Variation in recombination rate across the genome: evidence and implications

Abstract

Recent data from humans and other species provide convincing evidence of variation in recombination rate in different genomic regions. Comparison of physical and genetic maps reveals variation on a scale of megabases, with substantial differences between sexes. Recombination is often suppressed near centromeres and elevated near telomeres, but neither of these observations is true for all chromosomes. In humans, patterns of linkage disequilibrium and experimental measures of recombination from sperm-typing reveal dramatic hotspots of recombination on a scale of kilobases. Genome-wide variation in the amount of crossing-over may be due to variation in the density of hotspots, the intensity of hotspots, or both. Theoretical models of selection and linkage predict that genetic variation will be reduced in regions of low recombination, and this prediction is supported by data from several species. Heterogeneity in rates of crossing-over provides both an opportunity and a challenge for identifying disease genes: as associations occur in blocks, genomic regions containing disease loci may be identified with relatively few markers, yet identifying the causal mutations is unlikely to be achieved through associations alone.

Introduction

Meiotic recombination — the exchange of genetic information between homologous chromosomes during prophase I of meiosis — is widespread among eukaryotes, and the rate at which this exchange occurs may vary substantially among species, among individuals, between the sexes, and among different regions of the genome. Variation in the rate of recombination can have profound consequences for the structure of genetic variation and consequently for our ability to map and identify disease genes. Historically, the rate of crossing-over was measured cytologically, by observing chiasmata through the microscope, or by the number of recombinant individuals recovered in genetic crosses using phenotypic markers. With the availability of complete genome sequences and thousands of molecular markers, it is now possible to describe the amount and distribution of recombination in great detail. The pattern that emerges is complex and varies strikingly in different species and in different genomic regions.

Theoretical models indicate that the level of recombination can affect the amount and pattern of genetic variation in many ways. For example, in regions of the genome where recombination is either reduced or absent, non-random associations among alleles at different loci are expected. As a consequence of selection at linked sites, genomic regions with little recombination may also harbor fewer polymorphisms in addition to polymorphisms at lower frequencies. Moreover, the efficacy of selection is expected to vary as a function of recombination rate: interference due to linkage may reduce the chances of fixing beneficial mutations in regions of low recombination.

Here, I review evidence for variation in recombination rate, with special emphasis on humans and, to a lesser extent, Drosophila. I then discuss some of the theoretical predictions concerning the effect of variable recombination rate on patterns of genetic variation and I highlight recent data from flies and humans that address these predictions. Finally, I point to some of the implications of variation in the rate of meiotic crossing-over for our approach to mapping and identifying genes underlying complex traits, including many diseases.