Increased mutations in children can be traced back to errors in the father’s sperm

summary: Excessive mutation in children may be related to increased mutations in the biological father’s sperm, especially fathers who received certain forms of chemotherapy to treat cancer early in life.

source: Wellcome Sanger Institute

A new study has found that some rare cases of high rates of genetic mutations in children, known as hypermutation, could be linked to the father receiving certain chemotherapy treatments.

Scientists from the Wellcome Sanger Institute and their collaborators analyzed more than 20,000 families of genetic information and identified 12 children with mutations two to seven times more than the general population.

The team linked the majority of these mutations in the biological father’s sperm.

Research published today in temper natureshows that just under half of these fathers were treated with certain types of chemotherapy early in life, which could be linked to an increased number of mutations in their sperm cells.

While such hypermutations in children are rare, and in the vast majority of children will not lead to genetic disorders, hypermutation will increase a child’s risk of developing a rare genetic disorder. It is important to investigate this further because of its implications for patients who are receiving chemotherapy and want to have children in the future.

If additional research confirms the effect of chemotherapy, patients could be given the opportunity to freeze their sperm before treatment.

Genomes are transcribed at a very low error rate when passed from generation to generation. However, since the human genome contains three billion letters, random mutations in the sperm and egg are inevitable and are passed from parent to child. This means that each child usually has about 60 to 70 new mutations that their biological parents do not have.

These mutations are responsible for genetic variation along with many genetic diseases. About 75 percent of these random mutations come from the father.

Most genetic disorders occur only when both copies of an important gene are damaged, resulting in what is known as a recessive disease. If only one copy is damaged, for example, by a new mutation, the remaining working copy of the gene will be able to prevent the disease.

However, a minority of genetic disorders, known as dominant disorders, occur when only one copy of a gene is damaged. These dominant disorders are those that can be caused by a single random mutation.

One of the main factors influencing the mutation rate is the age of the parents, with mutations increasing by 1.3 mutations per year in fathers and 0.4 mutations per year in mothers. If there are more germline mutations, there is a greater risk of giving birth to a child with a dominant disorder.

However, being hyperactive in children does not always mean that they have a dominant disorder.

In new research, from the Wellcome Sanger Institute and collaborators, scientists used genetic data and family health history from existing databases to identify children with unusually high mutation rates, between two and seven times higher than average, to verify their source. .

The team analyzed data from more than 20,000 British families with children suspected of having genetic conditions and participated in deciphering developmental disorders and 100,000 genome projects.

They found that hyperactive children are rare among these families. Since the number of children with hypermutation was only 12 out of about 20,000, these increased mutation rates cannot be caused by common exposures, such as smoking, pollution or common genetic variation.

For eight of these children, the excess mutations could be linked to their father’s sperm. It was possible to investigate in detail seven of the families, in which the excess mutations came from the biological father. Two of the parents had rare recessive genetic variants that impair DNA repair mechanisms.

The other five men had previously been treated with chemotherapy before having a baby. Three of these children had a pattern of mutations characteristic of chemotherapy with platinum-based drugs, and the parents of the other two children received chemotherapy with alkylating agents derived from mustard.

However, by correlating the genetic data with anonymized health data, it can be shown that most parents who received chemotherapy before pregnancy did not have children with marked excess mutations.

This study exemplifies the value of linking nationwide genomic data and routine clinical records in safe, anonymous and trustworthy ways to provide unique insights into unexpected but important questions.

Through the efforts of Health Data Research UK and its partners, it will be easier to conduct these types of responsible analyzes of potential clinical relevance in the future.

While chemotherapy is one of the most effective treatments for cancer, it is widely known that it can have devastating and debilitating side effects. Doctors take these things into account when prescribing this treatment.

If these types of chemotherapy are shown to affect sperm in some patients, this could have clinical implications for treatment and family planning plans.

More research is needed to investigate this at a deeper level before changing cancer treatment in men. It’s currently not clear why these types of chemotherapy affect sperm more than egg cells.

“Excessive mutations in children, where they have between two and seven times more random mutations than the general population, is rare and therefore cannot be a common cause,” said Dr. Joanna Kaplanis, first author and postdoctoral fellow at the Wellcome Sanger Institute. carcinogen or exposure.

“Our research analyzes more than 20,000 families and highlights new causes for these mutations, linking them back to germline mutations in paternal sperm as well as identifying a new mutational signature.

“Understanding the effect of germline mutations in sperm can help us reveal why some people are more likely to have children with such high rates of random mutations, and help protect against these mutations if they cause disease.”

see also

This shows a diagram of the head of a man and a woman surrounded by cogwheels

John Danish, Director of HDR UK Cambridge, who supported the research, said, “Children hyperactivity is an uncommon but important phenomenon that increases the risk of life-altering genetic diseases. By collecting large-scale genetic data, linking them to routine clinical data such as hospital records for parents The team identified new risk factors that may influence future health care decisions.

This work elegantly illustrates how work at Health Data Research UK’s Understanding Aetiology is helping to connect nationwide genetic data and clinical records in safe, anonymous and trustworthy ways that provide unique insights into unexpected but important questions. “

This shows the sperm and the egg
If additional research confirms the effect of chemotherapy, patients could be given the opportunity to freeze their sperm before treatment. The image is in the public domain

Sir Mark Caulfield, of Queen Mary University of London and former chief scientist at Genomics England, said: ‘These findings were only possible due to access to whole genomes and health record data associated with family members from the 100,000 Genomes Project. These findings could help people with cancer to think in family planning.

Professor Matthew Herlis, senior author and chair of human genetics at the Wellcome Sanger Institute, said: “Chemotherapy is a very effective treatment for many types of cancer, but unfortunately it can have some adverse side effects. Our research found a plausible link between two types of chemotherapy and their effect. on sperm in very few men.

“These findings require further systematic studies to see if there is a causal relationship between chemotherapy and sperm mutants, and whether there is a way to identify individuals at risk prior to treatment so that they can take family planning measures, such as freezing sperm prior to treatment.”

“I would also like to thank the families who donated their genetic and health information to make this research possible.”

About this genetic research news

author: press office
source: Wellcome Sanger Institute
Contact: Press Office – Wellcome Sanger Institute
picture: The image is in the public domain

original search: open access.
Influences of genetics and chemotherapy on germline hypermutationWritten by Matthew Herlis et al. temper nature


a summary

Influences of genetics and chemotherapy on germline hypermutation

Mutations in the germline generate all developmental genetic variations and are a cause of genetic diseases. Parental age is the primary determinant of the number of new germline mutations in an individual’s genome.

Here we analyzed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 individuals with hypermutated genomes with two to seven times more single-nucleotide de novo variants than expected. In most families (9 out of 12), the extra mutations came from the father.

Two families had genetic drivers of germline hypermutation, with parents carrying deleterious genetic variation in DNA repair genes. For five of the families, paternal exposure to chemotherapeutic agents prior to conception was probably the main driver of hypermutation.

Our results indicate that the germline is well protected from mutational effects, hypermutation is rare, the number of excess mutations is relatively modest, and most individuals with a hyperstimulated genome will not have genetic disease.