NEW YORK (GenomeWeb News) – In a pair of studies published online in Nature and Nature Genetics, two independent research groups describe how they mapped recombination patterns in African American individuals.
"We had completely independent samples and pursued slightly different technical approaches," University of California at Los Angeles ecology, evolutionary biology, and bioinformatics researcher John Novembre, senior author on the Nature Genetics study, told GenomeWeb Daily News. The two groups also did complimentary but distinct analyses using the newly generated recombination maps, he noted.
Novembre's team, a collaboration of researchers from several American universities, used a computational method to find spots in the genomes of admixed individuals where ancestry flips from one parental population to another. After testing the approach in a series of simulations, the team used it to map recombination rates in more than 2,500 African Americans and nearly 300 African Caribbean individuals.
Although the recombination patterns in these populations generally resembled those in other populations, the team saw differences when they looked across smaller regions of the genome.
"It appears that recombination, on the broad scale, is very, very similar across all human populations," first author Daniel Wegmann, a post-doctoral researcher in Novembre's UCLA lab, told GWDN. "But then if we zoom in to a finer scale, we do find differences between populations."
Most previously published recombination studies have focused on individuals of European ancestry, researchers explained. For the current studies, though, the groups looked at populations with both African and European ancestry.
The proportion of African and European ancestry in individuals within these populations varies dramatically, Wegmann noted. But on average, African Americans and African Caribbeans have around 80 percent African and 20 percent European ancestry.
By looking for haplotype patterns found in African and European reference populations, it's possible to see places along the chromosomes where ancestry switches from African to European and vice versa in admixed individuals, he explained, pointing to past recombination events.
After using simulated data to test the performance of their method, the researchers used it to assess 2,864 admixed individuals — 2,565 African Americans and 299 African Caribbeans — who had been genotyped at more than 570,000 SNPs through four previous studies.
For ancestral references, the team relied on HapMap data on the Yoruban population from West Africa and on a population of individuals of European descent. "Although neither of these panels is an exact representation of the ancestral populations of the admixed individuals in the samples used here," they noted, "previous studies and our own principal component analyses suggest these two panels are reasonable proxies for the source populations."
The researchers found roughly 90 ancestry switch points per person, or around a quarter of a million unique recombination events overall — information that they subsequently used to map recombination in the admixed populations.
Comparisons to Decode recombination data and information on linkage disequilibrium in the HapMap sampled populations suggested that recombination patterns in these admixed individuals share broad-scale similarities with other human populations.
But the team detected population-related differences as well, particularly when they looked at parts of the genome that were less than a million bases long.
On average, the African American and African Caribbean recombination map shared more recombination hotspots with the Yoruban population, though recombination patterns in the admixed populations could largely be predicted based on the proportion of African and European ancestry in these populations.
"The recombination map in admixed individuals … seems to be predicted very well by taking the maps of European and African populations and producing a weighted average of these maps," Wegmann explained, "where we give a weight that corresponds to the admixture proportion."
Nevertheless, there were exceptions, especially in regions of the genome that are prone to inversions and other structural variations. Although recombination can give rise to structural variation, Novembre explained, individuals who are heterozygous for large inversions tend to have lower recombination rates in these inverted regions.
Given their findings in the African American and African Caribbean individuals, those involved in the study say it should be possible to use a similar strategy to map recombination in other admixed populations, including Latino individuals who often have African, European, and Native American ancestry.
The team is continuing to work on new methods for exploring population structure and ancestry, Novembre noted.
For their part, another large team from the UK and US mapped recombination using SNP data for tens of thousands of African Americans. Again, the map resembled that seen in individuals of European ancestry at the broad scale, but contained fine-scale differences, including thousands of recombination hotspots that are active in individuals with African ancestry but are largely inactive in Europeans.
Along with mapping recombination in the African American population, that team also explored some of the mechanisms underlying these recombination differences. For instance, their data suggests that the activity of African-specific hotspots coincides with the presence of a particular SNP in the histone H3 methyltransferase gene PRDM9 that is more common in individuals of African ancestry and which interacts with a binding motif found in and around these hotspots.
"More than half of African Americans carry a version of the biological machinery for recombination that is different than Europeans," co-corresponding author Simon Myers, a statistics researcher at the University of Oxford, said in a statement. "As a result, African Americans experience recombination where it almost never occurs in Europeans."
Myers and his colleagues used a computational strategy called HAPMIX to help find and map crossover events using SNP array data for 29,589 unrelated African Americans genotyped for past association studies done by five large consortia.
The team also used data for individuals from 222 African American families sampled through a subset of these studies to come up with a pedigree map for tracking crossover events — a resource that they used to test and verify their population-based recombination map.
While most recombination hotspots in Europeans overlapped with those in Yoruban and African American individuals, the researchers found, individuals with African ancestry used other recombination hotspots as well, including some 2,500 hotpots that were far more common in individuals of African ancestry.
In their subsequent experiments, researchers looked at each person's penchant for using these so-called African-enriched hotspots and tracked down genetic patterns corresponding to the use of these sites.
For instance, whereas previous studies have shown that recombination hotspots in European individuals often have a specific 13 base pair sequence motif, the new research shows that recombination in African Americans is not exclusive to these sites.
Instead, about a third of African-related recombination events seem to occur at sites with a distinct 17 base pair motif. In addition, this motif appears to interact with a version of the PRDM9 gene containing rs6889665, a SNP that's relatively common in individuals with West African ancestry but much more rare in Europeans.
"Over 82 percent of map usage variability is explained by the rs6889665 genotype alone," the researchers wrote. "Given that there are further influential PRDM9 variants, this gene may thus explain almost all differences in local [recombination] rate between the West African and European populations."
Such patterns may offer insights into some genetic diseases as well, they explained, since glitches occurring during recombination tend to show up at recombination hotspots.
"The places in the genome where there are recombination hotspots can thus also be disease hotspots," co-corresponding author David Reich, a Harvard University genetics researcher, said in a statement. "Charting recombination hotspots can thus identify places in the genome that have an especially high chance of causing disease."