Next Lesson - Gene Expression
Core
Our genotype, put simply, is the sum total of all our genes, encoded by DNA. Our phenotype is the physical manifestation of our genotype via proteins. For example, the human blood types are encoded by the ABO gene (named after blood groups A, B and O) found on chromosome 9 (genotype). When translated, the gene makes an enzyme that adds sugars to the surface of red blood cells. These sugars form the A and B antigens, which decide the blood type (phenotype).
It is important to note that other genes and the environment also affect our phenotype. Very few genotypes always lead to the same phenotype. Classic familial adenomatous polyposis (FAP) is one example. Hundreds to thousands of polyps (small growths) form in the colon, and bowel cancer is inevitable unless the colon is removed. Most genotypes have a weaker effect. For example, a harmful mutation in the BRCA1 gene (a gene whose protein helps to repair DNA) greatly increases a woman's risk of breast cancer. In a large 2017 study of women with BRCA1 mutations, the risk of breast cancer by the age of 80 was 72%. The 95% confidence interval was 65% to 79%, which is the range in which the true figure probably lies. However, as this risk is not 100% (that is, BRCA1 does not always lead to cancer), other genes and the environment must also play a part.
Humans have about 20,000 genes that code for proteins, and we typically have two copies of each gene. The two copies of a gene may be the same or through random mutation may be ever so slightly different. Different versions (variants) of the same gene are called alleles. We inherit one half of our nuclear DNA (the DNA in the cell nucleus) from our mother and one half from our father. This gives us two sets of genes, so for a given gene we may inherit different alleles. Mitochondrial DNA is the exception: it is almost always inherited from the mother alone (see below).
For a particular gene, an individual can be described as homozygous (both the allele from the mother and the father are the same) or heterozygous (both alleles are different). The third category is hemizygous (only one copy of a gene is present). Males are hemizygous for genes on the X chromosome, as they have only one X chromosome. Females usually have two X chromosomes, so they usually have two copies of each X-linked gene. A female with Turner syndrome (who has only one X chromosome) is also hemizygous for X-linked genes.
In a heterozygote, the dominant allele determines the phenotype. The other allele, which is masked, is called recessive.
In some cases, for example the ABO gene, both alleles in a heterozygote can affect the phenotype. This is known as co-dominance.
Figure: Blood Group Transfusion Table
SimpleMed original by Dr. Joshua Sturgeon
Please note that, in reality, a protein called Rhesus Factor also helps to decide a person’s blood type. A person can be Rhesus Factor positive (+) or negative (-). This is beyond the scope of this article (see our haematology section). Just appreciate that O negative (O-) donors are known as ‘universal donors’ because anyone can receive their red blood cells. For this reason, O negative red blood cells are used in an emergency when the patient’s blood group is unknown.
There are three main alleles of the ABO gene: IA, IB and IO. IA is dominant over IO. IB is also dominant over IO. However, neither IA nor IB is dominant over the other: they are co-dominant. This co-dominance allows us to have the blood type AB. IO is the only one of these three alleles which is recessive.
Figure: Possible Genotypes for Blood Groups
SimpleMed original by Dr. Joshua Sturgeon
Figure: Pedigree Key
SimpleMed original by Dr. Joshua Sturgeon
A pedigree is a family tree chart that shows who in a family is affected by a condition. It is drawn using the symbols shown above. Each generation is placed on a separate line, each of which is numbered with a roman numeral. When drawing a generation of offspring, it is convention to have the oldest offspring on the left hand side. Within a generation, each individual is numbered from left to right. An example of how to interpret a pedigree chart is shown below.
Figure: Example Pedigree Chart. All members of generations I and II are deceased. The relations of III.17 are: wife III.18, parents II.1 and II.2, a sister III.3, and a niece IV.1. III.17 is genetically unrelated to III.4 and III.5, and to III.13 and III.14, and is therefore genetically unrelated to their respective offspring.
SimpleMed original by Dr. Joshua Sturgeon
Being able to interpret or even draw a pedigree chart from a given family history is a useful skill to have. It is crucial to be able to work out the inheritance pattern of an unknown disease from a pedigree chart.
- Autosomal (carried on chromosomes 1-22 i.e. non sex chromosomes)
- Autosomal Recessive
- Autosomal Dominant
- Sex-linked
- X-linked Recessive
- X-linked Dominant
- Y-linked
- Mitochondrial (inherited through mitochondrial DNA)
- Polygenic/Complex (many genes) or Multifactorial (genes and the environment)
We will go into explanations for the above inheritance patterns, along with Punnett squares (grids that show the possible genotypes of offspring) and pedigree charts below.
For an individual to be affected with an autosomal recessive disease, they must be a homozygous recessive (carrying two recessive alleles for the disease gene). Heterozygotes are unaffected as they have a dominant allele, but they are known as carriers (people who have one copy of the altered gene but do not have the condition). If two heterozygous carriers reproduce, each parent has a 50% chance of passing on the recessive allele, giving a 25% chance that the child will be affected. If both parents are homozygous for the same recessive allele, all of their children will be affected. Males and females are equally affected. An example of an autosomal recessive disease is Cystic Fibrosis.
Figure: A Punnett square showing autosomal recessive inheritance with two heterozygotes. Note that there is a 25% chance of the offspring being affected by the disease
SimpleMed original by Dr. Joshua Sturgeon
Figure: Autosomal Recessive Pedigree Chart (Carriers Not Shown)
SimpleMed original by Dr. Joshua Sturgeon
An autosomal recessive disease can appear to a patient’s family to ‘come out of nowhere’. The disease can also skip generations. The key above has icons for carriers, but a pedigree may not always show them. Many people do not know that they carry the gene, so carriers are often missing from a family history. This makes it a little harder to determine the pattern.
For a person to suffer from an autosomal dominant disease, they only need one allele (heterozygous). The disease is rarely found in a homozygous state, potentially due to the increased morbidity associated with being a homozygote for an autosomal dominant disease. If an affected person has one altered copy of the gene and an unaffected partner, each child has a 50% chance of being affected. Males and females are affected equally. An example of an autosomal dominant disease is Huntington’s disease (an inherited condition that affects movement, thinking and mood, and gets worse over time).
Figure: Autosomal Dominant Punnett Square
SimpleMed original by Dr. Joshua Sturgeon
Figure: Autosomal Dominant Pedigree Chart
SimpleMed original by Dr. Joshua Sturgeon
One of the major differences between autosomal recessive and autosomal dominant in a pedigree chart is that autosomal dominant conditions usually affect successive generations. In some cases, reduced penetrance (when not everyone who carries the altered gene develops the condition) can make a condition appear to skip a generation.
An important point to note is that for an autosomal dominant condition to be passed on (as with any inherited condition), the affected person must survive to reproductive age. For example, if an autosomal dominant condition is lethal by the age of 5, it can’t be passed on. Huntington’s disease is notable because, although it is lethal, symptoms usually start between the ages of 30 and 50 (but can start at any age). This means that a person can have had children before symptoms start, so the altered gene may already have been passed on. Each child of an affected parent has a 1 in 2 (50%) chance of having the altered gene and developing the disease.
X-linked diseases refer to diseases for which genes are carried on the X chromosome. Therefore, females (XX) usually need two copies of the recessive allele (they must be homozygous), whereas a male needs only one (he is hemizygous). A female with one copy is usually unaffected or only mildly affected. As males have one X and one Y chromosome, males are much more likely to be affected by these diseases. Each son of a heterozygous female carrier has a 50% chance of being affected, and each daughter has a 50% chance of being a carrier. Affected males cannot pass the altered X chromosome to their sons, because a son inherits his father’s Y chromosome and his mother’s X chromosome. They pass it to all of their daughters, who become carriers. An example of an X-linked recessive disease is Haemophilia A (a bleeding disorder caused by a lack of a clotting factor, a protein that helps blood clot).
Figure: X-linked Recessive Punnett Square
SimpleMed original by Dr. Joshua Sturgeon
Figure: X-linked Recessive Pedigree Chart (Carriers Shown)
SimpleMed original by Dr. Joshua Sturgeon
The above pedigree chart shows that males and females are unequally affected. An affected male usually has a mother who is a carrier or affected. An affected female usually has an affected father and a mother who is a carrier or affected. There are rare exceptions. For example, about one in five cases of haemophilia A is thought to be due to a new mutation, so the family may have no earlier history of the condition.
X-linked dominant diseases affect hemizygous males and heterozygous females. Each child of an affected heterozygous female has a 50% chance of being affected. An affected male cannot give the trait to his sons but will give it to all his daughters. X-linked dominant diseases are uncommon compared with autosomal inheritance patterns. An example is X-linked hypophosphataemic rickets (XLH), a condition in which the blood phosphate level is low, which can cause bowed legs and other bone problems. In XLH, males and females are similarly affected. Some X-linked dominant conditions are different: male embryos with the altered gene usually miscarry, so the condition is seen mainly in females. An example is incontinentia pigmenti, a condition affecting the skin, hair, teeth and central nervous system.
Exam tip: X-linked dominant conditions are uncommon. Although it is important to know their inheritance pattern, when you analyse a pedigree, check whether more common patterns (see above) fit before you consider rarer ones. 
Figure: X-linked Dominant Punnett Square
SimpleMed original by Dr. Joshua Sturgeon
Figure: X-linked Dominant Pedigree Chart
Creative commons source by Hydra2114 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
Only males have a Y chromosome, so Y-linked diseases only affect males. A Y-linked mutation can only be passed from father to son. The Y chromosome contains genes which drive normal male development, such as the SRY gene (the gene that makes a fetus develop as a male). As there is only one Y chromosome in males, Y-linked traits are usually described without using dominant or recessive terminology, as any functional allele present is expressed. It is worth noting that Y-linked conditions are uncommon, because the Y chromosome carries few genes that code for proteins (an estimated 70 to 200), so there are few examples to study in the medical literature. An example of a Y-linked condition is Y chromosome infertility. Small deletions (missing pieces) of the Y chromosome in areas called azoospermia factor (AZF) regions affect sperm production, so sperm develop abnormally or do not develop at all (azoospermia means that no mature sperm cells are found in the semen). This makes it difficult or impossible to father children. An affected man can pass a deletion to his sons if he has children by ICSI (intracytoplasmic sperm injection, in which a single sperm is injected into an egg).
Figure: Y-linked Punnett Square
SimpleMed original by Dr. Joshua Sturgeon
Figure: Y-linked Pedigree Chart
Public Domain Source
Mitochondria contain DNA (mtDNA) which is used to encode proteins for the oxidative phosphorylation step of respiration. mtDNA is almost always inherited from the mother alone, because the egg cell supplies the mitochondria of the developing embryo and any mitochondria that enter with the sperm are normally destroyed. Very rarely, mtDNA from the father has been passed on. A mutation in mtDNA can affect the proteins needed to generate the large amount of ATP that cells need. This can lead to mitochondrial diseases.
Mitochondrial donation, sometimes called the ‘three parent baby’ technique, can reduce the risk of passing on an inherited mitochondrial disease. Healthy mitochondria from a donor egg are combined with the nuclear DNA of the mother and father, so the baby is still their biological child. Parliament made mitochondrial donation legal in the UK in 2015, and each request must be approved by the HFEA (Human Fertilisation and Embryology Authority, the UK fertility regulator). In 2025, a Newcastle team reported 8 live births after pronuclear transfer. In this technique, the nuclear DNA of the mother’s fertilised egg is moved into a fertilised donor egg that has had its own nuclear DNA removed. Read the BBC News report of the first baby born using spindle transfer (2016). In this related technique, the nuclear DNA of the mother’s unfertilised egg is moved into a donor egg that has had its own nuclear DNA removed, and the egg is then fertilised.
So far, we have only discussed traits which are caused by one gene. However, in reality more than one gene is usually involved in producing a phenotype, such as height or skin colour (shown below). Traits caused by many genes are called polygenic. Traits that depend on both genes and the environment are called multifactorial.
Figure: To demonstrate how multiple genes can have an influence on one phenotype
SimpleMed original by Dr. Joshua Sturgeon
Gene linkage is the tendency of genes that lie close together on the same chromosome to be inherited together. The closer two genes are, the more likely they are to be inherited together. During meiosis (the cell division that makes eggs and sperm), crossing over can swap parts of a chromosome with its homologous partner (the matching chromosome from the other parent). This swapping is called recombination. Genes that are close together are less likely to be separated by recombination, so they are ‘linked’. Genes on separate chromosomes, or far apart on the same chromosome, are not linked. Genes on separate chromosomes are inherited independently, and genes far apart on the same chromosome are usually separated by crossing over.
If you are struggling to understand gene linkage, don’t worry. Just remember that genes close together on the same chromosome tend to be inherited together, which makes it harder to predict the genotypes of offspring.
Exam Tip:
If an inheritance question is difficult, highlight the genotypes or phenotypes given in the question. Then use them to draw a Punnett square. This will allow you to easily calculate the probabilities of different offspring genotypes. This approach can even be used if you are asked to interpret a pedigree chart and determine the pattern of inheritance.
Another good rule to remember: if a question about a dominant condition does not state the parents’ genotypes, assume that an affected parent is heterozygous (has one altered copy of the gene). Also assume that an unaffected parent does not carry the altered allele, unless the question mentions reduced penetrance (see above).
Reviewed by: Dr. Marcus Judge
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