Genetic Mutation And Its Causes

 

In the 1860s, a French physician named J.J. Garin studied a family with eight siblings who had an unknown genetic disorder that caused bizarre behaviors and physical appearance, including facial tumors and mental retardation. In 1871 he wrote about this family in a medical journal article titled "Inherited Idiocy."

Garin hypothesized that what was causing the disorder was something passed from parents to children, but he didn't know how or why it worked. His work was largely forgotten until scientists started noticing similarities between this disorder and one called alkaptonuria (al-kap-TONE-ree-uh). People with alkaptonuria can have arthritis, heart disease, darkening of the skin, and eye problems – including the whites of their eyes turning brown. Scientists figured out that this same family might have a disorder that causes both alkaptonuria and mental retardation.

Today, we know that the cause is a genetic mutation – a change in DNA – passed from parents to children. We also know something else about this family: they all have another disorder called Ehlers-Danlos syndrome (EDS). EDS causes the tissue holding joints together to be weak and stretchy, so people with EDS can easily dislocate their joints. Although it's not clear why mutations like those seen in alkaptonuria and EDS exist, scientists know how these changes affect cells and even entire organisms: by changing proteins . A normal protein may lose some of its function, make a different kind of protein, stop working altogether, or do something we call "gain of function."

GARIN'S FAMILY AND THEIR ABILITIES

In Garin's family, some members have a mutation that changes the amino acid arginine to "stop" in position 71. This is a nonsense mutation because it makes a premature stop signal, which causes the ribosome to break down the chain early and skip over 70 amino acids. Without this chain, there are 79 fewer proteins attached to collagen fibrils in connective tissue. There are at least four kinds of collagen fibrils in connective tissue: type I (red), type II (yellow), type III (green), and type IV (blue).

Type I collagen is found several places, including skin and the lining of organs. People with EDS have weak connective tissue and can easily dislocate their joints because type I collagen is part of ligaments and tendons. But people with alkaptonuria don't seem to be bothered by this disorder. That's because those 79 missing proteins are the ones that attach types III and IV collagens to type I.

So although both disorders seem to affect different kinds of collagen, it's likely that they're doing so in a similar way: by affecting the same protein machinery – called a "collagen cross-linking complex" – which links together certain collagens at their source. The different effects on collagen result from where the mutation lies and what it changes.

Scientists also know how the change in arginine affects the RNA transcript – a string of molecules copied from DNA – that tells ribosomes to make a certain protein. This kind of change is called a missense mutation , because instead of telling ribosomes to start making a protein at a particular spot, it tells them to start earlier or later . And this can have different effects depending on where the mutation lies on the RNA transcript: if it's near the beginning, it can slow down production of proteins near those 79 missing ones; if it's near the end, it could speed up production of other proteins.

In Alkaptonuria, some mutations are associated with an increased risk of getting cancer. But whether this is true for EDS isn't known yet.

HOW GENETIC MUTATIONS WORK

Mutations are accidents that happen when DNA copies itself during cell division. If replication gets cut off or "stuck" anywhere along the way, there can be a mutation. These mutations can cause defective proteins to be made or they may even delete some parts of the gene, which could stop it from working altogether. This kind of change in our genes is called a genetic disorder.

The genes that make up our body's blueprint, found inside cells, carry information about who we are and how we work (our phenotype). Our genes consist of strands of molecules called nucleotides, paired together like rungs on a ladder. All nucleotides contain four different molecules: A (adenine), C (cytosine), G (guanine) and T (thymine). These nucleotide pairs spell out the genetic code, which tells our cells how to make proteins.

This process involves another kind of molecule called RNA, which helps transfer the information in DNA and uses it to assemble amino acids into proteins. It does this by matching up the bases in RNA with those in DNA, where each base can only pair up with its opposite: A with T, and C with G. In fact, there are three billion paired letters in our entire genetic code! Most mutations affect genes or parts of genes that control for one or more characteristics.

Genetic mutations are hereditary, which means they get passed down from parents to their children. Although some genetic disorders can be caused by environmental factors, others are inherited. Changing one nucleotide pair in the whole 3 billion-nucleotide code is enough to cause a disorder, even if it's just once in your entire life! If this happens during the creation of egg or sperm cells (meiosis), the mutation will show up in all the cells of that person's body and stay with them for their entire lives. But most changes happen during cell division, so only some of our cells have them... sometimes many years before any symptoms appear.

There are two kinds of inheritable genetic mutations: germline mutations affect genes that develop into sperm or eggs, so all of the children that person has (even if they never fulfil their genetic potential) will be affected. If these changes happen during meiosis, it's called a chromosomal mutation. Somatic mutations affect cells other than sperm and egg cells, like liver or heart cells. Only parts of our bodies that correspond to those mutated cells will show symptoms.

POPULATIONS WITH A HIGHER RISK OF GENETIC DISORDERS

Some ethnic groups have more risk factors for certain diseases; some regions also show higher frequencies of genetic disorders. For example, cystic fibrosis is way more common in people descended from northern European countries with cooler climates - not because it gets colder there, but because populations are more isolated, which makes it easier for certain genetic diseases to become common.

Epidermolysis Bullosa has a higher frequency in people from Japan, Greece and the United Kingdom. There may be less diversity in some populations, making them more vulnerable to inheritable changes. But this is true for everyone... especially since we're mixing our genes all the time! Any population changes affecting carriers of genetic disorders could also expose their children to an increased risk.

GENETIC MUTATION AND COMMON GENETIC DISORDERS

A BASE PAIRING: A (adenine) pairs with T (thymine); C (cytosine) pairs with G (guanine)

A genetic mutation is a permanent change in the sequence of nucleotides in a gene. They can be divided into two main types: base mutations and frame-shift mutations. Base mutations are changes to one type of nucleotide, while frame-shift mutations affect other kinds of nucleotide pairs. Frame-shift mutations can lead to an entirely different protein being made - causing genetic diseases like Tay Sachs disease, which destroys nerve cells and causes mental retardation. Lifestyle factors like radiation or viruses can also cause some kinds of cancer by inducing these kinds of genetic changes.

Nucleotides are molecules that form together into strands, paired off just like rungs on a ladder. The important thing is that always pair up with their opposite: A (adenine) pairs with T (thymine); C (cytosine) pairs with G (guanine). So if the nucleotide pair that usually makes up an ACGT sequence has just one of its members replaced by another AC, or GT, the gene gets disrupted.

A mutation is hereditary when it happens in someone's DNA before they are even born! Most mutations are caused by errors - mistakes! - During copying of cells. Every time a cell divides to create two new ones, this kind of error can happen. Sometimes it's because there's damage in the DNA strand being copied… so instead of an ACGT sequence being copied perfectly, one of its bases might get up. Other times there are DNA copying errors when genes are underexpressed (when there is less of the gene than it usually expects, so less copies of its product get made), or overexpressed (too many copies).

What changes in DNA can make a difference in proteins ?

-a base substitution: for example an A changing into another kind of nucleotide. This would change the sequence to ATG instead of ACGG -frameshift mutation: when nucleotides are skipped or doubled up (like adding more rungs to the ladder):  an extra C is added into the middle of an ACGT sequence, so it becomes CACGT instead -exon deletion: mutating part of a codon, so it doesn't code for amino acids anymore. The mutated exon (or part of it) gets removed along with its corresponding intron (the nucleotide sequence that used to separate them before, but is no longer needed once the mutated sequence is gone).

GENE TO DEVELOP A MUTATION

Different types of damage to DNA can cause different types of mutations - like radiation or carcinogens. But most genetic disorders are caused by random changes in the genetic material before someone's born! Most of these errors happen when sperm and egg cells are developing; some also get affected during meiosis, when sex cells divide. X-rays, exposure to chemicals or infectious diseases also have a chance of causing some mutations.

TYPES OF GENETIC MUTATIONS

There are several types of genetic mutations that affect the coding sequence. Base substitution can change one base into another or delete one completely, while frameshift mutation changes what amino acids get coded for by deleting, adding or doubling up bases within a codon (for instance this could either leave out an entire codon , or cause too many to be read). When there's an exon deletion, part of a codon is mutated so it can't code anymore - and whatever that amino acid was now gets left out of the final protein product. There are also splice mutations: these affect how the DNA strand gets cut around exons during transcription, changing the resulting mRNA sequence.

Much less commonly, there are mutations that affect regulatory sequences rather than coding regions. These changes can impact gene expression levels - for instance by making it more or less likely that the cell will transcribe a particular part of an organism's DNA.

It gets more complicated because some genes have multiple effects on their organisms' development! One example is the HOX genes, which control limb development in humans and mice. Based on where along this strand of DNA, different proteins are made at different times, these genes can affect limbs' size, shape and position... even though they're all found on one long molecule. This means you can't tell if a difference between two people with the same mutation actually came from the same gene! You'd have to know what kind of mutation it is, and how it affects the outcomes.

WHEN ARE GENETIC MUTATIONS HARMFUL?

Most genetic mutations have no effect at all, while some can be beneficial. If a change makes an organism's body work better or differently, that might give them a reproductive advantage over others - so their descendants would be more likely to pass on their genes with that change in them. Other times random DNA changes don't affect the resulting protein product... though they might alter gene expression. This can cause problems if there's no backup copy of this gene either: one faulty version means the whole thing gets shut down! In other cases both copies of a sequence get changed - these are called copy number variations. This means a person's cells only have a small fraction of the usual amount of the protein, which can lead to neurological disorders.

WHAT ARE THE IMPLICATIONS FOR MEDICINE?

Knowing about different kinds of mutations helps us figure out what caused them, and whether or not they'll impact an organism's health. We can look for places where DNA is unusually short, missing, extra or rearranged - all these often mean there was a mutation! Some other tests involve sequencing other molecules in someone's body: RNA, proteins, etc. These kinds of analyses help doctors figure out if that patient has one kind of mutation or many - and how those changes affect their development and potential to pass on disease-causing genes.

GENETIC MUTATIONS AND DISEASE

Every type of genetic mutation has its own implications for medicine. Some cause inherited diseases, like cystic fibrosis or sickle cell anemia. Others are acquired - these can be caused by immune system problems, certain medications, environmental toxins... even viruses! Sometimes mutations happen randomly without any known cause. This is why it's so important to understand how different types of disease-causing DNA changes can affect people's bodies. That way we know when someone falls into genetic risk groups that might put them at higher risk for certain conditions.

GOOD GENETIC MUTATIONS

Yes! Some mutations help us produce proteins with traits that are beneficial in the environment they evolved in. For example, in some places where malaria is common, people have mutations that make their red blood cells more resistant to the parasite. But this only gives an advantage when they're exposed to malaria - in other regions these changes would be a disadvantage!

GENETIC MUTATIONS CAUSE CANCER

Some mutations are caused by things like UV or chemical damage that can mutate DNA over time. This usually isn't enough to cause cancer though - the body has ways of repairing itself most of the time! There are several different kinds of genetic mutations that can give someone a much higher risk for developing certain types of cancer. We already know how most cancers work... so being able to see what kind of mutation causes certain ones helps us figure out how they happen, and how to fight them.

OTHER TYPES OF MUTATIONS

There are other kinds of genetic mutations that can affect what proteins a person makes. For example, if part of the DNA gets taken out or copied too many times, then the resulting gene won't produce enough protein for its job. If there's no backup copy, that failure will cause problems like growths called tumors. There are other types of changes that don't directly involve either DNA strand at all - sometimes one molecule is replaced with another, which might be similar but not identical! Lastly there are changes where parts of two different genes get switched between chromosomes (or entire sets get moved around) - these can be caused by certain viruses, and cause a variety of problems.

WHAT CAUSES GENETIC MUTATIONS?

Every kind of DNA change is caused by different things! For example, somatic mutations happen during a person's life - they're not inherited from their parents. Most are the result of environmental factors that damage DNA over time. There are also factors like spontaneous copying errors or other mistakes made when cells divide into two new ones (this happens every time someone's skin makes new cells). Finally there are mutations that can be passed on to other generations. These changes get copied when reproductive cells (eggs, sperm) form... which means these kinds will stay in all future generations too! This is how genetic diseases get passed down through families.

DIAGNOSE GENETIC MUTATION

Doctors already keep track of what kind of mutations someone has by looking at their DNA. Sometimes it can be hard to figure out exactly what causes a certain type of genetic change, so beyond that they also look at the person's symptoms. This means it's possible to have one mutation or many - and doctors might not be able remember all the details! Many diseases are caused by more than just one gene, which is part of why there can be so much conflicting information about what someone has. So it's important that patients share as much information as they can with their doctor.