The Recombinational Anatomy of a Mouse Chromosome

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Abstract
Among mammals, genetic recombination occurs at highly delimited sites known as recombination hotspots. They are typically 1–2 kb long and vary as much as a 1,000-fold or more in recombination activity. Although much is known about the molecular details of the recombination process itself, the factors determining the location and relative activity of hotspots are poorly understood. To further our understanding, we have collected and mapped the locations of 5,472 crossover events along mouse Chromosome 1 arising in 6,028 meioses of male and female reciprocal F1 hybrids of C57BL/6J and CAST/EiJ mice. Crossovers were mapped to a minimum resolution of 225 kb, and those in the telomere-proximal 24.7 Mb were further mapped to resolve individual hotspots. Recombination rates were evolutionarily conserved on a regional scale, but not at the local level. There was a clear negative-exponential relationship between the relative activity and abundance of hotspot activity classes, such that a small number of the most active hotspots account for the majority of recombination. Females had 1.2× higher overall recombination than males did, although the sex ratio showed considerable regional variation. Locally, entirely sex-specific hotspots were rare. The initiation of recombination at the most active hotspot was regulated independently on the two parental chromatids, and analysis of reciprocal crosses indicated that parental imprinting has subtle effects on recombination rates. It appears that the regulation of mammalian recombination is a complex, dynamic process involving multiple factors reflecting species, sex, individual variation within species, and the properties of individual hotspots. In most eukaryotic organisms, recombination—the exchange of genetic information between homologous chromosomes—ensures the proper recognition and segregation of chromosomes during meiosis. Recombination events in mammals are not randomly positioned along the chromosomes but occur in preferential 1–2-kilobase sequences termed hotspots. Different species such as humans and mice do not share hotspots, although the same principles almost certainly regulate their placement in the genome. Hotspot positions and activities depend on genetic background and show sex-specific differences. In this study, we present a detailed analysis of recombination activity along the largest mouse chromosome, finding that recombination is regulated on multiple levels, including regional positioning relative to the chromosomal ends, local gene content, sex-specific mechanisms of hotspot recognition, and parental origin. Our results will contribute to further understanding of one of the most fundamental biological processes and are likely to cast light on several aspects of population genetics and evolutionary biology, as well as enhance our practical ability to define the genetic components of human disease.