Research Article

Characterizing mutagenic effects of recombination through a sequence-level genetic map

See allHide authors and affiliations

Science  25 Jan 2019:
Vol. 363, Issue 6425, eaau1043
DOI: 10.1126/science.aau1043

Human recombination and mutation mapped

Genetic recombination is an essential process in generating genetic diversity. Recombination occurs both through the shuffling of maternal and paternal chromosomes and through mutations generated by resolution of the physical breaks necessary for this process. Halldorsson et al. sequenced the full genomes of parents and offspring to create a map of human recombination and estimate the relationship with de novo mutations. Interestingly, transcribed regions of the genome were less likely to have crossovers, suggesting that there may be selection to reduce changes in genetic sequences via recombination or mutation in these regions.

Science, this issue p. eaau1043

Structured Abstract


Diversity in the sequence of the human genome, arising from recombinations and mutations, is fundamental to human evolution and human diversity. Meiotic recombination is initiated from double-strand breaks (DSBs). DSBs occur more frequently in regions of the genome termed hotspots, and a small subset eventually gives rise to crossovers, a reciprocal exchange of large pieces between homologous chromosomes. The majority of DSBs do not lead to crossovers but end as localized transfers of short segments between homologous chromosomes or sister chromatids, observable as gene conversions when the segment includes a heterozygous marker. Crossovers co-occurring with distal gene conversions are known as complex crossovers.


Current meiotic recombination maps either have limited resolution or the events cannot be resolved to an individual level. The detection of recombination and de novo mutations (DNMs) requires genetic data on a proband and its parents, and a fine resolution of these events is possible only with whole-genome sequence data. Whole-genome sequencing and DNA microarray data allowed us to identify crossovers and DNMs in families at a high resolution. We resolved crossovers at an individual level, allowing us to examine variation in crossover patterns between individuals, analyzing which crossovers are complex and how crossover patterns are influenced by age, sex, sequence variants, and epigenomic factors. It is known that the mutation rate is increased near crossovers, but the rate of DNMs near crossovers has been characterized only indirectly or at a small scale.


We show that a number of epigenomic factors influence crossover location, shifting crossovers from exons to enhancers. Complex crossovers are more common in females than males, and the rate of complex crossovers increases with maternal age. Maternal age also correlates with an increase in the recombination rate in general and a shift in the location of crossovers toward later-replicating regions and regions of lower GC content. Both sexes show an ~50-fold increase in DNMs within 1 kb of crossovers, but the types of DNMs differ considerably between the sexes. Females, but not males, also exhibit an increase in the mutation rate up to 40 kb from crossovers, particularly at complex crossovers. We found 47 variants at 35 loci affecting the recombination rate and/or the location of crossover, 24 of which are coding or splice region variants. Whereas some of the variants affect both the recombination rate and several measures of crossover location in both sexes, other variants affect only one of these measures in one of the sexes. Many of these variants are in genes that encode the synaptonemal complex.


Our genome-wide recombination map provides a resolution of 682 base pairs. We show that crossovers have a direct mutagenic effect and demonstrate that DNMs and crossovers accumulate in the same regions with advancing maternal age. Furthermore, our results illustrate extensive genetic control of meiotic recombinations and highlight genes linked to the formation of the synaptonemal complex as determinants of crossovers.

Our search for crossovers in parents and their offspring.

Histone modifications influence crossover location. The DNM rate is higher within 1 kb from a crossover in both sexes, but the type of mutations differs between the sexes. The DNM rate is also higher up to 40 kb from crossovers in females with enrichment of G→C mutations. We used crossovers from many individuals to construct genetic maps and performed genome-wide association studies (GWAS) on the recombination rate and attributes of crossover locations to search for genes that control crossover characteristics.


Genetic diversity arises from recombination and de novo mutation (DNM). Using a combination of microarray genotype and whole-genome sequence data on parent-child pairs, we identified 4,531,535 crossover recombinations and 200,435 DNMs. The resulting genetic map has a resolution of 682 base pairs. Crossovers exhibit a mutagenic effect, with overrepresentation of DNMs within 1 kilobase of crossovers in males and females. In females, a higher mutation rate is observed up to 40 kilobases from crossovers, particularly for complex crossovers, which increase with maternal age. We identified 35 loci associated with the recombination rate or the location of crossovers, demonstrating extensive genetic control of meiotic recombination, and our results highlight genes linked to the formation of the synaptonemal complex as determinants of crossovers.

View Full Text