Hot and Cold Spots of Recombination in the Human Genome: the Reason We Should Find Them and How This Can Be Achieved

There is currently a great deal of interest in how the recombination rate varies over the human genome. The primary reason for this is the excitement about using linkage disequilibrium (LD) to map and identify human disease genes (reviewed in Ardlie et al. 2002; Nordborg and Tavare 2002; Cardon and Abecasis 2003). LD mapping (also known as “association mapping”) differs from traditional linkage mapping methods in that marker-disease associations are sought in populations of unrelated individuals. Such associations reflect the long evolutionary history of the chromosomal region (or the entire genome, in case of genomewide screens), involving recombination, mutation, demographic events, and (perhaps most importantly) random reproductive success. This is in sharp contrast with the associations utilized in linkage mapping, which simply reflect recombination and segregation of DNA markers and phenotypes in a small number of meioses in pedigrees or crosses. The dependence of LD on an unknown history has two important consequences for association mapping. First, although LD is expected to decay with increasing recombination, the relationship is expected to be extremely noisy (reviewed in Nordborg and Tavare 2002). Thus, although recent studies have identified considerable variation in LD across the genome (i.e., “haplotype blocks,” see Daly et al. 2001; Patil et al. 2001; Dawson et al. 2002; Gabriel et al. 2002; Phillips et al. 2003), it is by no means obvious to what extent this reflects variation in the underlying recombination rate (Reich et al. 2002; Wang et al. 2002; Innan et al. 2003; Phillips et al. 2003). It is clear that nonuniformity of recombination rates (hot spots and cold spots) along a chromosome could give rise to blocks of LD, but it does not follow that variation in recombination can explain all blocks of LD, nor does it follow that all blocks of LD are caused by variation in recombination. A second consequence of a long evolutionary history (and a correspondingly large number of meioses) is that LD decays along the chromosome over genetic distances far shorter than those used to find linkage associations when utilizing traditional mapping methods. In most studies, LD levels change over physical distances from as little as 10 kb to perhaps as much as 100 kb (Daly et al. 2001; Gabriel et al. 2002; Phillips et al. 2003). If we extrapolate from a commonly accepted genome average recombination rate of ∼1 cM/Mb, this means LD levels can vary over genetic distances ranging from 0.01 to 0.1 cM. (In this review, we will use the recombination fraction and the unit of genetic distance [cM] interchangeably, since the likelihood of a double crossover event in such small intervals is negligible.) Recombination-rate estimates in existing genetic maps are very inaccurate for intervals <1 cM (Kong et al. 2002; Weber 2002). This makes it impossible to determine the extent to which variation in LD is determined by variation in recombination. In what follows, we focus in particular on experimental methods for measuring recombination over distances <1 cM and discuss their strengths and limitations. Before turning to this, we address briefly why knowing more about the pattern of recombination is both important and interesting.