title: Parent-progeny sequencing indicates higher mutation rates in heterozygotes.
abstract: Mutation rates vary within genomes, but the causes of this remain unclear. As many prior inferences rely on methods that assume an absence of selection, potentially leading to artefactual results, we call mutation events directly using a parent-offspring sequencing strategy focusing on Arabidopsis and using rice and honey bee for replication. Here we show that mutation rates are higher in heterozygotes and in proximity to crossover events. A correlation between recombination rate and intraspecific diversity is in part owing to a higher mutation rate in domains of high recombination/diversity. Implicating diversity per se as a cause, we find an ∼3.5-fold higher mutation rate in heterozygotes than in homozygotes, with mutations occurring in closer proximity to heterozygous sites than expected by chance. In a genome that is a patchwork of heterozygous and homozygous domains, mutations occur disproportionately more often in the heterozygous domains. If segregating mutations predispose to a higher local mutation rate, clusters of genes dominantly under purifying selection (more commonly homozygous) and under balancing selection (more commonly heterozygous), might have low and high mutation rates, respectively. Our results are consistent with this, there being a ten times higher mutation rate in pathogen resistance genes, expected to be under positive or balancing selection. Consequently, we do not necessarily need to evoke extremely weak selection on the mutation rate to explain why mutational hot and cold spots might correspond to regions under positive/balancing and purifying selection, respectively.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Sihai
authors.initials: S
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Jian-Qun
authors.initials: JQ
authors.lastname: Chen
authors.affiliation: The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Hurst
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Dacheng
authors.initials: D
authors.lastname: Tian
mesh_terms: D000818:Animals; D017360:Arabidopsis / Q000235:genetics*; D016477:Artifacts; D001516:Bees / Q000235:genetics*; D003434:Crossing Over, Genetic / Q000235:genetics; D005260:Female; D016678:Genome / Q000235:genetics; D023281:Genomics; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D008540:Meiosis / Q000235:genetics; D005810:Multigene Family / Q000235:genetics; D016296:Mutagenesis / Q000235:genetics*; D059645:Mutation Rate; D012275:Oryza / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA