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From molecules to populations: appreciating and estimating recombination rate variation

Abstract

Recombination is a central biological process with implications for many areas in the life sciences. Yet we are only beginning to appreciate variation in the recombination rate along the genome and among individuals, populations and species. Spurred by technological advances, we are now able to bring variation in this key biological parameter to centre stage. Here, we review the conceptual implications of recombination rate variation and guide the reader through the assumptions, strengths and weaknesses of genomic inference methods, including population-based, pedigree-based and gamete-based approaches. Appreciation of the differences and commonalities of these approaches is a prerequisite to formulate a unifying and comparative framework for understanding the molecular and evolutionary mechanisms shaping, and being shaped by, recombination.

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Fig. 1: Recombination variation.
Fig. 2: Mapping functions.
Fig. 3: Single-gamete versus bulk-gamete sequencing.
Fig. 4: From inference to landscape.

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Acknowledgements

The authors thank the Dobzhansky Journal Club in the Division of Evolutionary Biology, LMU, Munich, for useful discussion and comments on this review. Funding was provided by the European Research Council (ERCStG-336536 FuncSpecGen) and LMU Munich.

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J.V.P. wrote the manuscript. J.B.W.W. edited the manuscript before submission. Both authors researched data for the article and substantially contributed to the discussion of content.

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Correspondence to Joshua V. Peñalba or Jochen B. W. Wolf.

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Nature Reviews Genetics thanks J. McAuley, S. Johnston and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Genetic drift

A stochastic change in allele frequency from one generation to the next due to random sampling in finite populations.

Gene flow

The movement of chromosomes across genetically structured populations.

Genetic diversity

The total number of non-identical genetic elements in a population.

Supergenes

A set of co-inherited, physically linked genes often contributing to complex phenotypes.

Heterochiasmy

A variation in recombination rates and, accordingly, genetic map length between sexes.

Heterogametic sex

The sex in which the sex chromosomes differ.

Structural variants

Any variations in the structure of a chromosome, including insertions, deletions, duplications, inversions or translocations.

Hill–Robertson interference

The reduction in the efficacy of selection when acting on alleles in physically linked genes.

Double-strand breaks

(DSBs). Lesions in the DNA double helix induced by a wide range of DNA-damaging agents. Programmed enzymatic induction during meiosis triggers homologous recombination.

Crossover interference

The non-random occurrence of multiple crossover events relative to each other during meiosis.

Gene conversion

The process whereby a fragment of DNA sequence is replaced by its homologue.

Crossover event

When a double-strand break (DSB) during meiosis results in exchange of homologous chromosomal regions. By contrast, a non-crossover event is when a DSB is repaired without homologous exchange of DNA material.

Recombination landscape

The variation in the local recombination rate plotted against the position along the chromosome.

Genetic mapping

A marker-based method to identify the order and genetic distance between loci.

Linkage disequilibrium

The non-random association of alleles at different loci.

Coalescent

A mathematical model describing the stochastic process of random reproduction backwards in time until all gene copies share a common ancestor. It predicts the distribution of gene genealogies of freely recombining segments of the genome.

Effective population size

(Ne). An abstract population genetic parameter describing the number of individuals in an idealized population in which the effect of genetic drift is representative of that in the real population.

Ancestral alleles

The allelic state of a locus that originated in the ancestral population. It is generally contrasted to the derived allele that arose by mutation in the evolutionary lineage or population under consideration.

Infinite sites model

A model in molecular evolution that assumes that there are an infinite number of sites where mutations can occur and that new mutations must occur in a novel site.

Four-gamete test

A test to detect historic recombination events by locating allelic combinations that could only have arisen as a result of recombination.

Ancestral recombination graph

A generalization of the coalescence tracing gene genealogies, integrating the recombination history of a population of samples.

Phased

The haplotype is inferred from genotype data.

Genotype likelihoods

The probabilities of genotypes, accounting for potential errors in the sequencing data that occur during sequencing and processing.

Linkage groups

Genetic markers that are inherited together as a unit, usually representing a chromosome.

Genetic map

Also known as linkage map. A representation of the order of genetic markers and inter-marker distance derived from the frequency of meiotic recombination.

Logarithm of the odds scores

(LOD scores). A statistical estimate of the likelihood that two entities are co-inherited, referring to the association of phenotypic and allelic variation or to the association between genotypes.

Physical map

The physical order of genetic markers along a chromosome.

Mapping functions

Algorithms to infer the additive genetic distance between two loci from measurable recombination fractions between them.

Haplotype blocks

Discrete stretches along the chromosome for which the phase can be unequivocally determined.

Demographic history

The history of a population with regard to change in size, structure and gene flow.

Whole-genome amplification

Genome-wide amplification of DNA, usually performed from DNA extracted from only one or a few cells.

Long-read sequencing

A class of DNA sequencing technologies and platforms that currently allows for sequencing of long (>20 kb) stretches of DNA.

Linked-read sequencing

A DNA library preparation method that incorporates unique barcodes to reads derived from a longer DNA molecule, such that the reads can be bioinformatically reassociated to the original DNA fragment.

Linked selection

A locus under selection causes corresponding changes in allele frequencies of other nearby loci owing to a lack of recombination between these loci.

Association mapping

A statistical approach to infer the association between phenotypes and genotypes.

Nucleotide diversity

A measure of genetic variation within a population or species, reflecting the average number of nucleotide differences between two chromosomes in a population.

Marker-assisted selection

Artificial selection whereby the founders for the next generation are selected on the basis of the genotype of a particular locus or set of loci underlying the phenotypic trait of interest.

Quantitative trait locus (QTL) mapping

A specific type of association mapping that focuses on a quantitative trait that is assumed to be encoded by multiple genes.

Meiotic drive

A mechanism acting during meiosis or gametogenesis that distorts the equal transmission of alleles.

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Peñalba, J.V., Wolf, J.B.W. From molecules to populations: appreciating and estimating recombination rate variation. Nat Rev Genet 21, 476–492 (2020). https://doi.org/10.1038/s41576-020-0240-1

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