A de novo mutation is a newly present mutation in an individual organism. These may occur in gametogenesis due to a germline mutation in a parent, or as a postzygotic mutation.
Types
Single-nucleotide polymorphism Single-nucleotide polymorphisms occur when a single nucleotide base is altered within the DNA sequence. They are one of the most common forms of genetic variation and occur when one is substituted for another. There are three types of point mutations; silent mutations, missense mutations and nonsense mutations.
Silent mutation
A silent mutation occurs when a change in the nucleotide sequence does not lead to a change in the protein product. This is likely due to alteration in the 3rd coding causing redundancy. For example, the codon CUA is mutated into CUG; which still codes for leucine, therefore not making any impact towards protein function. Even if silent mutations do not impact the overall function of the protein, they are still considered de novo if they arose spontaneously, which tends to be the case in an individual's genome.
Missense mutation
A missense mutation occurs when a single nucleotide change leads to a substitution of an amino acid for another. Depending on the significance of placement, the missense mutation may be beneficial or harmful.
Nonsense mutation
A nonsense mutation causes a premature stop codon in the nucleotide sequence, which leads to a discontinuation of protein synthesis for that transcript. De novo nonsense mutations often result in genetic disorders or severe developmental conditions. A common example of de novo nonsense mutation occurs in the CFTR gene, potentially leading to cystic fibrosis. Essentially what happens is it causes a stop to the production of CFTR protein, thus leading to a build up of mucus in the organs. The most common nonsense mutation in CFTR is delta F508 but there can be others as well. This typically occurs within the germline, or early in embryonic development.
Indels (insertion/deletions) Indels are genetic mutations which consist of two categories, insertions and deletions. Insertions are where one or more nucleotides are added, while deletions are when one or more nucleotides are removed from the sequence.
While similar, frameshift mutation is a specific type of indel where the amount of nucleotides added or deleted is not in a multiple of three codons. This is because each amino acid is made up of three codons, thus removing or adding three codons will only remove/add a singular amino acid. However, having one or two nucleotides inserted/deleted will cause not only that amino acid to change but also all the ones moving forward, resulting in a shift in the entire genetic code. The consequences of a frameshift are more severe and often lead to early termination of translation aka a nonsense mutations can arise spontaneously during DNA replication or repair, particularly in regions of the genome that are repetitive or prone to errors. When an indel occurs in a germ cell (egg or sperm), it can be passed down to the offspring as a de novo mutation, leading to the development of genetic conditions that were not present in the parents' genetic profiles.
An example of a frame shift is Huntington's disease, where a de novo insertion or deletion of a single nucleotide can impact the CAG trinucleotide repeat. This can result in heavy neurodegeneration and psychiatric symptoms. These symptoms include uncontrolled movements, emotional problems, and loss of thinking ability (cognition).The individuals have trouble walking, speaking and swallowing.
Frameshift mutations can occur as de novo mutations in both prezygotic and postzygotic stages of development. For example, if a frameshift mutation occurs during the formation of sperm or egg cells (prezygotic), it can result in a genetic disorder in the offspring, even though neither parent shows signs of the mutation.
A de novo frameshift mutation could result in a disorder like Tay–Sachs disease, where the HEXA gene undergoes a frameshift due to an indel. This mutation causes an altered enzyme that leads to the buildup of lipids in nerve cells, causing progressive neurological damage. As the disease progresses, children experience developmental regression, and by age 2 or 3, affected children often experience severe cognitive and motor decline. Most children with Tay–Sachs disease die by the age of 4 or 5 due to complications related to the disease, often respiratory failure or infections.
Copy number variants Copy number variants are de novo mutations where large segments of DNA are duplicated or deleted. In comparison to single nucleotide variants, copy number variants usually impact large regions of the genome, thus gaining or losing this can significantly impact the cell dosage. Like many they can arise from DNA replication, recombination or through repairing double stranded breaks in the DNA.
The most prone locations of copy number variants occurrence are where the genome is rich in repetitive sequences as its more likely for DNA mechanisms to get confused and thus misaligned during replication. This leads to unequal crossing over between homologous chromosomes, resulting in some regions having extra copies while others lose some.
These types of errors can occur pre zygotically, prior to fertilization in the germ cells, or postzygotic ally in early embryonic development. When mutations occur in de novo they can result in rare genetic disorders even for individuals who have no previous family history of the condition. This highlights how spontaneous genetic changes can lead to complex diseases, ultimately contributing to human genetic diversity. Depending on where, some can be harmless while others can impact critical genetic processes.
Genetic disease example
An example of a de novo copy number variants include autism spectrum disorder. Many cases of autism are linked to de novo copy number variants, particularly small deletions and duplications in the 16p11.2 chromosomal region. Individuals with deletions exhibit developmental delays, while individual duplication tends to have problems with coordination of speech and motor skills.
Another example is schizophrenia where studies have shown that rare de novo copy number variants result in large deletions or duplications of DNA. These often disrupt genes involved in brain development affect the synaptic and neuronal development, suggesting that genetic disruptions in neural pathways contribute to the increase risk of schizophrenia. Schizophrenia is a severe mental disorder that impacts a person's thinking, emotions, and behavior. Symptoms may include hallucinations, delusions, disorganized thoughts, and negative effects such as lack of motivation and social withdrawal.
DiGeorge syndrome is a result of a de novo deletion of a portion of chromosome 22, leading to disabilities, immune system abnormalities and congenital heart defects. Alongside these issues, individuals may experience cleft palate, distinctive facial features (such as low-set ears or a small jaw), feeding difficulties, kidney problems, and low calcium levels due to endocrine dysfunction. Muscle tone may be reduced (hypotonia), and learning difficulties are common. As individuals grow older, there is also an increased risk of mental health conditions such as anxiety, ADHD, and even schizophrenia. The severity and combination of symptoms can vary widely from person to person.
Charcot–Marie–Tooth disease leads to nerve damage due to de novo duplication of PMP22 Gene. The PMP22 gene is important for building and maintaining the myelin sheath, the fatty coating that wraps around nerves and helps them send signals quickly and efficiently. Without it, nerve communication can slow down or get disrupted.
Chromosomal arrangements Large parts of the chromosome are deleted, duplicated, indeed or exchanged between non-homologous chromosomes. Like other types of mutations, errors can occur spontaneously during meiosis (in the germline and can be passed onto offspring) or early embryonic development (will not be passed onto offspring). Chromosomal rearrangement is due to random mistakes in the DNA repair mechanism when the cell attempts to fix a double stranded break. Some key processes include non-homologous end joining (NHEJ), non-allelic homologous recombination (NAHR), or the breakage-fusion-bridge cycle.
Non-homologous end joining (NHEJ)
In the non-homologous end joining (NHEJ), This mechanism joins broken DNA ends without a template, which can lead to chromosome fusions, deletions, or insertions. This mechanism is not the most accurate causing random mutations to appear. An example is chronic myeloid leukemia. NHEJ errors lead to translocations between chromosome 9 and 22, forming a BCR-ABL fusion. This fusion causes uncontrolled growth of white blood cells, causing leukemia.
Non-allelic homologous recombination (NAHR)
The second mechanism, non-allelic homologous recombination (NAHR), occurs when DNA sequences that are highly similar but in different locations (such as repetitive regions) mistakenly recombine, causing structural variations like deletions or duplications. A common example is DiGeorge syndrome, where position 11.2 of the q arm is spontaneously deleted.
Breakage fusion cycle (BFB)
Lastly the breakage-fusion-bridge cycle (BFB) occurs when chromosome ends fuse after a break, leading to cycles of Chromosome with a broken end fuses with another chromosome, leading to repeated arrangements and lack of stability, similar to cancer. An example of this is osteosarcoma also known as bone cancer. It is caused by large chromosomal rearrangements causing a MDM2 amplification on the q arm of chromosome 12, which inhibits TP53 gene (a crucial tumor suppressor), resulting in rapid growth of a bone tumor.
Prezygotic vs postzygotic de novo mutation
Prezygotic de novo mutation Prezygotic de novo mutations are those that arise in the sperm or egg cells before fertilization, meaning that the mutation is passed on to all cells in the resulting embryo and, ultimately, the individual. Note that this mutation is not inherited from the parents, although since it spontaneously arises pre zygotically, it can be passed on from the person who acquired it to the offspring. These mutations typically occur during the formation of gametes, when DNA is being replicated and divided during meiosis. As gametes undergo division and genetic material is prepared for fertilization, errors can happen that result in mutations being carried into the zygote.
Schizophrenia
Schizophrenia is a complex psychiatric disorder influenced by both genetic and environmental factors. As men age, their sperm cells undergo numerous divisions, raising the likelihood of replication errors and subsequent de novo mutations. Studies have shown that individuals with sporadic (non-familial) schizophrenia tend to have fathers who are, on average, older than those with a familial history of the disorder. This suggests that de novo mutations arising in the sperm of older fathers may elevate the risk of schizophrenia in their children.
Achondroplasia
Achondroplasia is a rare genetic condition that is the most common type of dwarfism. Approximately 80% of mutations that occur in the fibroblast growth factor receptor 3 (FGFR3 gene) that primarily cause this condition, are de novo. The mutations in FGFR3 gene follows an autosomal dominant inheritance pattern. This leads to over activation, which causes inhibition of chondrocyte proliferation. This would ultimately lead to abnormal bone growth that causes limbs to shorten and other skeletal abnormalities.