Great Ideas of Biology Lecture 3 Alan Mortimer PhD
Molecular Biology
The Great Idea
Darwinian Evolution Darwin proposed a theory of evolution based on: Species overproduce There occurs variation in the offspring Among the variations, those most able to reproduce in a given environment will dominate Darwin did not address What causes variation in offspring How traits are carried from one generation to the next
Classical Genetics The first hints came through studies of plant hybridization Recall the section in Origins dealing with animal husbandry Early work by Linnaeus and Sageret (dominance) Most notable was Mendel
Classical Genetics Gregor Medel (1856-65) Studied inheritance in plants (peas) Demonstrated inherited trait followed a statistical pattern Mendel s First Law (segregation) Each individual possesses a pair of alleles (information) for a specific trait Each offspring receives one separate, randomly successful allele from each parent Mendel s Second Law (inheritance) Separate genes for separate traits are passed on independently
Inheritance of non-dominant traits: here the colours red (r), white(w), with the possible outcome pink in 3 rd generation Inheritance of dominant-recessive traits: here red (r) is dominant to white (w)
Classical Genetics Mendel s work remained largely unknown until 1900 (it had been published in a Czech journal) Reintroduced by William Bateson (Cambridge) Coined the terms genetics and allele Remained controversial because it implied discrete rather than the apparently continuous variations observable for many traits (Darwin) Argument was eventually settled by the statistician R.A.Fischer in 1918
Classical Genetics Continuous Evolution Darwin s model A continuum of small changes Explains wide variation seen in nature Strongly supported by Francis Galton (Darwin s cousin) and Karl Pearson (who built some limited statistical models) 1859-1918 Discrete Inheritance Mendel 1865 Rediscovered 1900 Individual traits can be inherited Dominant and recessive traits Supported by William Bateson Proved by R.A. Fischer using statistical techniques 1918
The Chromosome First observed under the microscope in late 1880 s by Theodor Boveri Behaviour of chromosomes during cell division was described in 1890 s independently by several scientists 1903 Boveri and Sutton proposed that the chromosome which separates in a Mendelian fashion are hereditary units
Chromosomes during cell division in an onion root tip Single chromosome contains a great deal of DNA
Down in the Weeds
DNA was first isolated from white blood cells nuclei in 1869 The primary nucleobases were identified in ~1879 via wet chemistry By 1919 the major components had been identified: base, sugar, phosphate nucleotide unit DNA
You can actually isolate DNA at home https://www.popsci.com/how-to-extract-your-own-dna
DNA Structure was a subject of debate until new techniques became available (the molecule was just too big for wet chemistry techniques) X-ray crystallography provided a different view X-rays bounce off a crystal of the bio-molecule Pattern depends on the size of each atom and its position Provides information on relative position (bond angles) of the various molecules Became a powerful tool in chemistry from 1920 s Limited by computing power
X-ray Crystallography DNA Schematic of x-ray crystallography X-ray crystallographic data from Mars Curiosity
DNA Much of the important x-ray crystallography work for DNA was done by Rosalind Franklin DNA structure was first published in Nature in 1953 by Watson and Crick Based on a single x-ray image by Franklin and Gosling The same issue of Nature included Franklin and Gosling: X-ray diffraction data Wilkins: in vivo B DNA diffraction patterns supporting a double helix
DNA Structure Double helix Binding between the helices Specific binding rules One neucelobase only binds with one other neucelobase There are only limited bases (usually 4) The bases repeat nonperiodically along each helix
What s so Special The molecule is REALLY rugged It can contain up to 3 billion base pairs It has survived millions of years It is actually being used as a structural element in nanotechnology DNA can be split down the middle during cell division The shape allows it to be an excellent template for creating copies
DNA can split and replicate the other half of the double helix This occurs during cell division
Three Types of Cell Division Binary fission occurs in cells without a nucleus like bacteria Occurs in cells with a nucleus eukaryotic cells
What is a Gene A gene is a section of DNA that can be related to a heritable trait e.g. hair colour, blood type They vary in length but seem to be of the order of 1000 base pairs First described in 1972 Herbert Boyer and Stanley Cohen
What is a Gene Proteins are the foundation of biological structures Genes provide the codes for synthesising proteins This includes proteins for the cell itself
What is a Gene There are a great many types of proteins DNA contains many genes
Anatomy of Protein Synthesis
DNA Sequencing Knowing the exact structure of DNA is required to be able to identify genes Exactly which nucleobase follows which The procedure is really brute force chemistry Now paired with very heavy duty computing Generally performed in a bulk solution after amplification (more later)
DNA Sequencing Procedure: cut up the DNA Using a specific enzyme identify the sequence of each piece Use a computer to look for overlaps Computation put the pieces together
DNA Sequencing The enzymes which perform the steps of cutting up DNA also work in vitro By introducing markers and doing a lot of chemical analysis and computing the order of the bases in the DNA molecule can be determined Recall there can be 1 billion base pairs in a DNA molecule
DNA Sequencing
DNA Sequencing The Human Genome was sequenced in 2003 That doesn t mean we know what it does
PCR Polymerase Chain Reaction Used to amplify DNA to permit sequencing The enzymes required are activated by temperature rather than other biological factors Were isolated from bacteria (Pyrococcus furiosus) living near hydrothermal vents This is the key step in DNA fingerprinting
PCR
The Human Genome Knowing the base sequence does not mean that we know what they do
Genes Each gene code for the production of a specific protein
Genes The DNA sequence for a gene includes The coding for protein production A promoter region that indicates where the RNA should start Some tag regions on either side
Initially genes were identified by looking for differences in DNA sequence when a change was observed in a cell Later look at the protein and use computer to find location
Genes A gene varies from hundreds to thousands of base pairs The human genome is about 3 billion base pairs As far as we can tell there is some DNA that does not actively participate in forming protein (certainly the case in bacteria)
Human Genes Unlike bacteria, human genes require a transcription factor to activate the promoter region to start transcription (protein synthesis) External to the DNA Allows activation of certain processes at different times Enzymes and factors act within the nucleus
Human Genes Intron: Non-coding sections Spliced out before transcription Exon: Coding sections Responsible for protein synthesis
Mutations Naturally occurring changes in DNA Can be caused by external factors: Radiation Chemical Can be caused by DNA replication errors If occur in early stages they can be propagated If the are too different cell dies
Genetic Engineeri
Genetic Engineering Based on a principle similar to mutation It should actually be called Gene Engineering Genes are added to DNA Sometimes a defective gene can be removed or inactivated Knowledge of the sequence for a specific gene and the surrounding region is required
Gene Engineering Steps in gene engineering Sequence the DNA Identify the defective gene you want to repair Identify the tags at either end of the gene sequence Synthesize the DNA sequence one base pair at a time (recombinant DNA) Insert the DNA fragment into the nucleus Hope that it gets incorporated into the cellular DNA
Gene Therapy
Gene Therapy
Problems with Gene Therapy There were problems with early experiments with gene therapy Three children were treated for enzyme deficiency developed leukemia A region adjacent to the replaced region was also activated: it caused leukemia Two early deaths led to a rethink of policy and a 10 year hiatus
Gene Therapy and Policy Gene therapy in human somatic cells is not permitted in and country Would allow actual changes to the human genome Genetic modification of adult stem cells is permitted Allows desired trait to be passed on to other cells Unlikely to end up in somatic cells In most cases gene therapy is a temporary solution.
Epigenetics Since Lamarck there has been the theory that acquired traits were heritable Something that happens during this generation can be passed on to future generations The DNA/gene model of heritance would rule out this possibility An individual either passes on its DNA or it doesn t (+/- mutations)
Epigenetics There has been a resurgence in this idea People are not willing to accept that our heritage is fully programed There remains discomfort with the slow speed of evolution due to the DNA/gene model There is experimental evidence that DNA activity can be modified and perhaps DNA structure can be changed within an individual
The interesting point is that when a cell divides the nucleus divides as well The DNA is duplicated Other components of the nucleus may also be duplicated and/or divided We don t know Epigenetics
Epigenetics Modification of gene expression not dependent upon gene sequence May or may not be heritable I.E. anything that is not in your DNA The key element here is that the activity of DNA is modified by other elements within the nucleus of the cell
Epigenetics
Epigenetics The most obvious modifier of DNA are histones Histones act as spools to wind up the ~1.5m of DNA in a chromosome As such they are in direct contact with the DNA
Molecular tails on the histone molecule interact with the nuclear environment Epigenetics
Epigenetics Histones are currently being studied as possible active sites for cancer therapeutics This may not be the only mechanism, but it is one possibility
Remember to look up at the stars and not down at your feet. Try to make sense of what you see and wonder about what makes the universe exist. Be curious. And however difficult life may seem, there is always something you can do and succeed at. It matters that you don t just give up.