How do we know the genome sequence?

Imagine someone asked you to explain how a car works. Even if you knew nothing about cars, you could take the car apart piece by piece, inspect each piece in your hand and probably draw a pretty good diagram of how a car is put together.  You wouldn’t understand how it works, but you’d have a good start in trying to figure it out.

Now what if someone asked you to figure out how the genome works? You know it’s made of DNA, but it’s the ORDER of the nucleotides that helps to understand how the genome works (remember genes and proteins?). All the time in the news, you hear about a scientist or a doctor who looked at the sequence of the human genome and from that information could conclude possible causes of the disease or a way to target the treatment. DNA sequencing forms a cornerstone of personalized medicine, but how does this sequencing actually work? How do you take apart the genome like a car so you can start to understand how it works?

As a quick reminder – DNA is made out of four different nucleotides, A, T, G, and C, that are lined up in a specific order to make up the 3 billion nucleotides in the human genome.  DNA looks like a ladder where the rungs are made up of bases that stick to one another: A always sticking to T and G always sticking to C.  Since A always sticks to T and G always sticks to C, if you know the sequence that makes up one side of the ladder, you also know the sequence of the other side.

DNA_ladder

The first commonly used sequencing is called Sanger sequencing, named after Frederick Sanger who invented the method in 1977. Sanger sequencing takes advantage of this DNA ladder – this method breaks it in half and using glowing (fluorescent) nucleotides of different colors, this technique rebuilds the other side of the ladder one nucleotide at a time. A detector that can detect the different fluorescent colors creates an image of these colors that a program then “reads” to give the researcher the sequence of the nucleotides (see image below to see what this looks like).  These sequences are just long strings of As, Ts, Gs, and Cs that the researcher can analyze to better understand the sequence for their experiments.

sanger_sequencing

This was a revolutionary technique, and when the Human Genome Project started in 1990, Sanger Sequencing was the only technique available to scientists. However, this method can only sequence about 700 nucleotides at one time and even the most advanced machine in 2015 only runs 96 sequencing reactions at one time.  In 1990, using Sanger sequencing, scientists planned on running lots and lots of sequencing reaction at one time, and they expected this effort would take 15 years and cost $3 Billion. The first draft of the Human Genome was published in 2000 through a public effort and a parallel private effort by Celera Genomics that cost only $300 million and took only 3 years once they jumped into the ring at 2007 (why was it cheaper and fast, you ask? They developed a fast “shotgun” method and analysis techniques that sped up the process).

As you may imagine, for personalized medicine where sequencing a huge part of the genome may be necessary for every man, woman, and child, 3-15 years and $300M-$3B dollars per sequence is not feasible. Fortunately, the genome sequencing technology advanced in the 1990s to what’s called Next Generation Sequencing. There are a lot of different versions of the Next Gen Sequencing (often abbreviated as NGS), but basically all of them run thousands and thousands of sequencing reactions all at the same time. Instead of reading 700 nucleotides at one time in Sanger sequencing, NGS methods can read up to 3 billion bases in one experiments.

How does this work? Short DNA sequences are stuck to a slide and replicated over and over. This makes dots of the exact same sequence and thousands and thousands of these dots are created on one slide. Then, like Sanger sequencing, glowing nucleotides build the other side of the DNA ladder one nucleotide at a time. In this case though, the surface looks like a confetti of dots that have to be read by a sophisticated computer program to determine the millions of sequencing.

NGS

So what has this new technology allowed scientists to do? It has decreased the cost of sequencing a genome to around $1000. It has also allowed researchers to sequence large numbers of genomes to better understand the genetic differences between people, to better understand other species genomes (including the bacteria that colonize us or the viruses that infect us), and to help determineexomee the genetic changes in tumors to better detect and treat these diseases. Next Generation Sequencing allows doctors to actually use genome sequencing in the
clinic. A version of genome sequencing has been developed called “exome sequencing” that only sequences the genes.  Since genes only make up about 1-2% of the genome, NGS of the exome takes less time and money but provides lots of information about what some argue is the most important part of the genome – the part that encodes proteins.  Much of the promise of personalized medicine can be found through this revolutionary DNA sequencing technique – and with the cost getting lower and lower, there may be a day soon when you too will have your genome sequence as part of your medical record.


For more information about the history of Sequencing, check out this article “DNA Sequencing: From Bench to Bedside and Beyond” in the journal Nucleic Acids Research.

Here is an amusing short video about how Next Generation Sequencing works described by the most interesting pathologist in the world.

Book Club: The Immortal Life of Henrietta Lacks

The_Immortal_Life_Henrietta_Lacks

Thanks to Wikipedia for the image

In 2002, one of my first set of experiments in graduate school was treating the prostate cancer cell line (named DU145) with a chemotherapeutic drug and comparing how these cells responded to how HeLa cells responded to this chemotherapy. Little did I realize at the time that 51 years earlier, these cells were removed from a poor black woman named Henrietta Lacks without her even knowing. She subsequently died, but her cells have lived on for over 60 years being used by researchers around the world to better understand cancer. It’s estimated that over 60,000 research papers have used HeLa cells (I just searched the literature for “HeLa” and found over 83,000 results). HeLa cells helped to develop the polio vaccine (HeLa cells were easily infected by polio, and therefore ideal to test the vaccine).  In 2013, HeLa cells were the first cell line to have its genome fully sequenced (the genome of HeLa cells is a hot mess with more than 5 copies of some chromosomes – likely caused by the number of times that the cells have divided over the past 60 years).  In fact, HeLa cells are so popular and so widespread that they have been found to be contaminating a large percentage of the OTHER cell lines that researchers are using (for example, the bladder cancer cell line KU7 was found to exclusively be HeLa cells in one research lab).

With all of this activity surrounding HeLa cells, you may think that she is famous and her family has received recognition from her donation.  However, as so artfully described in Rebecca Skloot’s “The Immortal Life of Henrietta Lacks” these cells were taken and grown without her consent and her family had no idea that Henrietta was was “immortal” through her cells growing in las around the world. Skloot describes the moral and ethical issues surrounding how these cells were obtained while weaving a story about Henrietta Lacks and her family’s life and discovery of HeLa cell’s fascinating rise to prominence.  Although the story is interesting to a scientist and a biobanker, the book is definitely written in such a way that the public will completely understand the scientific significance.

The best week ever – Nobel Prize week!

nobelLast week was one of my favorite weeks of the year – Nobel Prize week. Some people wait for the Emmys or the Superbowl or Christmas.  I wait for the Nobels. To be fair, I care most about the science Nobels – Physics, Chemistry and Physiology or Medicine, though one cannot ignore the amazing accomplishments of the winners in Literature, Peace, and Economics. Every year, I try to guess who may win – though Thomson Reuters and others are far more scientific about their guesses than I am.  And each morning of Nobel Week, first thing I do is check the news on my phone to see who won, what for and whether or not I know them (this year – no).  Let’s talk about who won the science awards this year and what amazing discoveries they won for.

Physiology or Medicine. A lot of attention has been given to infectious diseases this year with the huge Ebola outbreak in western Africa.  Although tens of thousands of people were infected and died, other infectious diseases are even more widespread and affect millions of people a year. Malaria is a parasitic disease transmitted by mosquitoes that 3.4 billion people are at risk of contracting and that kills over 450,000 people per year. Parasitic worms are also rampant in the third world, can affect up to a third of the human population, and cause such diseases as river blindness.  This is the second most common cause of blindness by infection, with 17 million people infected and 0.8 million blinded by the disease.  The three winners of the Nobel for Physiology or Medicine this year discovered novel treatments for these parasitic diseases.  William C. Campbell and Satoshi Ōmura for roundworm parasites and Youyou Tu for malaria, saving hundreds of thousands of lives each year.

Chemistry. This is by far my favorite award this year because it is directly related to how humans safeguard their DNA, but also why when this safeguard does work, that we get cancer.  Awarded to Tomas Lindahl (UK), Paul Modrich (USA), and Aziz Sancar (USA), this Nobel celebrates the discovery of the mechanism of DNA repair. I’ve discussed in this blog how UV and other environmental factors can cause mutations in DNA, and with too many mutations, people can develop cancer or other diseases.  However, the genome doesn’t mutate out of control because cell contain the machinery that is always working to fix any DNA damage using DNA repair mechanisms. It’s like a NASCAR race, where the car is always being monitored, wheels replaced, and minor problems fixed by the pit crew.  DNA repair is the genome’s pit crew and these three scientists figured out three different ways that the cells monitors and fixes the DNA depending on the type of damage that has occurred.

Physics. We all know I’m not a physicist, but I’ll try my best. The Physics Nobel was awarded to Takaaki Kajita of Japan and Arthur B. McDonald of Canada for discovering that neutrinos have mass.  You may remember from high school that atoms are made up of protons, neutrons and electrons. However, scientists now know that there are even tinier parts of an atom called subatomic particles that include the neutrino, fermions and bosons (and others). Other than photons, which are the particles of light, neutrinos are the most numerous subatomic particle in the entire cosmos, so understanding how they work is incredibly important.  These researchers found that the three different types of neutrinos can convert from one to the other. It was predicted by the Standard Model of Physics that these neutrinos wouldn’t have mass, but these scientists also proved that they did. Their studies help to better understand matter and the universe. My favorite reporting of this award was by NPR.

So until next year Nobel Prizes.  I will be waiting with baited breath!

 

Five Ways for You to Participate in Science – Citizen Science

Bunsen_burner

The Bunsen burner I didn’t have. Thanks Wikipedia for the image

I had a chemistry set growing up.  It was small with tiny white bottles holding dry chemicals that sat perfectly on the four tiny shelves of an orange plastic rack.  My dad would let me use the workbench in the basement to do experiments – entirely unsupervised!! You might expect that I did really interesting chemical reactions, and this formative experience helped me to develop into the curious scientist that I am today. Completely wrong.  I remember following the instructions, mixing the chemicals, and then getting stuck because I didn’t have a Bunsen burner.  So many chemical reactions rely on heat, and the green candle stuck to the white plastic top of an aerosol hairspray can wasn’t going to cut it.

My main options for doing science as a kid revolved my failed chemistry experiments, my tiny microscope and slides, and a butterfly net that never netted a single butterfly (not for lack for trying).  However, today with computers (that’s right – no computer growing up – that’s how old I am!) there are hundreds if not thousands of ways for people to get involved in science, without having to invest in a Bunsen burner. This citizen science movement, relies on amateur or nonprofessional scientists crowd-sourcing scientific experiments. I’m talking large scale experiments run by grant-funded university-based scientists that have the possibility of really affecting how we understand the world around us. One example you may have heard about is the now defunct Search for Extraterrestrial Intelligence (SETI) which used people sitting at their computers to analyze radio waves looking for patterns that may be signed of extraterrestrial intelligence. They didn’t find anything, but it doesn’t mean that they wouldn’t have if the program had continued!

Here are five ways that you can become involved in science from where you’re sitting right now!

americangut1. American Gut: Learn about yours (or your dog’s) microbiome

For $99 and a sample of your poop, you will become a participant in the American Gut project. After providing a sample, the scientists will sequence the bacterial DNA to identify all of the bacterial genomes that are present in your gut.  This study already has over 4,000 participants and aims to better understand all of the bacteria that covers and is inside your body – called your microbiome – and to see how the microbiome differs or is similar between different people or between healthy people versus those who may be sick. The famous food writer Michael Pollan wrote about his experience participating this the American Gut project in the New York Times.  They are also looking at dogs and how microbiota are shared with family members, including our pets!

2. Foldit: solve puzzles for sciencefoldit

Puzzles can be infuriating, but at least they have a point to them when you get involved in the Foldit project.  Proteins are the building blocks of life.  Made out of long strings of amino acids, these strings are intricately folded in your cells to make specific 3D shapes that allow them to do their job (like break down glucose to make energy for the cell).  Foldit has you fold structures of selected proteins using tools provided in the game or ones that you create yourself.  These solutions help scientists to better predict how proteins may fold and work in nature.  Over 240,000 people have registered and 57,000 participants were credited in a 2010 publication in Nature for their help in understanding protein structure.  Read more about some of the results here.

3. EyeWire: Mapping the BrainEyeWire-Logo

The FAQs on the EyeWire website are fascinating because as they tell you that there are an estimated 84 billion neurons in the brain, they also insist that we can help map them and their connections. After a brief, easy training, you’re off the the races, working with other people to map the 3D images of neurons in the rat retina.  You win points, there are competitions, and a “happy hour” every Friday night. The goal is to help neuroscientists better understand how neurons connect to one another (the connectome).

4. Personal Genome Project: Understanding pgpyour DNA

The goal of the Personal Genome Project is to create a public database of health, genome and trait data that researchers can then use to better understand how your DNA affects your traits and your health. This project recruits subjects through their website and asks detailed medical and health questions.  Although they aren’t currently collecting samples for DNA sequencing because of lack of funding, they have already sequenced the genomes of over 3,500 participants. The ultimate goal is having public information on over 100,000 people for scientists to use.

mindcrowd5. MindCrowd: Studying memory to understand Alzheimer’s Disease

Alzheimer’s Disease is a disease of the brain and one of the first and most apparently symptoms is memory loss.  MindCrowd wants to start understanding Alzheimer’s disease by first understanding the differences in memory in the normal human brain.  It’s a quick 10 minute test – I took it and it was fun!  They are recruiting an ambitious 1 million people to take this test so that they have a huge set of data to understand normal memory.

This is a randomly selected list based on what I’m interested in and things that I’ve participate in, but you can find a much longer list of projects you can participate in on the Scientific American website or through Wikipedia.  Also, if you’re interested in learning more about the kind of science that people are doing in their own homes, the NY Times wrote an interesting article: Home Labs on the Rise for the Fun of Science.  If decide to try one out, share which one in the comments and what you think!

Can your body contain DNA that isn’t yours? Yes! Chimerism

There was a House episode (Season 3 Episode 2 Cane an Abel) about a young boy who was convinced that he was being probed by aliens.  Though a series of very House-like (aka “unrealistic”) medical twists and turns, House’s team finds cells clumped together in different parts of this boy’s body, including his brain, that are functioning abnormally and causing his various systems.  From sequencing the DNA from those cells, House’s team finds that those cells have different DNA than the boy’s.  In the fictional world of House, the doctors were able to quickly create a probe for the foreign DNA, find all the cells that were different and remove them (House does brain surgery!!) also removing the symptoms including the alien hallucinations. This episode is so wildly out of the realm of current medical ability and practice – so much so that I participated in a “Science Fiction TV Dinner”  all about the science and “science” found in this episode. You can watch highlight from this discussion, which included Dr. Kenneth Ramos from University of Arizona Center for Precision Medicine, below or listen to the whole podcast here.

Science Fiction TV Dinner: House M.D. from Science & the Imagination on Vimeo.

However, what I found most interesting about this episode was the fact that the boy had TWO DIFFERENT genomes in his body. Can this actually happen in real life?  If so, how??

chimera

“Chimera d’arezzo, fi, 04” by I, Sailko. Licensed under CC BY-SA 3.0 via Wikimedia Commons

The answer is yes, and it’s called a chimera or chimerism. In mythology, a chimera is a terrifying hybrid animal that’s a lion, with a goat head coming out of it’s back and a tail with a snakes head on the end. It may be clear that I’m a scientist since I’m sitting here wondering whether all three heads eat and if so, do they all connect to the same or different stomachs. But I digress…  In genetics, a chimera is an organism composed of two distinct sets of cells with two different sets of DNA. As you may remember from other discussions on this blog, DNA is the genetic material that provides the blueprint to make an organism.  DNA is also what is passed along to offspring, so that a child has 50% of the DNA from one parent and 50% of the DNA from the other (more about hereditary here). This is also why paternity tests work – if the child has 0% of DNA from the father, it’s clear that he isn’t the father,

So how in the world can a person have two different sets of DNA?  Especially since all people start off as one fertilized egg with one set of DNA instructions?  There are a few ways:

  • Organ transplants or stem cell transplants.  That organ or cells (more about stem cell transplants here) come from another person who has entirely different DNA from the transplant recipient.  So when a person gets an organ transplant, they become a chimera.  This is also true, at least temporarily, for people who have blood transfusions.
  • Are you a mother or a person who a mother gave birth to?  In that case, you might also be a chimera.  This is called fetomaternal microchimerism.  Mothers usually have a few cells identical to their children that stay in their body long term. This is often caused by immune cells being transferred back and forth between the mother and the placenta during development.   Even 22% of adults were found to still have blood cells from their mother! These cells are really difficult to find – in part because there usually isn’t any reason to look for them – but easier if the mother has a boy because then the chimeric cells contain a Y chromosome whereas the mother’s cells do not.
  • In vitro fertilization (IVF) also has the possibility of resulting in chimeric adults.  Since IVF often implants multiple fertilized eggs into the mother, there is an increased possibility of two fertilized eggs fusing – resulting in one developing human developing into an adult with two sets of DNA.
chimericperson

Illustration of a chimeric person from and awesome article about chimeras from the EMBO journal

Let’s talk about this last option a bit more because this is what House and Co. blamed as the cause of the child’s chimerism, but also because this is really interesting medically and socially.  There have been several noteworthy stories about  women who, for different reasons, were found to be chimeras.  Lydia Fairchild was looking for child support after a divorce, but when DNA tests to prove paternity were requested, it was found that the father was the father, but Lydia wasn’t the mother.  After numerous traumatic events, including being accusing of trying to commit fraud to obtain benefits and having the birth of her third child observed (to prove that she was that child’s mother, even though genetically it didn’t appear that the child was), Lydia was lucky.  Her lawyer heard about Karen Keegan, a women in need of a kidney transplant several years earlier, but when testing her three sons for compatibility, the tests indicated that only one was hers.  Only by looking at other cells in her body were doctors able to determine that her body contained two sets of DNA – one set was passed on to two of her boys and the other set was passed on the other.  Fortunately for Lydia, this discovery prompted DNA testing of members of Lydia’s extended family as well as other parts of Lydia’s body.  This testing showed that Lydia’s cervical cells matched her childrens’ and she was able to obtain child support. The media LOVED this. Just an example of the titles for news articles about Lydia and Karen:

However, besides the obvious media hype, chimerism has practical and legal implications. For example, in 2005, a cyclist Tyler Hamilton was charged with blood doping because they found another person’s blood mixed with his own.  He blamed this on chimerism (New York Times article here) where he had chimeric blood cells that had different DNA than the rest of his body.  He lost his case 2-1, but it brings up an interesting idea.  If everyone knows about chimerism – either through the popular media or TV shows like House – then this could lead to the “reverse CSI effect” where the jury is so aware of the possibility of chimerism that they discard all mismatched DNA evidence blaming it on chimerism.

Besides how strange this all seems, what’s even stranger is that more people are probably chimeras that scientists even realize. The only reason we know that Karen Keegan and Lydia Fairchild are chimeras is because scientists were forced to look at them more closely.  For the rest of us, we likely won’t need a transplant or have alien-probing hallucinations that induce scientists to look at many different parts in our body to see if the DNA is different.  And if more of us are chimeras, what does that mean? This is still something scientists will have to figure out.

Want to hear more about this amazing phenonemon? Check out  or this great article from the EMBO journalNPR’s RadioLab story Mix and Match featuring Karen Keegan’s story.

What are all the “-omes” in science?

If you’re into yoga, you may be very familiar with “OM” or if you’re an electrician with “ohms”, but in science, we use “-ome” in a very different way.  To start off, let’s give a silly example: the studentome (which I’m fairly sure does not actually exist).  This would be the study of all “students” in a certain place.  Maybe we’re interested in all of the students in a particular high school or college, and they can be categorized and better understood by looking at the distribution of their ages, their heights, their grade level, their clothing style, etc.  The studentome would be different in an inner city school compared to a private Catholic school, and understanding these differences could help to improve or change aspects of the studentome in a certain place. The study of the studentome, would be called studentomics.

So what does this “-ome” mean? In Greek: “-ome” means “all” or “complete”. So whenever scientists put “-ome” at the end of a word, they are talking about all of something (like with the “studentome” all of the students), and in biology this usually is referring to all of something in an organism or a particular cell type.  It’s not clear when scientists started using words ending in “-ome”, though the word biome was coined in the early 1900s.  The modern usage likely started in the early 1990s as technologies, like computers and DNA sequencing, allowed scientists to study all of something in an organism with more ease.  A derivative of the “-ome” is “-omics”, which is the study of all of something in an organism or a cell.  This terminology is so common, there is even a wiki dedicated to “-omes” and “-omics” here.

Let’s explore some of the common “-omes” (you can find a more comprehensive list of scientific “-omes” here).

  • Genome: The most famous “ome” is the genome. The genome refers to all of the DNA in an organism.  In humans, this includes all 23 pairs of chromosomes (number 1-22 and the two sex chromosome, XX if you are female and XY if you are male). Scientists study the genome to understand the genetic blueprint of DNA because DNA codes for proteins, which are the functional machines that do everything in a cell.
  • Transcriptome: For DNA to make a protein, the DNA needs to be “transcribed” in RNA first (read more details about this process here).  All of the RNA in a cell is called a transcriptome.  Scientists study the transcriptome because not all DNA is “turned on” to make proteins in every cell.  This helps explain why certain cells look different (skin cells look different than eye cells) and have a different function (skin cells provide a barrier from the environment and specialized eye cells allow you to see).
  • Proteome: And this brings us to the proteome, which is all of the proteins in a cell or organism.  Since proteins are what’s actually doing stuff in a cells, by understanding what proteins are present in certain cells, scientists are able to better understand how those cells function. And in the case when there are problems, for example in cancer cells, it can help understand why there is a problem and possible ways to fix it.

omes

  • Interactome: Proteins interact with one another in a variety of ways.  The interactome maps all of these interactions.  The interactome is also different in different cell types because the proteins expressed are different in different cell types, so there are many interactomes
  • Metabolome: Even though proteins are the machinery in a cell, there are lots of other small molecules and chemicals called metabolites.  For example, glucose is a metabolite that is broken down to produce energy.  All of the metabolites in an organism are called the Metabolome.

And there are hundreds more of these “-omes”!  This “omeome” (originally and jokingly coined here) has even seeped into more popular culture.  For example, the Facebookome, described as “The totality of facebook social network connections and nodes information such as people’s names, relationships, and multimedia contents.”  Although it may seem to be an unnecessary wordy trend, these “-omes” and “-omics” are necessary for scientists to better understand health and disease.

 

 

What are examples of diseases caused by one gene?

Mutations. We know what they are.  Mutations change a gene, which can change the protein.  And this change in the protein can be either neutral, good or bad.  Let’s finally talk about how these mutations can be bad.

There are over 4,000 diseases that are caused by mutations in just one gene.  This means that if there is a mutation in one copy of the gene (if dominant) or both copies of the gene (if recessive), there is nearly 100% likelihood that you will get the disease.  Let’s look at some common examples.

Cystic Fibrosis

cfThis is a genetic disease of the lung that is caused by a recessive gene called the cystic fibrosis transmembrane conductance regulator (or CFTR for short). This gene makes a protein that transports chloride across the cell membrane.  The most common mutation in this gene is a deletion that causes a frameshift, which makes a much shorter protein.  This shorter protein doesn’t work properly at transporting chloride and results in fluid build up in the lungs and other organs that leads to cystic fibrosis (also known as CF).

Since this is a recessive disease, what this means is that you need TWO copies of the mutated CFTR gene to get cystic fibrosis. Remember those genetic squares we used to figure out what the possibility of a child inheriting a particular allele of a gene?  Let’s look at one for CFTR.  If you imagine that the normal CFTR gene (the one that isn’t mutated) is “C” (shown in blue) and the mutated CFTR gene is “c” (shown in orange).  If each parent has one copy of the non-mutated and one copy of the mutated CFTR gene Cc, then they have a 25% chance of having a child with CFTR.  Why?  Because only a child with two copies of the recessive trait (which in this case is the mutated CFTR gene) will have cystic fibrosis.

Huntington Disease

This is an example of a dominant mutation that causes a disease.  The huntingtin genehuntingtin
has a region that has lots of repeats of one codon CAG. Most people have less than 36 repeats of CAG.  However, if a person has more than 36 repeats, it creates a protein that is toxic to brain cells – exactly how and why it is toxic isn’t really well understood.  Since this is a dominant mutation, you only need one copy of this mutated gene to get Huntington’s disease.  So if you have one parent with the Huntingtin mutation (shown as H*), which means they have one copy of the Huntingtin gene with >36 CAGs, then a child has a 50% chance of also inheriting Huntington’s disease (HH*)

Now you may be wondering, how do we know if the mutation will be dominant or recessive?  That’s a complicated question.  In part, you may know if you look at the family history.  A disease caused by a dominant mutation will be inherited by more often by the children of an affected parent whereas a recessive mutation is less likely to be inherited because it is only inherited when both parents have one copy of the recessive gene.  Another option is to study the function of the mutation protein and see how the mutation in the gene affects the function of the protein.  Since there are two copies of every gene, if one copy is mutated, the second copy of the gene could compensate for this mutation (in the case of cystic fibrosis).  In other cases, the mutation could cause such dysfunction that even with the normal protein around, it still causes disease (like Huntingtin’s).

How do genes affect traits? It’s just like “50 Shades of Grey”

In “50 Shades of Grey”, there isn’t any mention of molecular biology or genetics, but maybe there should be, because it’s a great example of how to explain how genes affect traits. And yes, I’m talking about dominance. Don’t get too excited – there won’t be any photos or explicit descriptions of sexy time (aka business time, if you’re  Flight of the Conchords fan).  We’re going to be talking about dominant and recessive genes.

You have two copies of each gene – one on each chromosome – and these are called alleles.  One allele is from your mother and one from your father, and these genes can be slightly different.  In some cases, the gene is dominant, which means that the variant of the trait that it is responsible for will take over – this would be represented by the dominatrix or Mr Grey.  Other genes are considered recessive – or the submissive, Anastasia Steele.  Christian Gray is the boss and what he says goes.  Only when the dominant person isn’t around does the submissive get to do what it wants.
dominant_and_recessiveAnother way to think of this is if you have a bully.  The dominant bully will take over whenever any other kids are around.  Only when the bully isn’t there, can the other kids do what they want.

What does this mean in genetics?  First, let’s get some terminology out of the way.  The dominant gene is usually represented in capital letters (for simplicity let’s call it gene “A”) and the recessive gene is in lowercase “a”.  Whenever the dominant trait, A, is present on one chromosome, that trait will be visible.  So if you have two As (AA) or one dominant and one recessive gene (Aa), you’ll only see the dominant trait.  Only when you have two recessive genes (aa) will you see the recessive trait.

punnetsquareLet’s give an example using eye color.  Let’s say that the dominant gene trait (A) is from brown eyes and the recessive trait (a) is for blue eyes.  With AA or Aa, you will have brown eyes, and with aa you will have blue eyes.  If you look at the image on the right, you may be having nightmares back to high school biology.  All this is representing are the possibilities of what trait a child might have depending on the parents genes.  If each of the parents has one copy of A and one copy of a, the child will randomly get either the A allele or the a allele from each parent. The boxes represent those possibilities.  From there you can ask and answer some really interesting questions – what’s the likelihood that with two Aa parents that the child will have blue eyes?  What do you think?  The answer is here.

What we have just discussed is what’s called “Mendelian Genetics” or “Mendelian Inheritance” named after the Monk Gregor Mendel who in the 1800s discovered these rules with dominant and recessive genes in pea plants.  What’s most interesting for us, besides being able to understand traits like eye color, is that over 4,000 diseases can be attributed to a single gene, either because it was inherited or by chance.

 

What is heredity?

All the time, people say that I look more like my Dad and my sister looks more like my Mom.  My sister inherited by mom’s blue eyes and light hair, and I inherited the green eyes and brown hair from my Dad’s side of the family.  When we talk about heredity, we often discuss it in terms of traits – things you can see like eye color to whether or not you can roll your tongue.  But really anything that you inherit, like personality traits or risk of disease, all are part of heredity.

Before we go any further, let’s get some confusing vocab out of the way:

  • Hereditary: Cause is genetic and has the possibility of being passed down to children
  • Familial: Multiple people within a family have the disease but the cause may be due to shared environmental factors. For example, everyone in the family may be obese, but it’s because they all have the same die.  Or multiple people in the family develop lung cancer, but it is because they all smoke
  • Congenital: Caused by something in utero (while pregnant).  This may or may not be inherited
  • Sporadic: Occurs by chance

heredity

For now we’ll focus on heredity, but we can come back to these other terms later.

So HOW do people inherit  traits? Through their genes! Quick quiz (and this is related to the question, I promise).  How many pairs of chromosomes humans have? 23 pairs.  Now why in the world am I highlighting the word “pairs”? If you have two copies of each chromosome (which you do – hence, the word “pairs”) then you have two copies of each gene (because genes are located on the chromosomes).  Where do these two chromosomes come from?  One of the sets of chromosomes comes from your mother (from the egg) and the other set comes from your father (from the sperm). So when you inherit traits, it’s very literally because the you get half of your DNA from one parent and the other half from the other parent.

You may be wondering how even though the chromosomes are the “same” that the genes on each chromosome are different that they can inherit such a huge variety of traits.  Even though 99.9% of our DNA is the same compared to any other person you’re sitting next, there is 0.1% that is different.  This may not seem like a lot, but with 3 billion bases in the human genome, that means that 3 million of those may be different (how this happens is the topic of another blog post).  These small differences change individual genes slightly, and as we know, that changes the protein the gene makes as well.  So the gene from your mom is slightly different from the gene from your dad.  The technical word for these two genes that are the same but slightly different, are called alleles. A great example of this is blood groups.  If you are blood group AB, you have one A allele and one B allele.  Gene alleles are responsible for our amazing differences and our ability to inherit traits from our parents!

allele

Moxie with his corgi and lab traits

Moxie with his corgi and lab traits

Keep in mind, alleles and heredity isn’t just in humans.  Plants inherit traits because of gene alleles.  Dogs inherit traits based on different alleles – my dog Moxie is a corgi black lab mix and has traits of both (black body and short legs).  The majority of organisms (those with two copies of each chromosome) have heredity based on gene alleles from the parents.

 

Book Club – The Genome

genomeOur second book club book is The Genome The Autobiography of a Species in 23 Chapters written by the fabulous popular science author Matt Ridley.  So why do you think there are 23 chapters to this book? Do you remember how many pairs of chromosomes humans have?  Have 23 chromosomes, and Ridley devotes one chapter to each chromosome. The chapters weave stories about genes that are found on each of the chromosomes and how they affect our life (e.g., blood groups) or disease (e.g., Huntington’s disease). He also takes the time to provide information about the history of human evolution, genetics and biology, bringing the biology and its implications all together. What’s interesting about this book is that it was published 2 years before the first draft of the human genome sequence was complete in 2001.  It would be interesting to see how different this book would be if written today, 16 years later with the added knowledge and technology.

Besides really enjoying Ridley’s books, he was a visiting scientist at Cold Spring Harbor Laboratory, where I attended graduate school.  He presented to graduate class (which only had 6 people in it) in my first year Scientific Exposition and Ethics class two years after this book was written.  He also received an honorary doctorate from my graduate school the year before I received my PhD.  Although we met only briefly, his insight and ability to describe science is impressive and all of his books are worth a read.

For more Book Club books, click here.