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Study Suggests Biased Gene Conversion Can Ratchet up Homozygosity, Recessive Disease Risk

NEW YORK (GenomeWeb) – Recessive inherited disease risk may be incrementally notched up over time in human populations by a process called biased gene conversion, according to a study appearing online yesterday in the American Journal of Human Genetics.

University of Pennsylvania researcher Sarah Tishkoff and Joseph Lachance, a former post-doctoral researcher in her lab who is now based at the Georgia Institute of Technology, used allele frequency patterns in whole-genome sequence data for more than two-dozen individuals from Africa and Europe, together with comparisons to non-human primate sequences, to explore historical biased gene conversion effects.

Results from these analyses indicated that "biased gene conversion was resulting in excess of homozygotes," Tishkoff told GenomeWeb Daily News.

"That has a low but significant effect on the potential prevalence of disease caused by a recessive disorder," she explained.

During meiosis, gene conversion occurs when a small stretch of homologous sequence of paternal origin is traded for corresponding maternal sequence — or vice versa — during sperm or egg formation in a manner that alters the allele found at the affected site.

Past studies suggest this conversion is more apt to occur if there is an opportunity to change an allele to a guanine and cytosine nucleotide, producing so-called "GC-biased gene conversion," or gBGC.

Using genome sequences produced for prior studies, including a 2012 look at genetic features found in hunter-gatherer populations in Africa, Tishkoff and Lachance considered the frequency and distribution of gBGC events in the human genome, as well the potential role this process may play in recessive disease inheritance.

The researchers used several computational approaches to scrutinize relatively deep whole-genome sequence datasets — around 60-fold coverage per genome, on average — that had been generated at Complete Genomics for five individuals apiece from Pygmy populations in Cameroon, Nigeria's Yoruba population, Hadza and Sandawe populations in Tanzania, and populations in northern and western Africa.

"The point was to take advantage of these high-coverage whole-genome sequence datasets," Tishkoff said. "That's important because when you're looking at a subtle effect like this, you do not want to be dealing with uncertainty in the SNP calls."

Through comparisons with chimpanzee sequences, the duo was able to assess allele frequency patterns, along with changes from ancestral to derived alleles and vice versa.

As anticipated, for example, they saw that gene conversion events slightly weighted in favor of changes that resulted in guanine or cytosine alleles, leading to incremental shifts in allele patterns found in human genomes.

This biased gene conversion was detected across a wide range of demographic tests that interpret allele frequency information, Lachance and Tishkoff said. Consequently, they cautioned that it will likely be important to account for gene conversion contributions in future analyses of demography or selection.

"If you don't correct for this … you'll have allele frequency distributions that are not just due to demographic histories, but that are due to these other processes," Lachance told GWDN. "Your methods are going to try to attribute everything you see to demography."

But these gBGC events were not evenly distributed across the genome. Instead, they tended to turn up at recombination hotspots where crossover events and associated mismatch repair mechanisms are at work.

The team detected similar patterns in all five populations tested, hinting that the gBGC effects are widespread and not linked to a particular human population history. Even so, Tishkoff noted that overall homozygosity is typically higher in populations that have experienced population bottlenecks, small population sizes, and/or inbreeding.

Not surprisingly, sites in the genome where gBGC acts most frequently were also found to have higher-than-usual rates of homozygosity, the presence of matching copies of the same allele at a given site.

Whereas homozygosity was found at just over 42 percent of SNPs at unbiased conversion sites, the researchers saw homozygosity at almost 63 percent of derived alleles in gBGC-prone parts of the genome.

"It's almost like having very weak selection," Tishkoff said. "But weak selection over a long time can have an effect. And if you compound it with demographic effects like bottlenecks or inbreeding … you can get a much bigger boost."

Combined with an apparent over-representation of some recessive disease alleles at sites where gBGC tends to occur, the biased gene conversion effect is suspected of slowly increasing recessive disease allele retention and risk.

Lachance noted that this effect seemed to be more pronounced for disease alleles that are not ancestral or shared with chimpanzees, but derived. The consequences of biased gene conversion appeared somewhat more subtle when ancestral disease alleles were involved, though he cautioned that "more studies are needed, because we really don't know how much disease is due to brand new mutations or the old ones."