The Rate of Nonallelic Homologous Recombination in Males Is Highly Variable, Correlated between Monozygotic Twins and Independent of Age

Jacqueline A L Macarthur,Massimo Mangino,Raj Gill,Timothy D Spector,Matthew E Hurles,Sarah J Lindsay,Kerrin S Small,Gil Mcvean

doi:10.1371/journal.pgen.1004195

Jacqueline A L Macarthur, Massimo Mangino + Show 6 more

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https://doi.org/10.1371/journal.pgen.1004195

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Abstract

Nonallelic homologous recombination (NAHR) between highly similar duplicated sequences generates chromosomal deletions, duplications and inversions, which can cause diverse genetic disorders. Little is known about interindividual variation in NAHR rates and the factors that influence this. We estimated the rate of deletion at the CMT1A-REP NAHR hotspot in sperm DNA from 34 male donors, including 16 monozygotic (MZ) co-twins (8 twin pairs) aged 24 to 67 years old. The average NAHR rate was 3.5×10−5 with a seven-fold variation across individuals. Despite good statistical power to detect even a subtle correlation, we observed no relationship between age of unrelated individuals and the rate of NAHR in their sperm, likely reflecting the meiotic-specific origin of these events. We then estimated the heritability of deletion rate by calculating the intraclass correlation (ICC) within MZ co-twins, revealing a significant correlation between MZ co-twins (ICC = 0.784, p = 0.0039), with MZ co-twins being significantly more correlated than unrelated pairs. We showed that this heritability cannot be explained by variation in PRDM9, a known regulator of NAHR, or variation within the NAHR hotspot itself. We also did not detect any correlation between Body Mass Index (BMI), smoking status or alcohol intake and rate of NAHR. Our results suggest that other, as yet unidentified, genetic or environmental factors play a significant role in the regulation of NAHR and are responsible for the extensive variation in the population for the probability of fathering a child with a genomic disorder resulting from a pathogenic deletion.

Highlights

Homologous recombination (HR), leading to crossing over and exchange between homologous DNA sequences, occurs during meiosis and ensures that each gamete contains a unique mixture of maternal and paternal DNA
Many genetic disorders are caused by deletions of specific regions of DNA in sperm or egg cells that go on to produce a child. This can occur through ectopic homologous recombination between highly similar segments of DNA at different positions within the genome
Our results suggest that other, as yet unidentified, genetic or environmental factors play a significant role in the regulation of deletion. These factors are responsible for the extensive variation in the population for the probability of fathering a child with a genomic disorder resulting from a pathogenic deletion

Summary

Introduction

Homologous recombination (HR), leading to crossing over and exchange between homologous DNA sequences, occurs during meiosis and ensures that each gamete contains a unique mixture of maternal and paternal DNA. HR occurs ectopically between highly similar duplicated sequences or paralogous genomic segments, such as segmental duplications, in a process known as non-allelic homologous recombination (NAHR). The breakpoints of NAHR rearrangements cluster in defined hot spots within segmental duplications that reflect hotspots of HR activity [1]. Several NAHR hotspots have been identified due to their association with specific genomic disorders, with reciprocal deletion and duplication events being associated with different disorders at some loci [4,5,6,7]. For example NAHR between two copies of the CMT1A-REP segmental duplication on 17p12 leads to deletion of a 1.4 Mb region including the PMP22 gene resulting in hereditary neuropathy with liability to pressure palsies (HNPP), with reciprocal duplication of the same region resulting in Charcot-Marie-Tooth disease type 1A (CMT1A) [8]

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