Why your DNA is not like a blueprint

By Rich Feldenberg:

When future historians may look back on the 20th century they may critical of humanities violent tendencies, and rightly so. We drove ourselves to the point of near self-extinction with global warfare and the creation of nuclear weapons. But maybe they will also see a flowering of our more nobel side, as well, with the 20th century ushering up a new understanding and appreciation of nature and ourselves. Many areas of science saw exponential advancements, with general relativity, special relativity, and quantum mechanics, all being born in the last century. As important as these fields have become, the areas of life science have arguably had an even larger impact on society and our everyday lives. It was in the 20th century that we learned that DNA is the molecule of heredity, and the structure of DNA was described by Watson and Crick in 1953 as the now famous double helix. With improvements in the methods of molecular biology in the 1980s and 90s, genomics has lead us to a more complete understanding of the underlying mechanisms of disease and how the normal processes of life operate, develop, and evolve.

The word DNA is now common in the everyday vernacular, even if not everyone remembers that stands for deoxyribonucleic acid. Also nearly everyone has some idea that DNA is vital to genes and inheritance, and is used in forensics, paternity testing, genetic testing for disease mutations, and for mapping phylogenetic trees to understand the relatedness of all life. Somehow, though, we’ve been repeatedly told that DNA is like our blueprint. That it gives the plans for creating you and me, and anything else that has DNA. That analogy is a little misleading, as DNA doesn’t act as a blueprint at all. Looking at the full genetic code of an organism wouldn’t help you know very much about what that organism looked like. The only way you might really infer this from the genetic information would be by comparing the DNA sequences to other organisms that you already know a lot about. If the DNA you are looking at was very close to the DNA coding for octopus and squid then you could guess that this organism looks cephalopod-like. The DNA would not tell you the body plan by analyzing just the code on its own, however.

So how should we think about DNA? Is there something else we can compare it to that would make a more accurate analogy? Well, instead of being a blueprint, like a technical drawing that lays out the structural relationships of each part to the other parts, it is really more like a running computer program. DNA is a lot more like a large collection of computer programs, some are always running, and others are only running at certain times or in certain cell types. The DNA is giving instructions that are carried out by hardware running the code. In this analogy the DNA is the software and the cell and its molecular machinery is the hardware running the software. Software without hardware is hopelessly ineffectual, and hardware without software is nonfunctional. They both need each other to function. The DNA needs a living cell to carry out its instructions. In the proper setting these instructions are powerful, producing a whole human being from just a single cell, as it did with you during your 9 months of gestation in the womb. So how does it work?

Well, it’s important to recall how the information stored in DNA is interpreted by the cell’s internal machinery. The DNA itself is made of two long strands, forming the famous double helix. Each strand is made of sequences of nucleotide bases, and there are four nucleotide bases to choose from in the DNA alphabet – The DNA letters are A, C, G, and T. These letters are chemically distinct nucleotides, and you can picture a gene as being a string of these letters that make a unique sentence. A typical gene may be hundreds to thousands of these letters in length. For example, the human gene for the AVP-2 receptor, found on the X chromosome, codes for a protein located on the cell surface of certain kidney cells, and is critical to regulating normal water balance. The gene contains 4676 of these DNA letters.

Starting from letter one to ten of the AVP-2 receptor DNA code, the letters read out as CTGCCCAGCC, but all 4676 letters of the DNA code for this gene are known and can be found in genetic databanks. Each strand of DNA has a complementary strand where every base in one strand pairs to another base in the other strand. A:T are pairs, and C:G are pairs. In other words, if you know the sequence of one strand you can easily deduce the sequence in the other strand, so for our first ten bases in the AVP-2 receptor – CTGCCCAGCC we know that the complementary strand would have to be GACGGGTCGG, based on the pairing rule. It is this complementary base pairing that makes it possible for DNA to replicate itself. Each strand serves as the template for making a new DNA strand. The double helix just needs to be unwound at the right time, the complementary bases added to each of the now single stranded DNA strands, and you now end up with two identical double helix DNA molecules, where you initially had just one. This has to happen for cells to divide so both of the new cells created from the original single cell has the same DNA as the original.

There are two major cell processes involved for turning the DNA code into protein. For the most part it is the protein that does the actual work in the cell, while it is the DNA that is the code-like programming being run. The first process is transcription, where the DNA code is converted or transcribed into an RNA code. The second process is translation, where the RNA code is converted or translated into the protein product. For the sake of simplicity, we are only talking about protein-coding genes, but there are many non-coding RNA genes, as well – we’ll save that topic for another day.

During transcription a molecular machines known as RNA polymerase interprets the DNA code and converts it into an RNA code, in the form of a single strand of messanger-RNA. RNA is quite similar to DNA except for a few key differences. One distinction is that it is single stranded rather than double stranded like it’s DNA cousin. Another is that it contains an extra chemical group called a hydroxyl that is lacking in DNA, and a third distinction is that whereas the letters in DNA are A, C, G, and T, in RNA the T is missing and a U is there in its place. The RNA alphabet, therefore has the letters A, C, G, and U, with A:U forming pairs and C:G forming pairs. The RNA can then be transported to the cell machinery used to make protein, and the DNA (the original code or source code) can remain safe in the chromosome – only the transcribed copy is sent out.

The messenger-RNA (mRNA), finds it’s way to the ribosomes which are complex molecular machines that take the RNA code and make the actual protein. The RNA code is read by the ribosomes with every three bases forming a codon that specifies an amino acid. The protein is a string of amino acids. A few codons also tell the ribosome where the protein ends, and are called stop codons. The protein may still have a few steps to go before it is fully functional. For example it may need to have certain sugars or other chemical groups added at particular locations. It also needs to be folded into a very specific 3-dimentional shape, and it may need to associate with other proteins to form a part of a larger protein complex. Then it may need to be transported to specific sites in the cell, or even exported out of the cell, to do a job located in a different place in the body.

So why is our DNA not like a blueprint? Well, even if you could read the entire DNA code for all the protein producing genes, you would only see the ingredients that the DNA was coding for. That is far from a blueprint that might show you the structure of a building, where it’s doors, windows, elevators, stairwell, and so on, are located in spacial relation to one another. Knowing the protein products only gives you a list of ingredients. How those ingredients interact together, in time and space, is what creates an organism. The genetic code is a set of instructions that is executed on the code reading machinery of a living cell. The beauty of it is that not all the genes are transcribed at the same time and in the same amounts. Only a fraction of genes would be operational at any given time, and in a complex multicellular organism, only certain genes will ever be transcribed in any particular cell type. That is what makes a kidney cell different from a brain cell different from a cell in the heart muscle, and so on. Every cell has all the genetic programs, but only runs a subset of the total programs necessary for its own type.

DNA without the code reading cell machinery can do nothing on its own, which is why the vital flame of life must be passed down from living cell to living cell, uninterrupted since the very beginning of life itself. The genetic program is sophisticated enough that it causes genes to be transcribed that produce proteins that are themselves transcription factors secreted out of the cell to instruct neighboring cells as to which of their genetic programs to begin running. It is this complex coordination, leading to the switching on or off of particular genes in other cells, that starts the process of building a whole multicellular organism. In this way it is not just the genetic program that is necessary for building a animal, or person, or plant, but the local chemical environment that the program of each cell finds itself living in. The chemical neighborhood is just as important as genetic constituency.

In the language of Object Oriented Computer Programming, like Java for example, we might say that the complete genome of an organism is a program with many Classes (genes), and that when these classes are run instantiate Objects (proteins). Each and every cell in a body has the same program, but depending on it’s interaction with neighboring objects will Call only certain classes for use at any given time, and in some cases will never use particular classes that it has access to. These objects then go on to run all the functions necessary for that cell, including affecting other cells to call on certain objects in some cases. A human kidney cell has the entire “Human Program” as part of its software, but will only call on the classes used by a kidney cell, because it was derived from a cell that at one time could use all classes (Pluripotent stem cell), but at a certain point was instructed by its chemical environments to only allow use of the kidney classes. In other words, it differentiated into a kidney cell, thereby losing the ability to be a different cell type.

This is one reason, that even though we have completely sequenced the human genome, we still have a very incomplete understanding of what most the the genes are doing. Just by looking at their code it is not easy to determine what their affect is in a whole organism. The computer analogy may not be the perfect analogy, but it does illustrate the problem much better than the typical blueprint analogy does.

 

Other interesting things about DNA, and other fun topics:

1. “Intron Retention: a common cause for cancer“.  by Rich Feldenberg. ZME science. 1/25/2016.
2. Alternative Splicing.  Wikipedia.
3. Non-coding RNA.  Wikipedia.
4. “Why the Horta would not have looked like a rock monster“.  Darwin’s Kidneys.  June 18, 2015.

Why the concept of species is more fuzzy than you might think

By Rich Feldenberg:

The term species is viewed as a fundamental unit in biology. We are the species Homo sapiens, and we love to classify ourselves and other creatures into unique categories, giving them qualities that set them apart from other creatures. Charles Darwin’s evolution by natural selection gave the first proofs that all living organisms today descended from a common ancestor, which branded into an ever growing number of different evolutionary paths, resulting in a tree of life.  The trunk being the last common ancestor (LUCA) and all the tiny twigs at the ends representing all species that have ever existed. But is this really an accurate view of the living world – each species of organism occupying its own unique little cubby, completely distinct from it’s fellows in the cubbies next door? We have learned a lot since Darwin’s important discovery of Natural Selection. Modern biology tells us that, while evolution is on firm scientific ground, the concept of the species is less so. We humans have a tendency to think in a discontinuous way – that things do fall into distinct categories – that there is a separate essence that each thing has unto itself. That may be one reason why evolution is a difficult concept to accept for some people, because if each thing has it’s own essence of being, you can’t change it into something else. This idea was demonstrated in an experiment where children were told a story about a witch that turned a frog into a rabbit. The frog now looked like a rabbit, acted like a rabbit, preferred to eat carrots and not flies, wanted to hang out with other rabbits, but when the children were asked if this animal was now a rabbit they said it was really a frog. It’s underlying froggy essence could not be altered by the witches spell.

It turns out that the concept of species is really not a discontinuous one at all. It is a continuous variable, and that may be a difficult idea to wrap your head around. In medicine some diagnoses are continuous and others discontinuous, and in some others it may be difficult to know for sure. For example, having 6 fingers on your hand is discontinuous (you either do or you don’t), but systolic blood pressure is a continuous value, with a range of anywhere from 0 to somewhere quite high like 250 or perhaps rarely 300, with most people being in a certain range, like from 100 to 140. So why is the species also a continuous variable? Isn’t a rabbit a rabbit, and a frog a frog? Certainly a human is a human, and not a chimpanzee, right?

Well, keep in mind that names are just there for our convenience. How close they approximate reality may vary depending on the purpose of the name, and how good we are at understanding what we are describing. Ideally, a name would completely describe reality, but that will never be the case because a name is just a short hand way of talking about something else. Species tells us about taxonomic ranking. This is meant to help us determine which ancestors all the members of the species have in common, and how closely related those members are to members of another species. The problem arises in that the there is no defined line in the ground where one species ends and the next begins. One definition of species asserts that members of one species can not reproduce to have fertile offspring with members of any other species. This definition isn’t technically correct. The reason that this seems true most of the time, is that the many of the ancestral species happen to have died out, so it creates the appearance of very distinct groups of organisms (each in a separate and walled off little cubby).

Every generation is the same species as its parents and the same species as its own offspring. If this is true how could new species arise? It is precisely because the changes that occur due to evolution do so over much longer periods of time than a mere few generations. An organism could reproduce with a member of the prior generation, and if transported back in time to members from tens or hundreds of generations prior. At some point, however, there will be enough structural and/or behavioral differences that reproduction would no longer be possible.

Say that we took an organism back in time (it could be any organism, even a human). When we took him or her back 50,000 generations we find that he/she was able to reproduce with the contemporary population, but couldn’t reproduce with the individuals from 100,000 generations earlier. Now if we go back 50,000 generations from our starting point and take a subject from that era (one that could easily reproduce with our original organism) and then take him or her back to 100,000 generations before our starting point (50,000 generations before this individuals time) we find that it can reproduce with an individual from that long distant time period. So the original could reproduce with a subject from 50,000 generations ago, but not 100,000 generations ago, and the individual from 50,000 generations ago could reproduce with one from 50,000 generations ahead or behind its own time.

Since in the real world, those ancestors are mostly extinct it give the illusion of a discontinuous landscape of species. Richard Dawkins gave an excellent example in his book, “The Ancestors Tale” when he described ‘the salamander’s tale’. In that example Professor Dawkins described several species of salamander that live along a ring of high elevation in Central California. The ring forms a physical geographical structure that makes the species adjacent to any salamander’s location available to them, but prevents the species from interacting with species on distant parts of the ring. At the southern end of the ring are two distinct appearing species Ensatina eschscholtzil and Ensatina klauberi. E. eschscholtzil is brown and lauberi is spotted, and the two species, while in contact with each other do not interbreed – the very definition of separate species! That’s all well and good except that as you go up north on either side of the ring there are more species still, and each of these can reproduce with the species neighboring it.

It’s likely that the ancestral species arrived at some time in the past in the north. Two descendant populations emerged, one going south by the eastern route and the other going south by the western route. If all those other species on the ring had gone extinct we would be left with two species that could not interbreed and there would be nothing very special about the story. Those other species did not die out, however, and there is a continuous ring of salamanders that can reproduce with others of similar species, except in the case of the two southern species. As Dawkins says in the book, “Strikes a blow against the discontinuous mind”. The situation for these salamanders reveals what the situation would be like for any species (human included) if all of our ancestors were alive today. There would be a continuous stream of organisms that can interbreed with those close to them in time, but only over longer time scales do differences add up that make them distinct enough that interbreeding is no longer possible.  The sides of the ring represent a common ancestor, diverging and over time becoming two separate species, but having a path of “able to interbreed” individuals all the way down.  

In another post, I’ll illustrate another problem with the “tree of life” concept.  In actuality the tree concept is complicated by “lateral gene transfer” – basically genes being swapped by other organisms of different types.  This is very common in bacteria, but also seems to happen to some extent in more sophisticated organisms.  In any case, the idea of species should be used as a useful placeholder, but has important limitations.

Reference:

1. Species, Wikipedia.
2. “The Ancestor’s Tale: A Pilgrimage to the Dawn of Evolution”, Richard Dawkins. 2004.

3. Another clever Mesign by Mother Nature.  Darwin’s Kidneys.  July 8, 2015.

 

Happy Darwin Day 2016

February 12th, 2016 is Charles Darwin’s 207th birthday. Charles also happened to share the exact same date of birth with Abraham Lincoln – so happy birthday Mr. Lincoln, as well! Since this blog is dedicated to science, with a special emphasis on evolution, and in fact, has the name Darwin in the title, I want to be sure to honor our dear Mr. Darwin properly.

There are Darwin Day celebrations planned in the USA and around the world, but no ‘Official Darwin Day’ is recognized nationally. That could change as some efforts are being made to make it official. In fact, this year the Governor of Delaware declared an official Darwin Day in his state. In some cities there are lectures or parties to celebrate.  The Center for Inquiry has a take action page, where you can send your name in a letter  to members of congress to express the importance of creating a Darwin’s Day for public education of science.

Charles Darwin’s theory of evolution was the beginning of modern biological science. As the Russian evolutionary biologist Theodosius Dobzhansky is quoted as saying, “Nothing in biology makes sense except in the light of evolution”. Evolution is the thread that binds all of biology together. Every aspect of biology, from molecular genetics, embryology, comparative anatomy, populations and ecosystems all “make sense in the light of evolution”.

Darwin’s theory was a realization of origin from common decent. Evolution does not address the emergence of life from non-biological origins, but does an excellent job explaining the illusion of design seen in the complex structures of the living world. Of course, Darwin realized that the illusion was the product of natural selection working on variations in living things. Darwin had no idea about genetics, DNA, mutations, and so on, but as those fields of biology developed they only reinforced Darwin’s big idea. It could easily have been otherwise. If evolution by natural selection was not how the world worked, then molecular genetics, phylogenetic, developmental biology, and so on would not have provided additional support to a 150 year old theory. Yet, all these modern sciences fit in perfectly, continuing to build on the original theory. Even without the fossil record modern biology would still point the way to evolution. By the way, the fossil record also supports evolution, and has only become more robust during the last 150 years as many more fossil species have now been discovered.

I’m sure Darwin would have been delighted to learn about genes, how new mutations arise by damage due to radiation, chemical mutagens, or simply errors in the normal process of DNA synthesis. He would have loved to see how the genome is cluttered with the remains of dead viruses, pseudogenes, copying errors that we have been copying and passing down to our children for geological eons. And he would have certainly understood that we can see our degree of relatedness to any living species on the planet by looking at, not just the working genes and how closely they match to us, but also these dead viruses and pseudogenes.

Darwin’s voyage on the H.M.S Beagle remains one of the most exciting and most epic expeditions of discovery in history – certainly one of the most productive, since it resulted in much of the data Darwin needed to formulate his theory over the next several decades. Darwin was an amazing naturalist and keen observer. There is hardly any area of natural science of his time that he didn’t seem to make some meaningful contributions. Not just in biology but in geology, as well.

So this Darwin’s day I plan to celebrate at home with my family. Perhaps have a piece of Common Decent Cake or Evolution Pie, learn something new I didn’t know about evolution, and honor our Dear Mr. Darwin.  Let me know how you plan to celebrate.

Other Reading:

1. Darwin Day:  Wikipedia
2. Natural Selection:  Wikipedia
3. Youtube.  Climbing Mount Improbable.  Lecture by Richard Dawkins.
4. OxoG is how radiation turns your own water against you.  Darwin’s Kidneys blog
5. Cytosine Deamination.  Darwin’s Kidneys blog.  (another mechanism of mutation).
6. Another Clever Mesign by Mother Nature.  Darwin’s Kidneys blog.  New word mesign to differentiate apparent design in nature from when we mean a designed object.
7. How our ancestors promiscuous genes became more discriminating.  ZME Science. Feb. 9, 2016.  Article on how gene families arise by gene duplications.

Does Enceladus’ alkaline ocean make it friendly to life?

Recent data sent back to us by the Cassini space probe as it samples the geyser water being shot into space at Saturn’s moon Enceladus, has determined that the moon’s subsurface ocean has a very high pH.  The pH is estimated to be around 11 or 12.  This would be considered extremely alkaline, but the team analyzing the data concludes that this might improve the odds of supporting life.  They point to the alkaline hydrothermal vents, such as The Lost City, on the ocean floor of earth, where warm alkaline fluids flow out into the cold salty deep.  There is some thought in the astrobiology community that life on earth may have originated in a similar alkaline vent environment 4.5 billion years ago.  The difference, however, is that on early earth the alkaline vent fluid was flowing into an acidic ocean, with a thin mineral wall separating the fluids and allowing a proton gradient to form.  It was this proton gradient that generated the energy necessary to transport electrons from molecule to molecule.  This is exactly what living organisms do to generate energy – they pump protons across a cell membrane, transport electrons to an ultimate electron acceptor (oxygen in our case), and use the proton gradient to generate ATP (the energy currency of the cell).  Cells do the biological equivalent of what the alkaline vents are doing geochemically.  For that reason I wonder if the high pH of Enceladus’ ocean really would support the origin of life since it doesn’t necessarily imply situation where a proton gradient would occur.

 

Reference:

How Friendly is Enceladus’ Ocean to Life?  Astrobiology magazine.  Feb. 4, 2016

Mutation Monday (Your Mutation Station): Thymine dimers

by Rich Feldenberg

Welcome back to your mutation station.  Today we’ll look at a harmful effect on your DNA due to ultraviolet light, which leads to dimerization of the nucleotide bases thymine (T).  If there are two T bases next to each other in the DNA strand and they absorb UV light they can undergo a photochemical reaction that causes them to link-up.   The double bonds in the base break and then form single bonds to their neighbor.

This blocks normal base pairing on to the other DNA strand of the double helix, and results in a mutation.  Fortunately there are cellular repair mechanisms that can find and fix these errors, but some errors escape detection and cause major harm.  Some melanomas are thought to be due to thyimine dimers caused by the effect of UV sunlight.

Thymine dimers are actually a more specific form of what is called pyrimidine dimers.  The bases thymine and cytosine (T and C) are pyrimidines.  Two pyrimidines can dimerize under the same conditions leading to the same sort of DNA mutations.  You could have T-T dimers (thymine dimers), but also T-C, and C-C leading to the same problems.   So, remember to use sunblock and be careful about exposure to the sun!!

Fossil Friday: Dickinsonia

by Rich Feldenberg

Welcome to the long forgotten Ediacaran Period (635-542 Million years ago) in the Precambrian.  An assortment of unusual and fascinating fossils have been found dating to this time period, when multicellular life was just getting large enough to make good fossil imprints.  It is sometimes known as “The Garden of Ediacaran” because it is thought that at this early stage of animal evolution most creatures were basically filter feeders, and no major predation had yet developed (including the tools used by predators such as teeth, eyes, or sophisticated brains).  In that sense it may have been a very peaceful and “innocent” chapter in the history of life, before an evolutionary arms race between predator and prey began in the Cambrian and continues on to this day.

One common fossil found in rocks of this age is that of Dickinsonia.  This little guy was round shaped with a bilateral symmetry – something that shows some level of sophistication from the even earlier radially symmetric ancestors.  It seems to have had a head-end and a tail-end and was divided into segments.  It is not clear what kind of animal Dickinsonia really was, and there is a great bit of controversy in the scientific community in regards to its proper placement on the tree of life.  It seems to have been capable of movement over the ocean floor, as there have been fossilized tracts found that are thought due to its movements.   It may have belonged to a phyla that went extinct by the end of the Ediacaran period, or alternatively it may be related to modern day creatures.  Some experts have speculated that it is related to modern day jellyfish and some even think it may be related to animals that eventually became vertebrates.  Others have even gone so far as to say that it was not an animal at all, but part of a short lived, and ultimately unsuccessful evolutionary experiment in some type of multicellular life form that went extinct half a billion years ago.  What ever Dickinsonia was it made beautiful fossils!