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First Genome Sequence of Kalahari Bushmen, Africa’s “Forgotten People”

By Kevin Davies

October 23, 2009 | HONOLULU – Stefan Schuster, an evolutionary geneticist at Penn State University, presented the first data on the sequencing of Kalahari Bushmen, one of if not the oldest human ethnic groups in the world.

As Schuster described in the abstract of his talk at the American Society of Human Genetics convention, “the Kalahari Bushmen may be the last hunter-gatherers of our times.” Possibly the oldest human population, the Bushmen are nomadic, non-tribal, and do not practice agriculture or herbiculture. The population has a characteristically small stature, an adaptive measure to survive the brutally hot environment.

Schuster and collaborators, including researchers at the University of Limpopo, won the support of “these largely forgotten people of Africa” to undertake the sequencing project (as well as IRB approval). Schuster said the reasons were twofold: first, to demonstrate using modern technology the Bushmen’s unique perch in human history; and second, to shed light on the population’s genetic structure that could inform future pharmacogenetic therapies. Schuster also claimed in his talk that most modern drugs, developed in European populations, have little effect among the 150 million people in Southern Africa.

Platform 454

The flood of recent publications and reports on whole-genome sequencing of humans have used rival platforms, including Illumina, Applied Biosystems, Helicos and Complete Genomics. The Roche/454 next-generation sequencing platform was used for the first personal genome -- James Watson -- in 2007, but is typically pricier to run.

However, Schuster has been a long-term supporter of the 454 platform: the longer average read lengths suited his notable studies on ancient DNA, including the woolly mammoth, and endangered animal populations such as Tasmanian Devils. Without expressly addressing his platform choice, Schuster said he wanted to generate “a very high-quality genome” sequence, because the working hypothesis is “this will be the most diverse [human] genome.”

Schuster’s team performed whole-genome sequencing of two Bushmen genomes – one to 10-fold coverage, the other 2-fold -- together with exome sequencing (using Nimblegen target selection) of four Bushmen and a Bantu. In addition, the group is doing genotyping studies on a further dozen Bushmen using both Illumina and Affymetrix platforms.

Mitochondrial analysis showed that the Bushmen fall in the L0k and L0d mitochondrial haplotypes, among the deepest branching groups, about 150,000 years old. There are on average 20 mitochondrial differences between the Bushmen and European populations, but among the Bushmen population, the degree of diversity is around 70-80 nucleotides between individuals – another indicator of the age of the population.

Schuster also presented a phylogenetic tree based on sequenced personal genomes that showed clustering of Chinese, Korean and Yoruban (African) genomes. This has more to do with the platform used for sequencing than the true genetic diversity, he said. Without cross-platform validation, it will be difficult to compare 14-15 personal genomes because of these platform biases and algorithms used to call variants, Schuster said.

Initial genotyping analysis showed that the Bushmen showed reduced heterozygosity than other Southern African and other populations, but that did not hold up when looking at the sequenced genome. Put another way, the standard genotyping arrays are not a good match for this population. As far as SNP discovery goes, Affymetrix has already validated more than 300,000 of the putative novel SNPs in the Bushmen genome and Schuster expects that number to approach 1 million.

Schuster hopes the work will have many long-term benefits, not least in expanding the catalogue of polymorphism variation in databases such as dbSNP and affording greater precision in future genome-wide association studies. Schuster and colleagues hope that the Bushmen genome work “will help the development of drugs that benefit this ethnic group,” and “[spotlight] the need to assist indigenous groups in Africa and elsewhere in their fight against home-land loss, disease and famine.”

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