Inheritance and Genetic Diseases

If the base sequence of our DNA changes, it can sometimes have a harmful effect on the organism. This is known as a gene mutation and is responsible for diseases such as cystic fibrosis and colour blindness. On this page you’ll learn about the different types of mutation and how to draw a genetic cross to predict offspring genotypes.

Mutations

A mutation is a change to the base sequence of DNA occurring when the cell makes errors during DNA replication. Since the order of bases within a gene determine the amino acid sequence (or primary structure) of a protein, a mutation can result in an altered primary structure. Primary structure then determines later stages of folding, so a mutation can result in a change to the overall 3D structure (tertiary structure) of a protein. This could result in the protein losing its function.

Types of mutation:

• Substitution - one base is replaced for another e.g. TGCCTA becomes TGACTA. It results either in a change to a single amino acid, or the amino acid might stay the same because more that one codon can code for the same amino acid (the genetic code is degenerate).

• Insertion - one or more bases is added e.g. TGCCTA becomes TGCCCTA. This type of mutation will change the codon (and perhaps the amino acid) and all following codons (this is called a frameshift).

• Deletion - one or more bases is removed e.g. TGCCTA becomes TGCTA. Deletion mutations will change the codon at the point of mutation and all following codons, resulting in a frameshift.

• Inversion - a sequence of bases is reversed e.g. TGCCTA becomes TGCATC. It will result in a change to a single amino acid.

Some mutations can have a neutral effect on a protein’s function. This could be because:

• The mutation changes a base in a triplet but the amino acid that the triplet codes for doesn’t change. This happens because some amino acids are coded for by more than one triplet (the genetic code is degenerate).

• The mutation produces a triplet that codes for a different amino acid but the amino acid is chemically similar to the original so it functions like the original amino acid.

• The mutated triplet codes for an amino acid not involved with the protein’s function e.g. one that is located far away from an enzyme’s active site, so the protein works as it normally does.

However, some mutations will have an effect and it could be beneficial or harmful to the organism. An example of a beneficial mutation is antibiotic resistance in bacteria (from the bacteria’s perspective). The mutation would allow it to survive in the presence of the antibiotic whereas it would have previously been killed. Other mutations will have harmful effects, such as the mutations which cause cystic fibrosis or cancer.

Linked genes

The position of a gene on a chromosome is called its locus. If the loci of two different genes are on the same chromosome, they are likely to be inherited together and are said to be linked. The only way that the genes will not be inherited together is if crossing over separates them during meiosis (the chiasmata would have to form between the two genes). The closer the loci of the two genes, the less likely this is to happen and the higher the probability that the genes will be inherited together. This means that any offspring will probably express both phenotypes together than either phenotype separately.

The image below shows an example of gene linkage in rats. If the genes for coat colour and eye colour are located on the same chromosome, they will be inherited together and the offspring will show both phenotypes together. For example, there will be rats with both black fur and red eyes, and with both brown fur and white eyes but not many with black fur + white eyes (or likewise, brown fur + red eyes). To get these combinations of phenotypes, crossing over must have occurred between the homologous chromosomes to cause the alleles to end up on the same chromosome and be inherited together.

Sex Linkage

Genes which are located on one of the sex chromosomes (X or Y) are said to be sex-linked and their expression will depend on whether the offspring is male (XY) or female (XX). The Y chromosome is much smaller than the X chromosome, so most alleles are carried on the X chromosome (they are X-linked). Men only have one X chromosome which means that they will only inherit one allele for these genes, compared to women who will inherit two. This means that if men inherit a recessive allele (which causes disease) for a gene found on the X-chromosome, they will have the disease. Women who inherit the recessive allele will just be a carrier, since they have another X chromosome with the dominant, functioning allele. For women to have X-linked diseases, they must inherit two disease alleles (they will have a homozygous recessive phenotype). Examples of sex linked disorders include haemophilia and red-green colour blindness.

Monogenic vs polygenic characteristics

Characteristics which are controlled by the expression of a single gene are said to be monogenic. These kinds of characteristics typically give rise to discontinuous variation in the phenotype that is expressed - i.e. the phenotypes can be grouped into distinct categories. An example of a characteristic controlled by a single gene is blood type.

However, the majority of characteristics are controlled by many genes at different loci - they are polygenic. Polygenic characteristics show continuous variation which is when the individuals in a population vary within a range. Examples of characteristics which show polygenic inheritance are height, weight and skin colour.

Genetic diagrams

Monohybrid inheritance is the inheritance of characteristics controlled by a single gene. We can predict the characteristic in the offspring for this type of inheritance using Punnett squares. The parent gametes are written on the side, with the genotypes of possible offspring in the centre.

If the dominant P allele produces purple flowers and the recessive p allele produces white flowers, then we can see that breeding two heterozygous individuals will produce offspring with a 3:1 ratio of purple flowers to white flowers. This 3:1 ratio between the dominant phenotype and the recessive phenotype will always be seen in the offspring of two heterozygotes.

Pedigree Charts

Pedigree charts show how genetic characteristics are passed on through generations. They are used by medical professionals to determine the probability of a family member inheriting a genetic disease. Different symbols are used for male, female, healthy and diseased individuals. Horizontal lines show two unrelated individuals who have reproduced, with the vertical lines representing their offspring. In this pedigree chart, you can see that individuals 1 and 2 have had five children (individuals 3, 5, 7, 8 and 10).

We can use these charts to work out the genotypes of each individual. Since the affected father (individual 1) only passed on the disease to some of his children, we know that he must also have one healthy allele to pass onto his offspring, therefore he must be heterozygous. This means that the diseased allele must be dominant over the healthy allele, therefore all of the healthy individuals will have a homozygous recessive phenotype.

Cystic Fibrosis

Cystic Fibrosis is a genetic disorder that results from inheriting two recessive alleles. It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein which plays a role in transporting chloride ions out of the epithelial cells lining the trachea. In healthy people, CFTR plays an important role in making mucus thin and watery, since the transport of chloride ions decreases the water potential of the mucus lining the trachea, stimulating the movement of water by osmosis. Mutations in the CFTR protein means that water doesn’t move into the trachea, making the mucus thick and sticky. This thick mucus can clog up tubes in our respiratory, digestive and reproductive systems.

• Respiratory system - in healthy people, mucus traps bacteria which is moved into the stomach by the sweeping motion of cilia lining the trachea, where the bacteria-filled mucus will be destroyed by the stomach acid. In people with cystic fibrosis, the cilia cannot move the thick, sticky mucus. It builds up and blocks passages of the airways, reducing the surface area available for gas exchange and making it more difficult to breath. The bacteria inside the mucus can reproduce, leading to lung infections. People with cystic fibrosis can be given antibiotics to kill the bacteria inside the mucus lining their airways. They can also have physiotherapy to help to dislodge the mucus and facilitate gas exchange.

• Digestive system - in people with cystic fibrosis, mucus can also build up and cause blockages in the tube which connects the pancreas to the small intestine. This prevents digestive enzymes being secreted into the small intestine, making food digestion less efficient. The presence of thick, abnormal mucus can stimulate the growth of cysts in the pancreas, which also inhibits production of digestive enzymes.

• Reproductive system - abnormally thick mucus in men can cause blockages in the tubes which connect the testicles to the penis, preventing the passage of sperm. In women, thick mucus in the cervix can prevent sperm from reaching and fertilising the egg, resulting in reduced fertility.

Genetic Screening

Genetic screening can be used to check whether an individual is a carrier of a recessive allele which causes disease (such as the cystic fibrosis allele), or to check unborn fetuses for genetic abnormalities.

Checking whether an individual is a carrier

If an inherited recessive disorder, such as cystic fibrosis, runs in your family as well as your partners’, you may want to have your DNA checked to determine whether you are both carriers of the cystic fibrosis gene (which means there would be a 25% chance of having a child with cystic fibrosis). If both individuals find out that they carry the disease allele, they may want to undergo prenatal testing to make an informed decision about whether or not to have the child.

There are ethical and social issues with DNA testing, for example, the results are not 100% accurate - a false positive means unnecessary stress and may lead to a couple choosing not to raise children whereas a false negative may mean that the mother gives birth to a child with cystic fibrosis without being emotionally or financially prepared. The DNA test may discover other DNA abnormalities, such as a mutation in a gene which leads to breast cancer, which can cause further stress. Finally, there is a concern that life insurance companies or employers may use the results to discriminate against people with certain genetic disorders.

Prenatal testing

Prenatal testing involves testing the DNA of an unborn fetus while it is still growing in the mother’s womb. An expectant mother may choose to have prenatal testing if she thinks that the baby is at risk of a particular genetic disorder. There are two types: amniocentesis and chorionic villus sampling (CVS). If the tests indicate a positive result, the couple may either choose to undergo an abortion or to keep the child (in which case they have time to prepare themselves mentally and financially). There are ethical issues associated with this - many people feel it is unethical to abort a fetus due to a genetic disorder. Also, both methods involve a risk of miscarriage, so there is a small chance of the baby dying (regardless of whether is has a genetic abnormality).

Amniocentesis - this technique involves testing fetal DNA by taking a sample of amniotic fluid. This is done by inserting a long, fine needle through the abdomen. It is carried out during weeks 15-20 of pregnancy and there is a 1% chance of miscarriage as a result of the procedure. Results are not available until 2-3 weeks after the sample has been taken.

Chorionic villus sampling - this technique involves taking a sample of the placenta using a needle which is inserted either through the abdomen (transabdominal) or through the vagina (transvaginal). It is carried out during weeks 11-14 of pregnancy and there is a 1-2% risk of miscarriage. Results can be available just a few days after the procedure is carried out.

Since CVS can be carried out at an earlier stage in the pregnancy, and the results are available sooner, this means that if the couple decide to abort the child then the abortion will be less physically (and emotionally) traumatic since the fetus is less developed. However, CVS results in a slightly higher increase in miscarriage. Couples will have conversations with a medical professional about the pros and cons of each of these methods before making an informed decision about which type of genetic test to have.

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