Potential determinants of short stature in West African pygmy populations uncovered

Jeffrey Serrill, Genetic determinants of short stature west african pygmy

For centuries, the idea of pygmy culture has captured the imaginations of worldwide audiences, signifying the ends of the civilized world for Westerners. Through various films and works of literature (whether accurately portrayed or not), perhaps the most striking features of these groups of people has been their short stature, a characteristic which has never been completely understood or adequately defined by the scientific community. Recently, an interesting study conducted by the University of Pennsylvania’s Department of Genetics has shed some light on this mystery by identifying several of the genes which may be directly responsible for short stature in these groups. Their work, published in the April 26th edition of PLoS Genetics, pinpoints genetic loci which may serve to influence the development of short stature in at least one group of West African pygmy cultures.

Historically, the term “pygmy” has been utilized by anthropologists to refer to groups of people whose average adult height corresponds to 150 cm or less (roughly 4 feet, 11 inches). Groups of such people have been identified in a large number of countries, most notably in Africa and Southeast Asia; smaller groups have also been identified on the Australian continent and in regions of New Guinea as well. While the aforementioned short stature has been remarked upon since the “discovery” of these people by Westerners in the 17th century, the scientific community has yet to develop an all-encompassing theory for what the underlying cause of this stature may be.

Despite a lack of consensus regarding these genetic determinants, a number of various anthropological and evolutionary models have been proposed. The basis for many of these models is rooted in the fundamental (and largely agreed upon) processes of natural selection, and assumes that certain environmental pressures may have selected for short stature over an evolutionary time scale. In this regard, it has been suggested that a smaller body size could bestow a selective advantage in several ways; a reduced caloric requirement, improved resistance to heat stress, and younger age of reproductive capacity have been suggested as several of these potential advantages.

In the recent paper, the authors utilized high-throughput techniques to screen the genomes of several different sets of African people; by comparing the abundance of single nucleotide polymorphisms (SNPs, variations in single nucleotides at specific genomic locations) between West African pygmies and their much taller Bantu neighbors, it was hoped that some specific differences may be shown to account for the height difference between cultures. Following these screens, population genetics models were used to identify regions of the genome which may be contributing to the characteristic stature of the West African pygmies.

“Using all of these different approaches we kept seeing a lot of them highlight that region in chromosome 3,” said Dr. Sarah Tishkoff, one of the study’s collaborators. “It just seemed like a hot spot for selection and for very high differentiation and, as it turns out, very strong association with height as well.”

Through a more targeted analysis of chromosome 3, three promising gene candidates were identified which seemed to correlate positively with the authors’ hypothesis regarding stature determinants. These included the gene CISH, a cytokine signaling regulator which inhibits growth hormone signaling, MAPKAP3, a signaling kinase, and DOCK3, a guanine nucleotide exchange factor which has been linked to height variation in previous studies involving non-African populations. The identification of these genes as potential determinants of stature also allowed the researchers to make hypotheses as to how this stature may be affected by SNPs in these regions. The three most promising genes (as well as less significant “hits” which were also identified) seemed to be linked to a number of biological processes which may directly affect human stature, including growth hormone regulation, thyroid and reproductive hormone modulation, and both immune system function and insulin signaling processes. Collectively, this evidence suggests that we may now have at least a partial explanation for the West African pygmies’ predisposition to short stature.

“By performing a detailed genetic analysis, Dr. Tishkoff and her colleagues have identified many candidate genes that have played an adaptive role in Pygmy populations, including several related to stature,” said Irene Eckstrand, who oversees evolutionary-biology grants at the National Institutes of Health’s National Institute of General Medical Sciences, which partially funded the work. “This research illustrates the value of studying human traits in their evolutionary and ecological contexts for understanding how humans adapted to their local environments.”

Following these assays, it will be interesting to see whether any of the observed genetic findings can mesh with any of the previously hypothesized evolutionary models of natural selection that have been put forth, or whether these different explanations are not mutually acceptable. At least one of these discussions may already be underway involving previous hypotheses concerning early reproductive capacity. In the hunter/gatherer lifestyle that many of these pygmy groups utilize, a younger onset of reproductive capability could be seen as an advantage, since the life expectancy of such people tends to be very low.

“We kept seeing enrichment of genes involved in oxytocin, serotonin and thyrotropin-releasing hormone receptor signaling pathways in our genome-wide scans for natural selection,” Tishkoff said. “Genes in those pathways are important in reproduction and metabolism and that was intriguing in light of the hypothesis that the reason Pygmies are short is so that they can reach reproductive maturity early.”

Whether coincidental or not, future studies will necessarily seek to more adequately define the precise modulation of various growth hormone cascades by SNP variations in these different groups of people; regardless, this study provides an important, multi-faceted step in finally achieving a scientific understanding of the genetic basis for the short stature of various pygmy cultures.

"Our approach relied on multiple analyses and on the integration of the multiple signals we discovered,” said Joseph Jarvis, a post-doc collaborator. “The evolutionary process is incredibly complicated and rarely produces obvious genetic signatures, so it’s very important to be sensitive to subtle patterns. Ultimately our analyses repeatedly highlighted similar regions of the genome, and that overlap is what suggests that something interesting is going on.”

All quotes taken from University of Pennsylvania press release

For more information, see the original research article

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