When I think about models of evolution, I’m reminded of an episode of a cartoon show, “I am Weasel,” called I.M. Diety. Forgive me for taking us back to 1998, but the premise of this episode is that the super-genius main character, Weasel, and his nincompoop of a friend, Baboon, purchase these “instant life” packets which require the addition of DNA (spit) to grow your own society in a petri dish. It’s kind of like a chia pet, except you’re growing living beings.

To summarize, they watch life evolve on a petri dish from its earliest form all the way through advanced civilizations that worship them as “the gods in the sky.” The denizens of these science experiments are unaware of anything outside of the walls of their petri dish. Eventually, Weasel’s society develops sophisticated technology and flies to Baboons society. Intermixing of the species is cataclysmic and the experiment is over.

Evolution in a petri dish.

I am still amazed at how vivid my memory of this episode is. The really cool science aspect was that they simulated evolution in vitro. Directed evolution is a relatively common biological technique. For instance, when dealing with a normal strain of E. coli, if we wished to “create” a strain that is resistant to penicillin, we would simply plate some E. coli on penicillin infused culture media . While 99.99% of the E.coli would die from the penicillin, the remaining 0.01% will survive due to having received random mutations that conferred resistance to the compound. This can be viewed as evolution in vitro.

The dramatized, yet cool aspect of the “I am Weasel” episode is that highly complex life forms developed overnight. For organisms that we are familiar with to radically evolve in such a short period would be very unlikely (I have become accustomed to avoiding the word impossible). The main reason for such improbability is the long generational periods. A very large number of generations and different selection factors contributed to evolution on earth, and to replicate these results should take just as long!

While in vitro models of evolution might have us waiting forever, in silico models of evolution have already proven to be very worthy of consideration. Life forms on earth compete for resources in order to survive and reproduce. At the fundamental level, it is the perpetuation of a given sequence of DNA that drives animal instinct (even human beings): or so would argue those who believe in Dawkins’ Selfish Gene. With this in mind, we have identified some variables: resources, competitive ability, and reproductive ability. We have also identified DNA as giving the instructions on how to compete for these resources in order to reproduce. Adaptation occurs via mutation.

Moving from in vitro to in silico.

To create in silico models, these aspects of evolution had to be mapped to their computer counterparts. DNA can be substituted for by self replicating computer code that undergoes changes/rearrangement. Resources can be simulated by computer memory or RAM. The actions of competing and reproducing are executed by self-replicating code as they compete to take up more of the computer’s memory.

This is more or less what Thomas S. Ray created in Tierra, his model of artificial life developed in the early 1990s. In Tierra, strings of computer code compete for CPU time and computer memory by copying themselves with some rate of mutation. Ray’s program simulated a host-parasite battle where hosts were infected by parasites, and over time, it was seen that hosts developed immunity to the parasites in an evolutionary arms race occurring in silico.

Who is God of the Computer Realm?

In silico models of evolution are great because they allow for many generations to occur within a short period of time. The digital organisms being created by these investigators evolve and mutate just like biological organisms. While computer simulated evolutionary models have not created artificial sentient life, a real question that remains is, “Are these strings of computer codes real beings?” They compete for resources, they self replicate, and they perish just like biological beings. However, answering this question will likely require a bit more thought and ethical debate.

If it is concluded that these computer strings are real organisms, then it is simultaneously conceded that human beings have created life, an act though by many only possible by their god (throughout many religions in the world). Proper synthesis of silicon life through a model based on evolutionary principles also goes a long way to prove the theory of evolution (for those who were not convinced by fossil evidence, DNA evidence, and a plethora of other biological data). While this is truly exciting, I’m almost afraid of the emergence of a sentient silicon organism because its species would evolve at a much faster pace than us, mere biological organisms.

DNA – Crack the Code by Nyla

Protecting Our Personal Information.

In 2008, President George W. Bush signed into law the nearly unanimously approved Genetic Information Nondiscrimination Act of 2008 (GINA). This law is meant to prevent discrimination in employment and health insurance based on genetic information. The law effectively prevents group health plans and employers from requesting that individuals undergo genetic tests, thereby protecting what many view as basic human rights: healthcare and equal employment opportunity. While the GINA of 2008 prevents the use of genetic information with health insurance, it does not prevent the use of genetic testing in other arenas, such as life insurance.

Life Insurance: A Product in a Competitive Market.

With life insurance, an insurer agrees to pay a designated amount of money in response to the death of the policy holder. In return, the policy holder must pay a premium in regular intervals throughout the course of the policy. Accordingly, the insurance company charges a premium based upon a detailed underwriting and actuarial process.

Mortality rates for different age groups are used in determining an individual’s premium. For instance, it is predicted that 0.35 in 1000 non-smoking 25 years old males will die in the first year of policy coverage. This allows the insurance company to charge premiums to a group of individuals given an expected number of deaths and payouts.

Individual life insurance premiums are determined in an underwriting process. During this process, age, health, and tobacco use are the major factors that play into premium determination. However, more detailed questions about the health and lifestyle of the client are often asked to make a better judgement what type of premium would be required for that person. For older applicants, paramedical professionals are sent to perform more detailed tests including blood and urine tests.

What are they looking for in the blood test? Right now, the blood test screens for the presence of antigens to the HIV  virus, hepatitis, evidence for liver or kidney disorders, and certain types of autoimmune diseases. These are all increased risk factors for mortality. A positive test for one or more of these indicators may result in higher premiums or denial of coverage.

Enter genetic testing.

The blood test performed by the paramedic is all that would be required for a complete genome scan. This type of test can detect predispositions to over 100 complex genetic diseases such as Alzheimer’s Disease, Parkinson’s Disease, Heart Disease, and many different types of cancers. What would happen if insurance companies used genetic information in the underwriting process?

Genetic information will add an array of new dimensions to the current underwriting process as it allows insurers to account for a plethora of diseases beyond a typical life insurance exam. Moreover, a genetic test can show increased risk, normal risk or decreased risk for a particular disease. It is possible that this information may improve the likelihood of coverage and/or lower premiums for individuals.

The use of genetic information may be a disgusting thought in some peoples’ minds, but we must consider what happens if we ban the use of genetic information in life insurance. An individual may always get himself tested. What if a 50 year old male learns that he has an increased risk for three different late onset genetic disorders and decides to take out a large policy anticipating this decline. This “moral hazard” will cause the insurance company to charge a lower premium than what is actuarially fair, and it will begin to lose money for every individual that engages in this behavior. Eventually, it will prevent the proper functionality of the life insurance company, and it will disadvantage everyone who seeks to take out a life insurance policy.

To Know or Not to Know? That is the Question.

There are two issues at play with life insurance and genetic testing: protection of personal data, and avoiding a situation where there is asymmetry of information. If the consumer knows of a predisposition and the insurer does not, the consumer has the power to take out a policy at an actuarial loss to the insurer. However, some may believe that the insurer should not ever know about the consumer’s genetic information because that is both private and immutable material. What is the optimal solution here?

One solution would be to ban genetic testing altogether. We might decide not to let the consumer or the insurer employ this technology. I think this would be terrible. We would be taking several steps backwards if we decided to ban genetic testing.

Another solution is for knowledge to be spread all around. Life insurers should be allowed to use genetic information as long as the consumer is made aware of the results. This way, there is no asymmetry of information. Let’s not forget that genetic testing could even reveal a genetic protection against certain diseases (lower than average risk).

I do not believe that applying genetic testing towards life insurance is a violation of privacy or human rights. Life insurance is not a societal right. It is a product that consumers have the option of buying. If a consumer does not want to have their genes tested, then perhaps they should reconsider taking out a life insurance policy.

Consumer genetics is here, and it seems unlikely to disappear anytime soon. In fact, the next generation of consumer genetics products may very well be complete genomic sequencing, as promised by Complete Genomics, and even Illumina.

Although we may be decades away from it (or maybe only years), we will one day be confronted by some form of genetic identity theft. What does this mean, and how will this happen? Let me explain.

How can my genes be stolen?

My genes are unique to me, and there is essentially a 0% chance that anyone else in the world has the exact set of As Cs Gs and Ts as I do (with the exception of identical twins). How could someone possibly steal my genetic profile?

In the not so distant future, any cellular sample may be viable for complete DNA sequencing. For instance, after enjoying a nice lunch at the diner, leaving behind just one strand of hair may be enough for a stalker/mad scientist to determine your entire DNA sequence. They would have the entire blueprint of you.

What can be done with stolen genes?

Okay, so someone may steal and sequence my DNA, but what good does that do them?

Right now, nothing. They might learn that you carry a mutated version of the HFE gene and may potentially have a child afflicted with Hemochromatosis. Even worse, they could find out that there is a 70% chance that you are lactose intolerant!

In the future, the chimeric child of DNA sequencing, Stem Cell Research, Developmental Biology, and Cellular Reprogramming would allow for someone to derive stem cells from your one strand of hair. These stem cells might then be transformed into sperm or egg precursors, and  these cells would essentially allow anyone to have a child with you (without you). Think of the market for a service that advertises to prospective mothers: “Have a baby with Brad Pitt!” It’s actually kind of creepy.

It gets worse, and more obsessive. What if said “crazy Brad Pitt fan” decided that  having Brad Pitt’s child was not enough. No. She wanted more…she wants Brad Pitt for a child! Stealing Brad’s DNA, sequencing it, and reprogramming cells with his DNA would allow for the creation of a Brad Pitt embryo. An in vitro fertilization procedure later, and Brad Pitt’s ultimate fan can now also be his mother (to crazy fan: seriously, don’t do this…running a fan website is enough devotion).

Holy $h*t That’s Messed Up! How Can I Prevent This (esp. if I am Mr. Pitt)?

Truthfully, this is not something you have to worry about right now. The technology just is not there yet, although all methods necessary for something like this to happen are either developed or in development.

When we do reach the point where this is a real possibility, I cannot think of any way to stop someone who was committed enough to having your child (or you as their child). Maybe you can hire a personal assistant to walk around and make sure that all strands of hair, saliva and any other DNA containing materials are properly collected and destroyed.

Only with the extreme case of celebrities can I imagine there being a “black market” for stolen DNA, and even then, I doubt demand would be high enough to fuel such an industry. However, I will never say never when predicting the future in this field. To all celebrities out there: Let me know when you get that phone call, “So I’m your mother…sort of.” I give it 5-10 years.

This has to be the longest title of any post, but it covers the diverse functions of the identity-by-state method of analyzing high-density SNP data.

Elisha Roberson and Jonathan Pevsner published a paper this August titled, “Visualization of Shared Genomic Regions and Meiotic Recombination in High-Density SNP Data.” This paper describes methods and results for comparing the genome between any two individuals in search of shared genomic regions.

While many methods for determining genomic similarity rely on knowledge of family tree structure (identity by descent methods), the method described by Roberson and Pevsner compares SNPs based on identity by state, which allows them to compare any two individuals without knowledge of the family structure.

Genomic Comparison via Identity by State: A Brief Overview

Identity by State examines pairs of SNPs between two individuals and puts them into one of three categories:

1. Identical: Both individuals have the same genotype call (Ex. AA and AA; BB and BB; AB and AB).

2. One-Allele Shared: Only one call is shared between both individuals (Ex. AA and AB; AB and BB).

3. No alleles shared: No alleles are the same (Ex. AA and BB).

For individual SNPs, this type of analysis really does not provide any extra information. The real advantage is gained when high-density SNP information is taken for the whole genome (23andMe customers have this, and many other Illumina and Affymetrix platforms cover the whole genome).

In the paper, identical Identity by State (IBS) is referred to as situation 2; one-allele shared is situation 1; and no alleles shared is situation 0. For each chromosome, these three different “situations” can be plotted along an ideogram separated based on IBS. Here are a few images from the paper.

As we can see, when we plot the various IBS calls across chromosome 10 between two parents (unrelated individuals – as far as we know), there are tons of 2’s and 1’s, and even large numbers of 0’s. The data does not seem to have any rhyme to it. In fact, a distribution of 1’s 2’s and 0’s like this is evidence that the two are very unrelated. I can only see one small region that seems to be devoid of 0’s (arrow), which signifies something special!

Whenever there is a consistent lack of 0’s (a lack of unshared SNPs), it is evidence that the two individuals share actual haplotypes. In the example above, the region without the 0’s does contain a good number of 1’s and 2’s. This indicates that these two individuals share one haplotype in that region. If there were no 1’s in that region, that would be evidence that the individuals shared both haplotypes. The chart to the left summarizes how to interpret what is shared given the IBS calls in a region.

Roberson and Pevsner continue to show what type of IBS call distributions are made by various combinations of relations. For example:

Mother V. Son

Siblings

The results from comparing a mother to her child show that only 2’s and 1’s are expected to be visible (the occasional 0 might slip in due to genotyping error, or more rarely, mutation). This is consistent with the fact that the child receives one of his/her chromosomes from the mother.

The situation when the siblings are compared is a bit more complicated, but also more informative! We can see regions where 1’s, 2’s, and 0’s are all present, which indicates that the children inherited completely different alleles from the parents. Regions where only 1’s and 2’s are present indicate that the same allele was inherited from one parent, but a different allele from another. Finally, regions where only 2’s are present indicate that the children inherited the same allele from each parent in that region. Transitions from regions with 2,1,0 to 2,1 to 1 and vice versa indicate a meiotic recombination event had occurred. Very cool!

Exploring What We Can Learn with IBS Analysis

It has been shown pretty well that IBS analysis can be used to look at recombination events and allele sharing between siblings. This is extremely useful. However, IBS Analysis can apply towards a few other items:

• Examination of Hemizygous Deletions: Normally, parent-child comparisons only present with regions of IBS-2 and 1. We wouldn’t expect any 0’s since the child HAS TO inherit something from the parent. Except, of course, if the parent does not pass on any genes in that region. That is why, if a region of heavy IBS-0 is seen in a parent-child analysis, it indicates that a hemizygous deletion has been passed on from that parent to the child.
• Identification of Relatives/Potential Inbreeding: 23andMe recently released their relative finder. As a bad scientist and a worse journalist, I have done little investigation into how it works, and even less playing around with it. However, IBS is certainly one way relatives may be identified. Potential inbreeding will not show up as pronounced as relatives because there is likely more distance between people considering marriage than closer relatives, but IBS analysis on a couple who come from the same population produced the following picture:

The program which I wrote to create the above output colors the chromosome gray in regions with no SNP information, black in regions with no allele sharing, red in regions where one allele is shared, and green in regions where both alleles are shared. Two completely unrelated individuals would have completely black chromosomes. The picture above is of unrelated individuals with a more recent common ancestor, likely due to the fact that they come from the same population.

Implementing IBS Analysis: GenomicRelator!

Again, I got bored around 3 am one night and decided to write a program. Now I’m going to be giving it away for free, because I’m cool like that (I have been told to write the following: If you wish this program (or a version of it) for commercial use, you must contact me). Sweet.

Genome Relator is the program I have for you. I decided to not write a GUI, but instead make it double-clickable within a working directory (don’t worry, I’ll cover all this). It does two things:

1. General IBS Calls: It compares any two genome files and it draws pictures of the actual IBS calls on each chromosome (Green/Red/Black).
2. IBS Data Smoothing: IBS Calls are not as perfect in real life as they are in the world of published papers (for some reason), but we can look at the frequency of different calls across a fixed number of SNPs and decide whether or not the region contains 0’s, 1’s, or 2’s. It paints a prettier, easier to understand picture this way.

The Program

Download here. It’s a ZIP file with four JAR files inside: GenomeRelator, GenomeRelatorRAW, LaunchGenomeRelator, LaunchGenomeRelatorRAW. To use this program, simply extract the files to a folder, and place both genomes you would like to compare (named file1.txt and file2.txt respectively) into that same folder. Then just double click the proper JAR file.

You will need the most recent Java Runtime Environment on your computer as well. You should always click on the file with Launch in front of the name when using since it helps the computer allocate more memory (otherwise you run out of RAM and nothing happens). Read a little more to find out what the program does, the difference between RAW and normal, and the rules for the input files.

GenomeRelatorRAW compares the two files and processes them according to the IBS calls producing the following picture:

This just presents the data to you in a cool picture without really interpreting it, although you can visually interpret quite a bit from it. This takes much longer to render than the other version of the program since each SNP is actually evaluated and then illustrated (23andMe files might take 20 minutes to process!). I find these useful to compare to the output from the regular version of the program.

The regular version, GenomeRelator, produces output that “smooths” the data. The following picture comes from the regular (not RAW) version of the program:

Essentially, it moves throughout the genome with some preset rules: 250 SNPs at a time, the region must have greater than 1% IBS-0 and greater than 5% IBS-1, then it is assumed to have 2,1,0 (no relation). If it has less than 1% IBS-0 and greater than 5% IBS-1, then it is assumed to have 2, 1 (one allele shared). If it has less than 1% IBS-0 and greater than 5% IBS-1, then it is assumed to have 2 (both alleles shared). These numbers 250, 1%, and 5%, are the variables that are at play in the program, and hopefully I will come out with a GUI version that allows you to decide what you want to set it to.

The rules for the input files:

1. The input files must be called file1.txt and file2.txt, and they must be placed within the same folder as the program (the jar files).
2. The input files must have one line of headers (no more no less).
3. The input files must have the same SNPs. For 23andMe customers, I am not entirely sure, but in my experience, male files have contained four extra SNPs (rs3091244, rs1229984, rs4420638, and rs34276300). Remove any SNPs necessary until both files have only the same ones.
4. The input files must contain four columns in the following order: rsid, chromosome, position, genotype. The genotype column must be one or two letters (yes, I fixed it so that male X chromosomes can survive when only one letter is there).

Program Output

The program will not only draw a picture, but if you run the regular version, it will also generate a number of files. A text file will be generated for each chromosome. This is just an intermediary file that the program needs in the middle of the process. A file called “IBS Summary” will also be generated for each chromosome. This file contains the list of regions (250 SNPs at a time) by their starting and ending genomic positions (the position in the genotype file). These are useful if you want to more closely examine regions of overlap (or deletion).

No Hosting On Your Own

I’m sorry, but I only want people to be able to download this from me, so just send them a link here if you want to distribute the program to others. It’s free for “academic” use and for “fun” use. No making money. Thanks to any who’ve read and used the program. I’d appreciate any feedback and please report all errors to me so I can do my best to fix them!

In 1993, Steven Spielberg captured audiences with his prehistoric thriller, “Jurassic Park.” Using fossilized DNA, scientists were able to bring back to life the once extinct dinosaurs. The amazing thing about this movie is that the scientific achievement that was a prerequisite to reanimating extinct creatures was not realized until a full three years later.

The Advent of Cloning

In July of 1996, Ian Wilmut and colleagues at the Roslin Institue in Scotland successfully cloned Dolly the Sheep, by reprogramming an adult mammary gland cell into an embryo through a process known as somatic cell nuclear transfer. The creation of an organism from an adult cell opened the door for a whole new variety of techniques and processes that have become essential to modern biology and genetics.

Dolly proved to the scientific community that a complete organism can be created from the genetic material obtained from ANYWHERE in the organism’s body. The basic method for “cloning” can be broken into three steps: 1. Obtain DNA that specifies the organism you wish to clone. 2. Transfer DNA into enucleated oocyte for reprogramming. 3. Transfer reprogrammed cell into surrogate mother for implantation and fetal development.

Bring Back the Dead: Consumer Cloning

What did I just say?! It’s not like you think, I swear. You cannot bring back your lost relatives. Even if you clone your dead loved ones, there is no way (currently) to recreate the memories and experiences that will have shaped the person that you once knew. So, even though the clone will look exactly alike, they are not the same person as your loved one. Also, when a cloning takes place, the person is “born” just like any other baby, and they must grow and mature just like any human being. There is currently no way of speeding up the process of growing up.

Is cloning publicly available? Yes. Not for humans. Congress, republicans and democrats alike, would have a field day with that one. However, commercial cloning is available for man’s best friend. Up until September of 2009, BioArts International offered commercial cloning of a pet cat or dog to niche consumers for the lofty price of $150,000. However, they recently closed their doors because of, among many reasons, competition from RNL Bio, a South Korean Stem Cell Company which has begun to offer the same service.

As explained by Lou Hawthorne, the CEO of BioArts International, the market size for cloned pets does not seem to be that large right now. However, it is still a developing technology, and one day it may be offered at the right price with the right market exposure. BioArts International, successfully cloned seven dogs for consumers throughout its product offering. The take home message: cloning is commercially available, although not popularized just yet.

Bring Back the Long Dead: Extinct Species

Jurassic Park was a visionary movie because it described a scientific process that was not yet possible at its time. However, we are closer now than ever to being able to bring back dead species. Let’s look at the Wooly Mammoth as a case study.

The Wooly Mammoth, also known as the tundra mammoth, is suspected to have vanished around 8,000 BCE likely due to the warming of their climate. Unlike many extinct species, the wooly mammoth remains have, in many cases, been organically preserved due to their frozen environment and the large size of the animal. Organic preservation has allowed scientists to study much of the mammoth DNA, and leads many to claim that cloning of the mammoth will one day be possible. Despite the preservation of dead mammoth, extracting the DNA and rebuilding the genome is an ongoing process.

How will this cloning occur? Scientists hope that they will be able to salvage whole cells of preserved mammoth DNA from frozen mammoth cells. While more recent attempts at this have not yielded completely salvageable genomes, many parts of the mammoth genome including the complete sequence of a mitochondrial DNA have been determined. From this information alone, it has been concluded that the wooly mammoth is more closely related to the Asian elephant than it is to the African elephant.

Who will be the surrogate mother of the wooly mammoth? The Asian elephant of course. Although the two species diverged several thousand years ago, it is suspected that the Wooly Mammoth and the Asian elephant are still genetically similar enough such that one can carry the offspring of another. Scientists at Penn State University believe they have mapped more than 50% of the mammoth genome. Once this is complete, reprogramming and surrogacy will likely allow for cloning.

When will we see this creature roaming the planet? Pretty soon I hope. We’ll be able to pay admission at Jurassic Park, which will likely be located on a remote island in Japan. Just remember to bring your shotgun!

Fantasy Becomes Reality: Creating Unicorns

Genetic engineering will not be limited to the cloning of dead dogs and the rebirth of extinct species. By attaining an understanding of the development of all species, one day, the creation of new species may be possible. Note: If you believe this counts as “playing God” then you should not be reading this blog.

The unicorn will be our case study here. What is a unicorn? Essentially, it is a white horse with a horn on its head. According to a survey of five year old girls, some unicorns have wings, and some have magical rainbows follow them. We’ll stick with a white horn for now.

We already know where to find white horses, but where do we find a horn? Thousands of creatures have horns: deer, antelope, some lizards. After doing some research, I have decided that the horn that best fits the description of the unicorn horn is the horn of a Narwhal. From here, we get the following equation:

White Horse + Narwhal = Unicorn

Okay, so how do we make this equation into reality? One answer: Get yourself a white horse, capture a narwhal, cut off the narwhal’s horn, and glue it onto the horse’s head! Simple. But not what we’re looking for.

Figuring out how to make a unicorn species will be difficult. It will require knowing exactly what set of genes contribute to the development of the narwhal horn, and exactly where these genes would be able to create a horn (in the proper location) for a unicorn. There will not simply be a copy and paste ability, but eventually through experimentation and trial and error, I believe that a unicorn species can be created which develops a horn on its own. Any horse can be the host species (for surrogacy) since the unicorn will be related enough genetically. This technology is a bit further in the future, but I believe it will be a possibility.

Once someone solves the unicorn, we can move onto other legendary creatures like cerberus, the sphinx, and all manners of chimera. Imagine a chihuahua with wings! It will be studies in genomics, cellular reprogramming, and developmental biology that will unlock pandora’s box and enable legendary creatures to be born.