Impact of Genetic Ancestry and Parental Smoking on Children's DNA Changes

Recent research indicates that both genetic ancestry and parental smoking habits may significantly influence the occurrence and nature of new genetic mutations in children. Conducted by scientists at the Wellcome Sanger Institute and the University of Cambridge, this study analyzed the whole-genome sequences of 10,000 parent-child trios to explore how these factors contribute to de novo mutations (DNMs), which are genetic changes that emerge in the egg or sperm and are inherited by offspring.

Published in Nature Communications, the study is a landmark investigation into the factors that shape genetic variation in humans. The findings are expected to enhance future research in population and medical genetics, particularly where mutation rate models are critical.

Germ cells, which include eggs and sperm, are essential for maintaining the integrity of genetic information passed to children. Although most mutations are harmless or have minimal effects, a small percentage can lead to severe genetic disorders. Thus, a low mutation rate in germ cells is vital for reducing the risk of transmitting harmful genetic changes.

While it is established that older parental age, particularly that of the father, correlates with an increase in genetic mutations, it accounts for only a portion of the variability in mutation rates. There has been limited understanding of other contributing factors influencing DNMs.

To better understand this, the researchers conducted the largest study to date on DNMs, encompassing around 10,000 parent-child trios from the 100,000 Genomes Project. By comparing the DNA of children with that of their parents, the team identified nearly 690,000 unique DNMs that arose in the egg or sperm but were absent in the parental genomes.

The study revealed slight variations in the number of new genetic mutations associated with different ancestry groups. For instance, the average number of DNMs was approximately 64 per generation among European, American, and South Asian groups, while African groups averaged around 67. However, the impact of parental age, particularly paternal age, was found to be much more significant; with each additional year of a father's age contributing approximately 1.5 mutations, compared to 0.4 mutations per year attributed to the mother.

These variations could result from environmental factors or genetic differences among populations. The analysis did not find substantial evidence linking common genetic variations to DNM rates in individuals of European ancestry, although it remains possible that genetic differences between ancestry groups might influence these rates.

Additionally, the study uncovered a correlation between parental smoking and an increase in DNMs in children. Children of parents with documented smoking histories exhibited a statistically significant rise in DNMs, estimated at around 2%. This effect, while small, is comparable to having a father who is one year older at conception.

However, the researchers caution that it is premature to conclude that parental smoking directly causes these mutations, as it may merely be associated with other mutagenic factors.

These findings could significantly impact future genetic research, particularly in understanding population history and dynamics, as well as identifying genes related to rare disorders through DNMs. Current models in these studies typically assume uniform mutation rates across different ancestry groups, but the new insights may necessitate adjustments to enhance their accuracy and efficacy.

Dr. Aylwyn Scally, a co-senior author of the study, emphasized the importance of the extensive data from the 100,000 Genomes Project in clarifying the effects of various exposures on mutation rates. He stated that while parental age is the primary driver of new mutations, factors like ancestry and environmental influences, including smoking, also play a minor role.

Dr. Raheleh Rahbari, another co-senior author, noted that while evolutionary mechanisms have developed to safeguard DNA passed to offspring, their research indicates that certain exposures can still affect mutation rates. Future studies with larger datasets and comprehensive environmental exposure data may uncover additional elements influencing DNM variation.

Dr. Hilary Martin, also a co-senior author, highlighted the role of new genetic changes in fostering genetic diversity within populations and the potential for these changes to result in rare genetic disorders. The study illustrates how ancestry and family lifestyle choices, such as smoking, are associated with the frequency of new DNA alterations, thus enhancing our understanding of this fundamental biological process.