In recent weeks, I’ve been talking about my work as a computer programmer for the Indiana University Department of Medical Genetics. This week, we take a departure to talk about the work that we did in that department. We will take a deep dive into basic genetics, and you will learn a little bit about the genetic disorder that causes my disability.

Hi, this is Chris Young. Welcome to episode 77 of Contemplating Life.

In recent episodes, I’ve been discussing my work as a computer programmer for the IU Department of Medical Genetics. I wanted to tell a little bit about what we did in that department and how the computer database was used, but you know me. I can’t do anything halfway. So, this episode is going to be a little bit of a departure. It’s an explanation of everything I knew about genetics at the time, along with what I’ve learned in recent years. While trying to explain some of these things, I came up with questions I couldn’t answer, so I had to do some pretty hefty research to fill in those gaps in my knowledge. It marginally relates to my life story because we will also discuss how genetics play a part in my disability caused by Spinal Muscular Atrophy.

Hold on to your hats. This is going to be a deep dive into Genetics 101.

In the nucleus of every cell in your body are 46 strands of a molecule called deoxyribonucleic acid, or DNA for short. These 46 strands are called chromosomes.

By the way, everything I will say about chromosomes refers only to human chromosomes. Other species have different numbers of chromosomes, or their DNA may be arranged differently in the cell. So, I’m limiting our discussion to human chromosomes.

You’ve probably seen illustrations of what a DNA molecule looks like. I have some images in the YouTube version of this episode. Imagine a rope ladder that has been twisted. This shape is called a double helix. Each “rung” of the ladder consists of two molecules of amino acids. There are four such varieties of amino acids in DNA. They are adenine, thymine, cytosine, and guanine. They are designated by the letters A, T, C, and G, respectively.

Each ladder rung is either an A paired with a T or a G paired with a C. An A cannot pair with a G or C, nor can a T pair with a G or C. This is because A and T connect using two hydrogen atoms, while C and G connect using three hydrogen atoms

The “ropes” that hold these rungs in place are made of two strands that alternate between a sugar molecule and a phosphate molecule. The sugar molecule contains an asymmetrical ring of 5 carbon atoms. The phosphate groups connect to either carbon atom at position 3 or position 5. So, at the end of a DNA sequence, you always have either a 5-connected phosphate or a 3-connected phosphate. By convention, scientists read from the 5 end towards the 3 end because that’s the direction in which nature reads the DNA when it copies it during cell division.

For example, if you have a string of DNA that is AAGG because the A is always paired with a T and the G is always paired with a C, it could be just as easy to say that this sequence is TTCC. So you have to look at the end of the DNA sequence and see if its phosphate group is connected to carbon atom 3 or carbon atom 5. Always start at the end with the 5.

These strings of letters A, T, G, and C are codes that tell your body chemistry how to create proteins. They are divided into three character words called codons. There are 64 possible combinations. Each one is an instruction to create a particular amino acid. Proteins are long strings of amino acids. There are not 64 different amino acids. Some combinations of three letters produce the same amino acid. See the table linked in the description that shows which combination of DNA bases produces which amino acids.

An area on your chromosome that contains the instructions for producing one particular protein is called a gene. Not everything on a chromosome is significant. It is estimated that only 1.5% of human DNA actually does anything. The rest of it is random noise.

When a cell wants to produce a protein, it temporarily unzips the two halves of the DNA molecule, like cutting the ladder’s rungs. More amino acids connect to these broken ladder rungs to create a new molecule called messenger RNA, or mRNA. Once the mRNA is created, the DNA halves zip back together. The mRNA then produces the protein based on information provided by the DNA.

As I mentioned, chromosomes are simply long strands of DNA. Under a microscope, you normally cannot see DNA strands because they are all tangled up. However, when the cell divides, duplicating itself, the chromosomes bunch up and become visible lines. Before the cell divides, think of the tangled-up DNA as a bunch of USB cables tangled up in your junk drawer. You can’t make any sense of it. But as the cell divides and the DNA duplicates itself, each strand bunches up sort of like the curly cue cable on a landline telephone handset. When it’s all coiled up like that, you can see it under a microscope.

If you’ve seen photographs of chromosomes, they seem to have a characteristic X shape. Think of two long balloons, the type of which you use to make balloon animals, sitting side-by-side and tied together somewhere in the middle with a tight string. However, these are actually two chromosomes fastened together by something called a centromere. The centromere isn’t exactly in the center, so the short arm of the chromosome is called the “p” arm, and the long arm is called the “q” arm. When a cell completes division, the centromere breaks apart, giving two exact copies of the same chromosome. One goes into one cell and the other into the other cell. So, chromosomes are not really X-shaped except when they are self-duplicating. Normally, they are just single strings of DNA.

I learned this five minutes ago. My whole life, I thought chromosomes were roughly X-shaped because all the photos depict them that way. You learn something new every day.

Okay, let’s talk about human chromosomes, whatever the hell shape they really are.

Each cell contains 23 pairs of chromosomes, the first 22 of which are numbered 1 through 22. These are called autosomes. The longest one is chromosome 1, and the shortest is 22. Chromosome 1 is nearly 3 times longer than 22.

Well, almost. That ordering isn’t exactly accurate. For example, 21 is actually the shortest, and 20 is actually longer than 19. This is because back when they were numbering chromosomes, it was difficult to determine the exact length. They got it wrong. But by then, the labels had already been established, and they didn’t fix it.

You also have another pair of chromosomes called allosomes–also known as sex chromosomes. There are two varieties: X and Y. By the way, those labels have nothing to do with the appearance of the chromosomes; they are just labels they were given. I learned that about a year ago. I thought they looked like X and Y. But then again, I thought that all chromosomes had sort of an X-shape, and that was wrong, too.

By the way, the X chromosome is the eighth largest, and the Y is the third smallest.

In most human beings, females have two X chromosomes, while most males have an X and a Y. I said “most” because there are variations such as XXX, XYY, and all sorts of other combinations resulting in an intersex individual, but we won’t go into that right now.

You have two copies of chromosomes 1 through 22. One copy is from your mother, and the other is from your father. For the sex chromosomes, your mother gave you an X because she only had Xs to give. Your father had an X and a Y, so if he gave you an X, you would end up with two of them, and you would be female. If your father gave you a Y, then you ended up with an X and a Y, and you are male.

So, you are a mix of the genetic information from your mother and father. They each gave you one of each variety of chromosomes. But how do you pass that information along to your children?

I said that every cell contains 46 chromosomes, but that’s not entirely true. Men produce sperm, and women produce ova. These specialized cells (collectively known as gametes) only have 23 chromosomes. When the sperm and ovum combine during fertilization, that brings the number back up to the full 46.

Gametes are produced by specialized cells called germ cells, which undergo a special type of division known as meiosis. Meiosis is a complicated multi-step process that results in a unique mixture of maternal and paternal genetic material.

How do we determine which 23 of the 46 chromosomes go into your sperm or ova? Does it take a random sampling of the chromosomes given to you by your parents? Perhaps one of my sperm contains chromosomes 1, 3, 5, 9, etc., from my mom and 2, 4, 6, 8, etc., from my dad?

If that were the case, and we were sampling entire chromosomes, we wouldn’t have as much variety in human beings. Our family resemblance would be much more significant. The beauty of sexual reproduction is that we get a random mix of all of our genetic material each generation. The mix is more complicated than simply picking an entire chromosome from either grandma or grandpa.

During meiosis, the chromosomes undergo a process called recombination. Each chromosome is chopped up into random-length pieces, creating a new chromosome that contains sequences from both your mother and your father. This swapping between maternal and paternal DNA typically occurs between one to four times for each chromosome.

By the way, this creates a problem when creating sperm. Females have 2 X chromosomes, and they can be easily chopped up and recombined. However, men only have the maternal X and the paternal Y. How do you mix that up? The X and Y have a shared region known as the pseudoautosomal region or PAR. The PAR undergoes frequent recombination between the X and Y chromosomes, but recombination is suppressed in other regions of the Y chromosome that are unique to that chromosome. These regions contain sex-determining and other male-specific genes.

The bottom line is that the reason your children are not more identical than they are is because they have a truly random set of genetic material from you and your spouse–from your parents and your spouse’s parents.

This mixing of genes from both paternal and maternal sources when creating a gamete is important when you are trying to figure out if your children are going to inherit some genetic trait. Most importantly, the clients of our genetics department wanted to know if their children would inherit some genetic disorder. They might know that certain diseases, such as hemophilia, muscular dystrophy, Huntington’s disease, etc., run in their family. They want to know the odds their children will inherit the disease.

As mentioned previously, genes are instructions on how to create proteins. But there are varieties of each gene. For example, there is a gene that determines eye color. Or at least, to a certain extent, the difference between brown and blue eyes. There can be all sorts of shades of both, but the basic color is controlled by one gene. This eye color gene is in the same location, but the DNA sequence in the gene differs between brown-eyed people and blue-eyed people. Genes that have multiple varieties, such as the blue-eyed gene versus the brown-eyed gene, are called alleles.

In general, the brown-eyed allele is dominant, and the blue-eyed allele is recessive. Lots of genes have dominant and recessive alleles. So, let’s generalize this.

If we describe the brown allele as “D” for dominant and the blue allele as “R” for recessive, there are four possible combinations: DD, DR, RD, and RR. If we are talking about brown versus blue lies, then the DD, DR, and RD combinations give you brown eyes. Only people with two copies of the recessive allele, those with RR, will have blue eyes. That’s why we say the brown-eyed allele is dominant over the blue-eyed allele.

Designations such as DD, DR, RD, and RR are known as genotypes. However, your phenotype is the way you look externally, that is, whether you have brown or blue eyes.

The alleles for genetic disorders are mostly recessive. If they were not, genetic disorders would be much more common. Someone with a genotype of DR or RD is said to be a carrier of the disorder. You don’t exhibit the symptoms of the disease, but you can pass it along to your children if your spouse is also a carrier.

My disability is caused by a disease known as Spinal Muscular Atrophy. SMA for short. It is a recessive condition. So, my parents were both carriers. They had a genotype of DR or RD. If I had gotten the D allele from both of them, I would neither have the disease nor carry it. On average, there is a 25% chance of that happening. If I got an R from one and a D from the other, I would either be RD or DR, and like them, I would be a carrier but would not exhibit the disease. The odds of that happening are 25% + 25% = 50%. The odds of getting RR are 25%. Lucky me… That’s when I have. I exhibit the disease, and I naturally am a carrier. In this way, the disease can be passed down for many generations before it might appear. You have to have a mate who is also a carrier. Even if you have a partner who is also a carrier, on average, only one-fourth of your children will exhibit the disease.

Specifically, SMA is caused by a problem with the Survival Motor Neuron gene, also known as SMN1. It creates a protein called the SMN protein. This protein is essential to the survival of your motor neurons. These are the nerves that control your muscles – not the nerves for sensation. The SMN1 gene is located on the fifth chromosome at a location labeled 5q13.1. That means it’s on the number five chromosome on the q arm at location 13.1. I don’t know the details of how they came up with 13.1. It wasn’t worth it to research that.

Chromosomes consist of coded sections called exons and filler sections known as introns. The SMN1 gene consists of 9 exons. Somewhere along the way in my genetic history, the 7th exon was deleted. Something during the DNA replication process caused that section to be left out. Think of cutting a scene out of a piece of film and splicing it back together. Without that properly formed gene, the SMN protein is not properly created to feed your motor neurons. The motor neuron dies off, which eventually causes your muscles to atrophy.

The only reason people with SMA survive is that we have at least one backup gene, SMN2. Most people have at least one copy of SMN2 and may have as many as four or five copies. Unfortunately, in everyone’s SMN2 gene, there is a problem. It is identical to SMN1 except for one letter in the sequence. There is a T where there should have been a C. The end result is that SMN2 only creates the proper protein about 10% of the time. People with the deleted section in SNM1 have lower levels of the SMN protein because the SMN2 gene doesn’t work as well as it should. People with less severe forms of the disease generally have multiple copies of SMN2. Specifically, I have two copies. Even among individuals with the same number of SMN2 backup genes, there can be a variety of severities of the disease. There must be other factors involved besides the number of SMN2 genes.

For nearly 3 years, I’ve been taking a drug called Evrysdi, which makes the SMN2 genes work better. Children who begin receiving the drug at an early age can keep their motor neurons from dying off. At best, the drug keeps me from getting worse, or if I deteriorate, I will do so much more slowly than I would have without it.

Sometimes, the gene which causes a particular disorder is located on the X chromosome. For example, the most common type of muscular dystrophy, Duchenne muscular dystrophy, is that way. So is hemophilia. If you are female, you would have a good X and a bad X, but the good one is dominant, so you would carry the disease but not exhibit it. However, if you are male, your Y chromosome doesn’t have that section, so it can’t compensate for the bad X. So typically, only males get the disease. The females carry it.

The only way a female could get muscular dystrophy or hemophilia is if their mother was a carrier and their father had the disease. Then you can get a bad X from both. But that’s extremely rare.

Such conditions are called “sex-linked traits” because males exhibit the disease and inherit it from their mothers.

I always knew that whatever I had, it wasn’t Duchenne muscular dystrophy, but for many years, I incorrectly presumed that it was probably a sex-linked condition just like DMD. It isn’t. My disease comes from chromosome 5 and not X or Y.

Here’s a funny story for you…

One day, I was at a conference with my friend Joyce. I was trying to explain to someone this phenomenon of a sex-linked trait. After telling people about my condition, which I presumed was sex-linked, they misunderstood me. Later, Joyce overheard them discussing it, and they thought a sexually transmitted disease caused my disability.

Well… In some respects, it was. All genetic conditions are sexually transmitted. Your parents had sex, and you inherited the disease. I don’t know if this confusion has occurred in other settings, but more modern terminology is that such conditions are called X-linked dominant, X-linked recessive, and Y-linked diseases rather than sex-linked.

Okay, here’s an old Dad joke. Did you know that diarrhea is genetic?

It runs in your jeans.

Anyway… Let’s get back to the story about the work we did in the genetics department. When I worked there in the late 1970s, the state of the art of genetics was not as advanced as it is today. I don’t know if it was impossible or just extremely difficult to find out the exact sequence of A, T, C, and G in a particular location. Scientists were uncertain about the location of a gene or genes that cause a particular disorder.

Our database stored information on “genetic markers” for each person in the database. A genetic marker is a gene or other sequence of DNA at a known location on a particular chromosome. For it to be most useful, it should be something you can easily test for, such as blood type. In addition to blood types A, B, AB, and O with both positive and negative Rh factors, there are other blood types and biological serums that can easily be collected and tested. Our database included information on about 15-20 different genetic markers. I forget exactly how many markers we could track or what they were.

So, if you have a genetic trait that you cannot directly test for but you know that the gene is adjacent to something you can test for, the way that chromosomes get chopped up and recombined during meiosis means that it is highly likely that if you inherited a genetic marker from your parents, a gene near that marker would also be inherited.

Hypothetically, let’s presume your mom is blood type O and your dad’s blood type A. Your blood type will be A because that’s dominant over type O. Now, let’s presume there is a gene that is near the blood type gene on the same chromosome. Let’s presume that this mystery gene causes some genetic disease. We have no way to test for it directly. Or at least we didn’t in the late 1970s.

Furthermore, let’s say your dad is a carrier of this disease, but your mom is not. You want to know if you inherited that bad gene from your dad or if you got a good variety from your mom. If your blood type is O, that means that section of that chromosome came from your mom. It is highly unlikely that during meiosis, the recombination will split exactly between your blood type gene and the bad gene we are worried about. That means it’s likely that section of chromosome came from your mom and not your dad, so you don’t have anything to worry about. On the other hand, if your blood type is A, like your dad’s, it is highly likely you also inherited that adjacent bad gene.

Scientists also used this method to determine the location of particular genes. For example, Huntington’s disease is an inherited degenerative neurological disease. By studying the genetic markers of thousands of individuals who either have or carry the disease, scientists could indirectly determine the location of the gene that causes it. Scientists at some other universities narrowed down the location of the Huntington’s gene, and data from our database, which included a large number of Huntington’s families, was used to verify the results of their findings.

In the YouTube version of this podcast, you can see an article from the Journal “Nature” where they announced the discovery of the genetic marker for Huntington’s disease. I’ve also linked the article in the description.

One of the co-authors of the article is P. Michael Conneally, who was a geneticist at the IU Department of Medical Genetics when I worked there. He was the guy with the thick Irish accent who took my phone call when I first applied for the job.

Although this article wasn’t published until November 1983, we knew that they had discovered the gene in the late 1970s when I still worked there. Apparently, they just narrowed it down. Wikipedia reports that the exact location wasn’t determined until 1993.

By the way, I’ve also linked the Wikipedia article about Dr. Conneally, who had many accomplishments, including the discovery of over 20 human genes. He was a founding member of the department. He died in 2017. He was a great guy.

In 1990, the Human Genome Project was started. Its goal was to sequence the entire human set of chromosomes. They took samples from several donors and produced a map of all 24 varieties of human chromosomes, that is, chromosomes 1 through 22 and X and Y. They were able to sequence 92.1% of human DNA. The parts they could not sequence are the little regions where the chromosomes get tied together, called centromeres, and the ends of the chromosomes, called telomeres. But those generally are not significant.

The guesswork that had to be done using genetic markers and probabilities that we worked on in the 1970s is no longer necessary, but we did some groundbreaking work at the time.

I’m proud to know that the database I helped build was used to identify the gene that causes a serious genetic disorder like Huntington’s disease.

That was a very long, highly technical podcast just to explain what that previous sentence meant. But you learned a little genetics along the way, especially as it relates to my disability.

In our next episode, we will discuss my remaining work at the department and the circumstances under which I eventually left for health reasons.

If you find this podcast educational, entertaining, enlightening, or even inspiring, consider sponsoring me on Patreon for just $5 per month. You will get early access to the podcast and other exclusive content. Although I have some financial struggles, I’m not really in this for money. Still, every little bit helps.

As always, my deepest thanks to my financial supporters. Your support means more to me than words can express.

Even if you cannot provide financial support, please post the links and share this podcast on social media so that I can grow my audience. I just want more people to be able to hear my stories.

All of my back episodes are available, and I encourage you to check them out if you’re new to this podcast. If you have any comments, questions, or other feedback, please feel free to comment on any of the platforms where you found this podcast.

I will see you next time as we continue contemplating life. Until then, fly safe.