…most decisions make in G1, but G2 can make
emergency decisions too
Genes are individual units of DNA that encode functional
molecules such as proteins and certain RNAs
- Information stored as DNA is transcribed into RNA, and
messenger RNA (mRNA) is translated into proteins
- Functional information: DNA info directly controls
function of its gene products, cells and organism
- DNA replication and mitosis ensure that all cells within an
individual organism have identical genetic material (e.g.
nucleotide sequence), with minor exceptions
Variety in cell types (appearance and function) achieved
- Cell types defined by pattern of functional molecules (mostly proteins) in the cells
- Example: muscle cells contain many contractile proteins, neuronal cells synthesize specific receptors and
neurotransmitters, and intestinal cells secrete specific digestive enzymes.
- All cells of a multicellular organism have the same genetic information, but only a subset of material is active
when certain genes are expressed in a given cell.
- As cells specialize during development, pattern of gene expression becomes more specialized and restricted.
Information types in DNA:
- Functional info: coding sequence; determines structure/function of gene products
- Regulatory info: controls when/where gene expressed (additional regulatory info packaged in DNA)
- This info is very conserved within a species; all humans have a very similar nucleotide sequence.
Specialization achieved at a molecular level through regulatory information
- Much of the info on which genes are active in a given context is contained in the DNA sequence
- Sequences regulate when and where a gene is switched on or off, in response to external stimuli the level of
gene expression changes, etc.
Three-Dimensional Structure of DNA: Chromatin and Nucleosomes
- Nucleosome: DNA wrapped around histone octamer
- DNA Folding:
o Euchromatin – relaxed
o Heterochromatin – highly folded
- Inverse relationship between gene expression and folding and methylation of DNA
2. The Human Genome
Genetic Factors Control:
- Development of physiological systems (tissue architecture, morphology)
- Functional properties (e.g. which receptors of channels are expressed and active in a particular cell)
Genetic Factors Contribute to most Diseases
- Germ line mutations directly give rise to diseases (cystic fibrosis)
- Genetic variances (polymorphisms) contribute to the risk for common diseases (e.g. diabetes, cardiovascular
diseases, Alzheimer’s disease, arthritis)
- Somatic mutations responsible for most cancers
- Genetic factors control our response to exogenous substances such as drugs
o Some drugs work only in patients with a certain genetic makeup
o Other drugs have severe side effects in people with specific genotypes
Knowledge of Genetic Principles and the Human Genome are thus Necessary For:
- Understanding of the development and homeostasis of organs and organisms
- Identification of pathophysiological leading to disease
- Personalized medicine: design of novel preventive, diagnostic and therapeutic approaches
- Led to design of the Human Genome Project (publication of complete sequence in 2001)
Human Genome Project:
- Designed to sequence the entire human genome
- Completed in 2001 by two groups:
o International Human Genome Sequencing Consortium, Publicly Funded (Nature)
o Venter et al. Company funded privately (Science)
What does the haploid human genome consist of?
- 3x109 nucleotide pairs distributed over 23 chromosomes
- Human genome consists of 46 chromosomes variable in size; 2 copies of chromosomes 1 – 22 each, and either
2 X or 1X and 1Y chromosome
Highlights of the Human Genome Project
- Sequence variation between two randomly chosen
individuals is 0.1%
- The human genome consists 20,000 protein-coding
genes, less than many other organisms
- 1,750 of these genes have been directly linked to
disease (sometimes don’t see mutation in others
because person dies early…such as mutation in cell
- Only 1.0% of the human genomic sequence appears
to be coding for proteins
Humans have few genes giving rise to many
different proteins through alternative splicing,
posttranslational modification…they use more
complex regulation of expression and function.
Structure of A Gene
- Human exons are on average shorter than introns
(more possible combinations)
- Contain a 5’-flanking end
- Contain a 3’-flanking end
What can we do with the information obtained in the Human Genome Project?
1. Identify new genes governing physiological and pathological processes
- BRCA2: Breast Cancer Susceptibility
- CNGB3: Total colour-blindness (Cyclic Nucleotide Gated Channel Beta 3)
- MYH9: Nonsyndromic Hereditary Deafness DFNA17 (Myosin, Heavy Polypeptide 9, non-muscle)
- Follow up Study: Gene Mountains and Hills
2. Identify novel drug targets
3. Identify regulatory regions in the DNA (promoter),
e.g. through comparison with other species
4. Studies on human evolution
5. Link variation in genetic sequence to differences
between individuals, including disease susceptibility
and different responses to drugs
DNA sequence determines our genotype. Variations in gene sequence can directly affect protein sequence
(functional information) or gene expression (regulatory information), or have no consequence at all. In
combination with environmental factors, the genotype shapes the phenotype.
Average tumor has mutations in approximately 90 genes (different in all people)
About 200 genes are mutated in many samples (many of them have not been implicated with cancer before)
Some genes come up in lots of cancers, some very different.
Most cancers are spontaneous, but 10% have inherited component (BRCA 1 and 2)
Physiological genomics: genetic control of cell physiology. Cellular physiology: trying to understand how cells function. Mammals have hundreds of different cell types, each with unique biological roles and specialized properties. These differences (shape, size, function) have to be taken into account when studying cell function. Most of the neurons in the brain no longer proliferate. Two main processes required for a mature, healthy organism. For each cell doubling this information must be duplicated in the process of dna-replication. Replication coupled to cell division through cell cycle. Cell division, including equal distribution of dna into the two daughter cells, occurs in the m phase (mitosis) M and s phases separated by two gap phases, g1 (cell decides what to do next; proliferate/differentiate, die, or not do anything) and g2 (prepares for mitosis) Nothing much goes on in g phases g2 shorter than g1 most decisions make in g1, but g2 can make emergency decisions too.