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Team Detects New Immune Alleles With Suspected Pregnancy Effects in Khoe-San Population

NEW YORK (GenomeWeb) – Members of South Africa's Khoe-San population carry versions of natural killer cell receptor immune genes expected to be beneficial for pregnancy and newborn health, a new study in PLOS Genetics suggests.

A Stanford University-led team used a combination of bead-based hybridization genotyping and targeted sequencing to scrutinize immune genes in dozens of Khoe-San individuals from Upington, South Africa and other nearby villages.

The researchers were particularly interested in the diversity present in Khoe-San human leukocyte antigen (HLA) genes and genes coding for the killer-cell immunoglobulin-like receptors (KIR), which natural killer cells use to discern between friendly or foreign HLA proteins. In the process, they found previously undescribed KIR alleles that alter HLA interactions, boosting birth weights and reducing preeclampsia risk in the process.

This effect seems to reflect the role that natural killer cells and their KIRs play in placental formation and other features of early pregnancy, explained senior author Peter Parham, a structural biology, microbiology, and immunology researcher at Stanford University.

"The [natural killer] cells are involved at the beginning of pregnancy in helping develop the maternal blood vessels in the placenta," Parham said in a statement, "where they can supply a lot more blood to the developing embryo."

The click-speaking Khoe and San populations of sub-Saharan Africa have long been of interest to geneticists due to the early divergence of their ancestors within the modern human lineage.

In a SNP study published in 2012, for example, an international team led by investigators in Sweden looked at genetic diversity and relationship patterns in the Khoe-San based on data for 220 individuals.

Meanwhile, whole-genome sequencing studies of Khoe-San individuals published in 2010 and 2014 provided a more refined look at ancestry patterns in Khoe-San individuals, many of whom showed little to no evidence of past admixture with other populations.

For their current analysis, the researchers hoped to get a glimpse at immune variation and its consequences in the genetically diverse Khoe-San group.

"Only a handful of studies have investigated the function of immune genes in African populations. As a result, we have probably greatly underestimated the breadth of human immune variation," Parham said.

While the KIR gene KIR2DL1 frequently interacts with an epitope of the HLA-C gene called C2 in most human populations studied so far, he and his team found that a subset of Khoe-San individuals carry two versions of KIR2DL1 that are far more prone to interacting with the C1 epitope of HLA-C.

Through targeted KIR gene sequencing and/or pyrosequencing-based genotyping on 61 Khoe-San individuals, the researchers identified 10 KIR2DL1 alleles in the population. Two of those — known as KIR2DL1*022 and KIR2DL1*026 — represent new alleles with enhanced C1 epitope binding.

The first, KIR2DL1*022, turned up in 17 percent of the Khoe-San individuals tested, while KIR2DL1*026 occurred in 4.2 percent, though neither had been detected in previously studied populations.

A search for the new alleles in a click-speaking Hadza population from northern Tanzania and two pygmy populations from central Africa came up blank.

The team tracked down three Zulu individuals with KIR2DL1*022 and two Zulu individuals with KIR2DL1*026 using genome sequences generated for the African Genome Variation Project. But the lower frequencies of the new alleles in that population suggested the alleles had been introduced through prior Khoe-San admixture.

The researchers concluded that the new alleles are part of a spectrum of KIR variants in the Khoe-San that tend to decrease the KIR recognition of the C2 epitope of HLA-C. That, in turn, appears to reduce the risk of pregnancy complications associated with the KIR-C2 interaction, including spontaneous abortion, preeclampsia, and low birth weight.

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