Hidden source of genetic diversity found in human sperm
Scientists have identified an unexpected source of genetic variation in human sperm that occurs earlier in sperm development than previously thought.
Published today (26 August) in Nature, researchers at the Wellcome Sanger Institute, the University of Cambridge and their collaborators, found that one type of genetic recombination involving the chromosomes, called non-crossover gene conversion, happens before the cell divisions that produce sperm.
The findings suggest that genetic recombination events in sperm happen in two stages, both before and after cell division. The team found that these DNA recombination patterns can vary between individuals, including between identical twins. This study opens new opportunities to investigate biological mechanisms underlying fertility, genome evolution and inherited disease.
Every child inherits a unique combination of DNA from their parents. Much of this diversity is generated through recombination, where the two copies of a chromosome — one inherited from each parent — exchange or copy segments of DNA as sperm and eggs are formed.
The cells that ultimately produce sperm first undergo many rounds of ordinary cell division, or mitosis, before entering meiosis — the specialised cell division that generates reproductive cells.
Scientists have generally assumed that most genetic recombination occurs during meiosis, through crossovers or non-crossover gene conversion. Crossovers are where large sections of chromosomes are exchanged in a two-way swap. Non-crossover gene conversion is a one-way copying of a short stretch of DNA from one chromosome to the other. These short events have been much harder to study directly.
In this new study, the researchers were investigating whether all non-crossover gene conversions found in sperm originate during meiosis, or whether some arise earlier, during the pre-meiotic cell divisions.
The team analysed 15 sperm samples from 13 donors aged 24 to 74.1 Using highly accurate long-read sequencing, they identified 7,143 crossover events and 2,382 non-crossover gene-conversion events directly from sperm DNA. They compared these patterns with long-read genomic data from blood and previously published data.
For the first time, researchers discovered that a substantial proportion of gene conversion appears to originate before meiosis begins. It occurs during the normal cell divisions that maintain the cells responsible for producing sperm throughout a person’s life.
These pre-meiosis DNA changes carry molecular signatures that distinguish them from changes that occur during meiosis. The researchers found that these signatures closely resemble DNA repair processes observed in normal body tissues.
The scientists also revealed that not only does the frequency and location of gene conversion vary between individuals, but they also differ between identical twins.2 This indicates that genetic diversity is shaped not only by inherited factors but also by biological processes that vary from person to person. Together, these breakthroughs challenge a long-standing view of human genetics by providing new insight for understanding the roots of human diversity.
The researchers also observed that these DNA copying events often happen in areas of the genome that are naturally prone to breaking. As these sites are unstable, the way they are repaired could lead to changes that cause inherited disease. Therefore, these findings open a new path for studying how reproductive health and genome integrity are protected as DNA is passed from one generation to the next.
“We found that gene conversion in sperm does not appear to come from a single process. Alongside the familiar meiotic pathway, there is a substantial component with features consistent with DNA repair before meiosis. Being able to see thousands of these events directly in sperm gives us a new window into how genetic diversity is generated.”
Dr Regev Schweiger, first author at the Gray Faculty of Medical and Health Sciences, Tel Aviv University
“High-accuracy long-read sequencing lets us observe both crossovers and the much harder-to-detect non-crossovers directly in sperm. This gives us far greater power to study recombination within individuals and has revealed biology that would be very difficult to resolve from previous data.”
Professor Richard Durbin, co-senior author at the University of Cambridge and associate faculty at the Wellcome Sanger Institute
“Understanding where and when genetic variation arises is fundamental to understanding how the human genome maintains integrity while generating diversity. Our findings show that DNA repair before meiosis contributes more to genetic diversity in sperm than previously appreciated and opens new opportunities to investigate why these processes vary between individuals and how they shape the variation passed to the next generation.”
Dr Raheleh Rahbari, co-senior author at the Wellcome Sanger Institute
More information
Notes to Editors:
- Nine samples were from the TwinsUK Project, and six were obtained from the Sudmant lab at University of California, Berkeley. The samples were of European ancestry.
- The TwinsUK cohort consists of more than 14,000 volunteers, mostly middle‐aged females, who have participated over the last 30 years in a longitudinal cohort study. This has included lifestyle and health questionnaires, biomedical measurements, biological sample collection, and the generation of multi‐omics profiles (such as genetics, metagenomics, and metabolomics), over multiple visits. For more information on the TwinsUK Project, based at King’s College London, please visit: https://twinsuk.ac.uk/
Publication:
R. Schwieger, et al. (2026) ‘Long-read sequencing reveals pre-meiotic gene conversion in sperm’. Nature. DOI: 10.1038/s41586-026-10901-0
Funding:
This research was supported by Wellcome. A full list of acknowledgements can be found in the publication.
