Crossing over a boundary

Abstract

Where does recombination occur in the human genome? If it is not uniform, as it appears not to be, are there any regularities in its distribution? In the human genome the GC content tends to be consistent over large domains (upwards of 300 kb), the ‘isochores’, and the variation in GC content is also thought to reflect differences in the recombination rate. The mean GC content of individual autosomes correlates with the density of chiasmata. At a higher resolution, chiasmata tend to be found in R and T bands rather than G bands. G bands contain most GC-poor isochores, whereas T bands, a subset of the R bands, are the only bands where the GC-richest isochores are found. But is there a strong connection between isochore GC content and recombination? What, for example, if one looks across a boundary between isochores: is there a step up in the recombination rate as one moves to the higher GC content?Eisenbarth et al.1xAn isochore transition in the NF1 gene region coincides with a switch in the extent of linkage disequilibrium. Eisenbarth, I. et al. Am. J. Hum. Genet. 2000; 67: 873–880Abstract | Full Text | Full Text PDF | PubMed | Scopus (52)See all References1 are the first to look at this issue, examining the region around the NF1 gene on 17q11.2. They examined 93 individuals selected at random and characterized eight polymorphic markers over ∼300 kb. From haplotype frequencies they could calculate the degree of linkage disequilibrium, and from assumptions about the age of the variants they could estimate the recombination rate between markers. Knowing the genomic distances allowed them to estimate the local recombination rate per megabase.The NF1 gene resides in a GC-poor region and over the ∼200 kb surrounding the gene there is very strong linkage disequilibrium. Eisenbarth et al. estimate the recombination frequency to be only 0.0001 per Mb in this region (assuming variants are about 5000–10 000 generations old). By contrast, in the neighbouring GC-rich isochore, there is no linkage disequilibrium between markers 26-kb apart. The recombination rate is about two orders of magnitude higher. Plotting the recombination rate against the GC content shows both a sharp transition in GC content between isochores and a sharp transition, coincident with the isochore boundary, in the local recombination rate.If isochore boundaries are typically also recombination-rate boundaries, this has major implications for those searching for genes associated with disease. The methods typically rely on non-random associations between alleles (i.e. linkage disequilibrium), but this is broken down by recombination. The number of polymorphic markers that will be needed in a given genomic region increases, therefore, as the local recombination rate goes up. Finding genes in GC-rich regions could then prove harder than previously thought.