It's raining SNPs, hallelujah? (original) (raw)

Nature Genetics volume 19, pages 216–217 (1998)Cite this article

In August 1974, I arrived for graduate study in the US in the midst of a raging debate. The initial availability of protein sequences in multiple species and protein polymorphisms within species raised fundamental questions regarding how sequence variation is created and maintained through evolutionary time. The world was divided into two parts: those who believed that almost all extant variation has been vetted by natural selection and those who advocated a new hypothesis — that the majority of variation has been selectively neutral throughout evolution1. Even ignorant graduate students were not spared: they were assigned either to the 'selectionist' or 'neutralist' camps. The arguments have dissipated with time, not because the principals have settled the score, but because, as with most debates, there has been and still is, little data to sway new recruits in either direction. The central question of how the nature and causes of sequence variation impact phenotypic variation is still largely unresolved. The impending human genome reference sequence and its variation in health and disease will bring these questions to the forefront once again, but this time, in the context of data in hand2. The answers will cheer the hearts of evolutionary biologists and every human geneticist who is trying to understand the nature of genetic variation underlying the common and genetically complex diseases. The study reported by Deborah Nickerson and colleagues3 on page 233 of this issue and a companion article by Andrew Clark et al. appearing in August's issue of American Journal of Human Genetics4, however, give reason to ponder how patterns of genetic variation and the dissection thereof are best matched. The authors of these manuscripts have determined the DNA sequence diversity in 9.7 kb of the cardiovascular disease candidate gene that encodes lipoprotein lipase (LPL) and discovered extensive molecular variation.

The rise of molecular genetics has witnessed a fascination with 'markers', polymorphisms in anonymous DNA segments, as these are ideal for tracing meioses in families, thereby gaining information by which to positionally clone rare disease genes. However, we still have scant knowledge about the extent and nature of sequence variation in human genes and adjacent regulatory signals. We understand even less of what such variation means; our grand plans to explain the genetic basis of development, disease and evolution need to be on a much firmer footing.

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  1. Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, 44106, Ohio, USA
    Aravinda Chakravarti

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Chakravarti, A. It's raining SNPs, hallelujah?.Nat Genet 19, 216–217 (1998). https://doi.org/10.1038/885

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